What this pathway does
The methylation pathway transfers methyl groups where the body needs them. That matters for homocysteine recycling, DNA maintenance, neurotransmitter chemistry, and many routine cellular reactions.
Why it matters
This pathway matters because several common genes can influence how smoothly it runs. When pressure builds, people often start chasing folate, B12, or methyl donors without first validating whether the pathway is actually constrained.
What creates pressure on this pathway
- folate-processing inefficiency
- limited B12 transport or functional status
- higher methylation demand from neurotransmitter or detox pathways
Validation markers to consider
- homocysteine
- serum or red blood cell folate
- methylmalonic acid or functional B12 markers
Genes and SNPs connected to this pathway
B vitamins help your body make energy, support nerves, and run basic repair and maintenance chemistry.
Study rows support the SNP/gene claim. The pathway connection comes from the curated gene-to-pathway map.
What may run higher
You may burn through B vitamins faster. Low intake may affect energy, mood, nerves, or recovery more easily.
What may work more slowly
Your body may use B vitamins less efficiently. This can affect energy, nerves, and repair.
What to check next
Check homocysteine, B12, methylmalonic acid, folate, CBC, MCV, diet, alcohol, and medication context.
10mapped genes
17mapped SNPs
27SNP/gene claims
20report eligible
PEMT2 SNPs - 6 claimsShow SNPs
Open gene pagers123258173 claims - 9 study rows
expression - CC
PEMT gene expression
rs12325817 CC is associated with reduced PEMT gene expression.
PEMT rs12325817 is scored as a lower hormone-responsive PEMT expression tendency for C-containing genotypes, strongest for CC.
Likely effectLower gene expression signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs12325817 as a PEMT variant with transcript annotations in or near PEMT regulatory regions. This supports curation against PEMT expression rather than a protein-coding enzyme-change score.PubMed 16816108biomarker association - loose proxyDa Costa et al. fed 57 people a low-choline diet and reported that 18 of 23 carriers of the PEMT -744C allele, rs12325817, developed organ dysfunction under that controlled low-choline challenge. This supports a C-allele tendency that matters most when dietary choline is limited.PubMed 21059658functional assay - directResseguie et al. reported that rs12325817 was strongly linked with choline deficiency syndrome in women and was near a critical estrogen response element. The risk allele failed to bind estrogen receptor or FOXA1 in their experiments, supporting lower hormone-inducible PEMT expression as the curated effect.
expression - CG
PEMT gene expression
rs12325817 CG is associated with reduced PEMT gene expression.
PEMT rs12325817 is scored as a lower hormone-responsive PEMT expression tendency for C-containing genotypes, strongest for CC.
Likely effectLower gene expression signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs12325817 as a PEMT variant with transcript annotations in or near PEMT regulatory regions. This supports curation against PEMT expression rather than a protein-coding enzyme-change score.PubMed 16816108biomarker association - loose proxyDa Costa et al. fed 57 people a low-choline diet and reported that 18 of 23 carriers of the PEMT -744C allele, rs12325817, developed organ dysfunction under that controlled low-choline challenge. This supports a C-allele tendency that matters most when dietary choline is limited.PubMed 21059658functional assay - directResseguie et al. reported that rs12325817 was strongly linked with choline deficiency syndrome in women and was near a critical estrogen response element. The risk allele failed to bind estrogen receptor or FOXA1 in their experiments, supporting lower hormone-inducible PEMT expression as the curated effect.
expression - GG
PEMT gene expression
rs12325817 GG has no scored directional claim for PEMT gene expression.
PEMT rs12325817 is scored as a lower hormone-responsive PEMT expression tendency for C-containing genotypes, strongest for CC.
Likely effectNo clear expression signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs12325817 as a PEMT variant with transcript annotations in or near PEMT regulatory regions. This supports curation against PEMT expression rather than a protein-coding enzyme-change score.PubMed 16816108biomarker association - loose proxyDa Costa et al. fed 57 people a low-choline diet and reported that 18 of 23 carriers of the PEMT -744C allele, rs12325817, developed organ dysfunction under that controlled low-choline challenge. This supports a C-allele tendency that matters most when dietary choline is limited.PubMed 21059658functional assay - directResseguie et al. reported that rs12325817 was strongly linked with choline deficiency syndrome in women and was near a critical estrogen response element. The risk allele failed to bind estrogen receptor or FOXA1 in their experiments, supporting lower hormone-inducible PEMT expression as the curated effect.
rs79463 claims - 12 study rows
enzyme activity - TT
PEMT enzyme activity
rs7946 TT is associated with reduced PEMT enzyme activity.
PEMT rs7946 is scored as a lower PEMT enzyme-activity tendency for T-containing genotypes, with a stronger score for TT than CT.
Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs7946 as a C/T variant in PEMT. Transcript annotations include NM_007169.3:c.523G>A with a predicted p.Val175Met protein change for the T-containing genomic allele, supporting use of C, CT, and TT genotype letters in this file.PMC1256033functional assay - directSong et al. reported that the PEMT V175M variant showed diminished activity in transfected cells and was more common in people with nonalcoholic fatty liver disease than controls in their study. This supports scoring T-containing genotypes as a lower PEMT enzyme-activity tendency, with a larger score for TT than CT.PubMed 26636496review - directTan et al. performed a meta-analysis of PEMT rs7946 and nonalcoholic fatty liver disease and reported that the transcript A allele was associated with higher NAFLD susceptibility, especially in East Asian subgroup analyses. This supports biological relevance but is still disease-association evidence, so the JSON limits interpretation to enzyme-activity tendency rather than disease prediction.PubMed 16816108functional assay - directA controlled feeding study on choline requirement noted rs7946 as a functionally significant PEMT SNP, but also reported that the low-choline response was not explained by this SNP alone. This supports a conservative certainty score and highlights that diet, sex, hormones, and other variants can affect practical interpretation.
enzyme activity - CT
PEMT enzyme activity
rs7946 CT is associated with reduced PEMT enzyme activity.
PEMT rs7946 is scored as a lower PEMT enzyme-activity tendency for T-containing genotypes, with a stronger score for TT than CT.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs7946 as a C/T variant in PEMT. Transcript annotations include NM_007169.3:c.523G>A with a predicted p.Val175Met protein change for the T-containing genomic allele, supporting use of C, CT, and TT genotype letters in this file.PMC1256033functional assay - directSong et al. reported that the PEMT V175M variant showed diminished activity in transfected cells and was more common in people with nonalcoholic fatty liver disease than controls in their study. This supports scoring T-containing genotypes as a lower PEMT enzyme-activity tendency, with a larger score for TT than CT.PubMed 26636496review - directTan et al. performed a meta-analysis of PEMT rs7946 and nonalcoholic fatty liver disease and reported that the transcript A allele was associated with higher NAFLD susceptibility, especially in East Asian subgroup analyses. This supports biological relevance but is still disease-association evidence, so the JSON limits interpretation to enzyme-activity tendency rather than disease prediction.PubMed 16816108functional assay - directA controlled feeding study on choline requirement noted rs7946 as a functionally significant PEMT SNP, but also reported that the low-choline response was not explained by this SNP alone. This supports a conservative certainty score and highlights that diet, sex, hormones, and other variants can affect practical interpretation.
enzyme activity - CC
PEMT enzyme activity
rs7946 CC has no scored directional claim for PEMT enzyme activity.
PEMT rs7946 is scored as a lower PEMT enzyme-activity tendency for T-containing genotypes, with a stronger score for TT than CT.
Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs7946 as a C/T variant in PEMT. Transcript annotations include NM_007169.3:c.523G>A with a predicted p.Val175Met protein change for the T-containing genomic allele, supporting use of C, CT, and TT genotype letters in this file.PMC1256033functional assay - directSong et al. reported that the PEMT V175M variant showed diminished activity in transfected cells and was more common in people with nonalcoholic fatty liver disease than controls in their study. This supports scoring T-containing genotypes as a lower PEMT enzyme-activity tendency, with a larger score for TT than CT.PubMed 26636496review - directTan et al. performed a meta-analysis of PEMT rs7946 and nonalcoholic fatty liver disease and reported that the transcript A allele was associated with higher NAFLD susceptibility, especially in East Asian subgroup analyses. This supports biological relevance but is still disease-association evidence, so the JSON limits interpretation to enzyme-activity tendency rather than disease prediction.PubMed 16816108functional assay - directA controlled feeding study on choline requirement noted rs7946 as a functionally significant PEMT SNP, but also reported that the low-choline response was not explained by this SNP alone. This supports a conservative certainty score and highlights that diet, sex, hormones, and other variants can affect practical interpretation.
SLC46A14 SNPs - 4 claimsShow SNPs
Open gene pagers2818752091 claims - 3 study rows
transport activity - GG or compound-heterozygous SLC46A1 deficiency context
Proton-coupled folate transporter activity tendency
rs281875209 G (forward-genomic; SLC46A1 c.1012G>C / p.Gly338Arg transcript context) is associated with lower proton-coupled folate transporter activity tendency and impaired folate absorption in recessive or compound-heterozygous hereditary folate-malabsorption contexts.
SLC46A1 rs281875209 G is staged as the forward-genomic recessive hereditary folate-malabsorption allele affecting PCFT folate transport and methylation folate supply.
Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 30925clinical curation - directClinVar maps rs281875209 to SLC46A1 c.1012G>C / p.Gly338Arg and hereditary folate malabsorption, supporting exact-allele pathogenic PCFT deficiency curation.PMCID PMC3081934functional assay - directThe checked PCFT functional study reports complete loss of transport activity for the G338R mutant in folate transporter-deficient cells, matching the rs281875209 p.Gly338Arg allele biology.GeneReviews Hereditary Folate Malabsorptionclinical curation - directGeneReviews supports SLC46A1/PCFT loss of function as the molecular basis for hereditary folate malabsorption with impaired intestinal and CSF folate transport.
rs803387691 claims - 2 study rows
transport activity - biallelic or compound-heterozygous SLC46A1 c.194del context
PCFT folate transport activity tendency
rs80338769 / SLC46A1 c.194del frameshift is associated with lower PCFT folate transport activity tendency in recessive or compound-heterozygous deficiency contexts.
SLC46A1 rs80338769 is staged as a recessive hereditary folate-malabsorption frameshift allele affecting proton-coupled folate transport.
Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 851clinical curation - directClinVar maps rs80338769 to SLC46A1 c.194del / p.Gly65fs, identifies it as a 1 bp deletion, and classifies it as pathogenic for congenital defect of folate absorption.MedlinePlus SLC46A1clinical curation - directThe checked MedlinePlus SLC46A1 source states that PCFT transports folates from the small intestine and into brain/CSF context, and that SLC46A1 variants can produce shortened PCFT with little or no activity.
rs803387701 claims - 2 study rows
transport activity - AA or compound-heterozygous SLC46A1 deficiency context
PCFT folate transport activity tendency
rs80338770 A on the genomic plus strand / SLC46A1 c.337C>T / p.Arg113Cys is associated with lower proton-coupled folate transporter activity in recessive or compound-heterozygous hereditary folate malabsorption contexts.
SLC46A1 rs80338770 A is staged as a pathogenic PCFT folate transport allele relevant to methylation support.
Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 855clinical curation - directClinVar maps rs80338770 to SLC46A1 c.337C>T / p.Arg113Cys and classifies it pathogenic for hereditary folate malabsorption.MedlinePlus SLC46A1clinical curation - directMedlinePlus describes SLC46A1 as the proton-coupled folate transporter needed for intestinal folate absorption and folate transport into the brain; pathogenic variants cause hereditary folate malabsorption.
rs803387751 claims - 2 study rows
transport activity - TT or compound-heterozygous SLC46A1 deficiency context
PCFT folate transport activity tendency
rs80338775 T on the genomic plus strand / SLC46A1 c.1082-1G>A is associated with lower PCFT folate transport activity tendency in recessive or compound-heterozygous deficiency contexts.
SLC46A1 rs80338775 T is staged as a recessive hereditary folate-malabsorption allele affecting proton-coupled folate transport.
Likely effectLower transport signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 850clinical curation - directClinVar maps rs80338775 to SLC46A1 c.1082-1G>A and classifies it as pathogenic for hereditary folate malabsorption.PMCID PMC3012536functional assay - directThe checked functional source supports SLC46A1 splice-disrupting hereditary folate-malabsorption alleles as reducing PCFT expression, localization, or folate transport function.
COMT1 SNPs - 3 claimsShow SNPs
Open gene pagers46803 claims - 9 study rows
enzyme activity - AA
COMT enzyme activity
rs4680 AA is associated with reduced COMT enzyme activity.
COMT rs4680 is scored as a lower COMT enzyme-activity tendency for A-containing genotypes, strongest for AA and intermediate for AG.
Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs4680 in COMT as NM_000754.4:c.472G>A with a Val-to-Met protein substitution at residue 158 in the membrane-bound COMT transcript. The A allele corresponds to the Met form in these transcript annotations.PubMed 15457404functional assay - directChen et al. measured COMT mRNA, protein, and enzyme activity in postmortem human prefrontal cortex and reported that Val158Met, rs4680, significantly affected protein abundance and enzyme activity. Their results support lower COMT activity for A-containing genotypes, with AA lower than AG.Evidence 3clinical curation - loose proxyNCBI MedGen summarizes COMT activity variation as a codominant pattern: Met158 has lower thermostability and lower activity than Val158, and heterozygotes have intermediate activity. This supports the three-level genotype scoring used here.
enzyme activity - AG
COMT enzyme activity
rs4680 AG is associated with reduced COMT enzyme activity.
COMT rs4680 is scored as a lower COMT enzyme-activity tendency for A-containing genotypes, strongest for AA and intermediate for AG.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs4680 in COMT as NM_000754.4:c.472G>A with a Val-to-Met protein substitution at residue 158 in the membrane-bound COMT transcript. The A allele corresponds to the Met form in these transcript annotations.PubMed 15457404functional assay - directChen et al. measured COMT mRNA, protein, and enzyme activity in postmortem human prefrontal cortex and reported that Val158Met, rs4680, significantly affected protein abundance and enzyme activity. Their results support lower COMT activity for A-containing genotypes, with AA lower than AG.Evidence 3clinical curation - loose proxyNCBI MedGen summarizes COMT activity variation as a codominant pattern: Met158 has lower thermostability and lower activity than Val158, and heterozygotes have intermediate activity. This supports the three-level genotype scoring used here.
enzyme activity - GG
COMT enzyme activity
rs4680 GG has no scored directional claim for COMT enzyme activity.
COMT rs4680 is scored as a lower COMT enzyme-activity tendency for A-containing genotypes, strongest for AA and intermediate for AG.
Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data identify rs4680 in COMT as NM_000754.4:c.472G>A with a Val-to-Met protein substitution at residue 158 in the membrane-bound COMT transcript. The A allele corresponds to the Met form in these transcript annotations.PubMed 15457404functional assay - directChen et al. measured COMT mRNA, protein, and enzyme activity in postmortem human prefrontal cortex and reported that Val158Met, rs4680, significantly affected protein abundance and enzyme activity. Their results support lower COMT activity for A-containing genotypes, with AA lower than AG.Evidence 3clinical curation - loose proxyNCBI MedGen summarizes COMT activity variation as a codominant pattern: Met158 has lower thermostability and lower activity than Val158, and heterozygotes have intermediate activity. This supports the three-level genotype scoring used here.
MTHFD12 SNPs - 2 claimsShow SNPs
Open gene pagers10769911 claims - 2 study rows
expression - T
MTHFD1 promoter activity
rs1076991 T is associated with reduced MTHFD1 promoter activity in vitro compared with C.
MTHFD1 rs1076991 is scored only as a promoter-activity tendency for the T allele compared with the C allele.
Likely effectLower gene expression signal
Signal sizeModerate signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs1076991 on chromosome 14 in the MTHFD1 region and lists T, C, and G alleles on the current preferred genomic placement. This supports the variant identity only; the rare G allele is not scored because the functional source compared only T and C promoter constructs.Carroll et al. MTHFD1 promoter analysisfunctional assay - directCarroll et al. reported that rs1076991 is located in the MTHFD1 transcription initiation window and that the T 0.59 kb promoter construct had significantly lower luciferase reporter activity than the C construct. The paper reports T construct activity at about 38% of the C construct, supporting a lower promoter-activity direction for T versus C in vitro.
rs22362251 claims - 2 study rows
enzyme activity - A
MTHFD1 one-carbon enzyme activity
rs2236225 A, encoding MTHFD1 Arg653Gln, is associated with reduced MTHFD1 enzyme stability and one-carbon metabolic activity.
MTHFD1 rs2236225 A is staged as a reduced folate-cycle enzyme function allele with one-carbon metabolism relevance.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
PubMed 18767138functional assay - directThe checked PubMed abstract for the MTHFD1 p.Arg653Gln study reports that the purified Arg653Gln enzyme has reduced thermal half-life and that cells transfected with Arg653Gln show reduced formate incorporation into DNA compared with wild-type protein. This directly supports lower enzyme stability/metabolic activity for the A allele encoding Gln653.PMCID PMC9224796clinical curation - directThe checked folate-pathway article describes rs2236225 as a well-studied MTHFD1 polymorphism leading to enzyme thermolability and decreased enzyme activity. The article itself is disease-context, so it is used only as supporting functional curation, not disease-risk evidence.
MTHFR2 SNPs - 6 claimsShow SNPs
Open gene pagers18011313 claims - 9 study rows
enzyme activity - GG
MTHFR enzyme activity
rs1801131 GG is associated with reduced MTHFR enzyme activity.
MTHFR rs1801131 is scored as a mild lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportLimited support
Report useIncluded in pathway scoring
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3521 identifies rs1801131 as MTHFR NM_005957.5:c.1286A>C, protein p.Glu429Ala, also named MTHFR 1298A-C / GLU429ALA. The canonical SPDI shown by ClinVar is NC_000001.11:11794418:T:G, so this file uses the dbSNP/GRCh38 forward-strand genotype letters T and G. ClinVar classifications for listed germline conditions are mostly benign or benign/likely benign, so this record is limited to enzyme-activity tendency.PubMed 9719624functional assay - directWeisberg et al. 1998 characterized MTHFR A1298C as an E-to-A substitution and reported that the polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. The abstract also reported lower activity in people heterozygous for both C677T and A1298C, but it does not give an equally direct single-heterozygote A1298C estimate, so GT is assigned a small magnitude and lower certainty.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
enzyme activity - GT
MTHFR enzyme activity
rs1801131 GT is associated with reduced MTHFR enzyme activity.
MTHFR rs1801131 is scored as a mild lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectLower enzyme activity signal
Signal sizeMinimal signal
Evidence supportLimited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3521 identifies rs1801131 as MTHFR NM_005957.5:c.1286A>C, protein p.Glu429Ala, also named MTHFR 1298A-C / GLU429ALA. The canonical SPDI shown by ClinVar is NC_000001.11:11794418:T:G, so this file uses the dbSNP/GRCh38 forward-strand genotype letters T and G. ClinVar classifications for listed germline conditions are mostly benign or benign/likely benign, so this record is limited to enzyme-activity tendency.PubMed 9719624functional assay - directWeisberg et al. 1998 characterized MTHFR A1298C as an E-to-A substitution and reported that the polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. The abstract also reported lower activity in people heterozygous for both C677T and A1298C, but it does not give an equally direct single-heterozygote A1298C estimate, so GT is assigned a small magnitude and lower certainty.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
enzyme activity - TT
MTHFR enzyme activity
rs1801131 TT has no scored directional claim for MTHFR enzyme activity.
MTHFR rs1801131 is scored as a mild lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3521 identifies rs1801131 as MTHFR NM_005957.5:c.1286A>C, protein p.Glu429Ala, also named MTHFR 1298A-C / GLU429ALA. The canonical SPDI shown by ClinVar is NC_000001.11:11794418:T:G, so this file uses the dbSNP/GRCh38 forward-strand genotype letters T and G. ClinVar classifications for listed germline conditions are mostly benign or benign/likely benign, so this record is limited to enzyme-activity tendency.PubMed 9719624functional assay - directWeisberg et al. 1998 characterized MTHFR A1298C as an E-to-A substitution and reported that the polymorphism was associated with decreased enzyme activity; homozygotes had approximately 60% of control activity in lymphocytes. The abstract also reported lower activity in people heterozygous for both C677T and A1298C, but it does not give an equally direct single-heterozygote A1298C estimate, so GT is assigned a small magnitude and lower certainty.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
rs18011333 claims - 9 study rows
enzyme activity - AA
MTHFR enzyme activity
rs1801133 AA is associated with reduced MTHFR enzyme activity.
MTHFR rs1801133 is scored as a lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3520 identifies rs1801133 as MTHFR NM_005957.5:c.665C>T, protein p.Ala222Val, also named MTHFR 677C-T / ALA222VAL. The canonical SPDI shown by ClinVar is NC_000001.11:11796320:G:A, so this file uses the dbSNP/GRCh38 forward-strand genotype letters G and A. ClinVar condition classifications are mixed and include benign, uncertain, conflicting, and drug-response contexts, so this record is limited to enzyme-activity tendency rather than disease interpretation.PubMed 7647779functional assay - directFrosst et al. 1995 reported a common MTHFR mutation that changes a conserved amino acid. The PubMed abstract states that heterozygous or homozygous mutation status correlated with reduced enzyme activity and increased thermolability in lymphocyte extracts, and that homozygous individuals had significantly elevated plasma homocysteine. This supports a negative enzyme-activity direction for A-containing genotypes, with a larger magnitude for AA than AG.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
enzyme activity - AG
MTHFR enzyme activity
rs1801133 AG is associated with reduced MTHFR enzyme activity.
MTHFR rs1801133 is scored as a lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportLimited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3520 identifies rs1801133 as MTHFR NM_005957.5:c.665C>T, protein p.Ala222Val, also named MTHFR 677C-T / ALA222VAL. The canonical SPDI shown by ClinVar is NC_000001.11:11796320:G:A, so this file uses the dbSNP/GRCh38 forward-strand genotype letters G and A. ClinVar condition classifications are mixed and include benign, uncertain, conflicting, and drug-response contexts, so this record is limited to enzyme-activity tendency rather than disease interpretation.PubMed 7647779functional assay - directFrosst et al. 1995 reported a common MTHFR mutation that changes a conserved amino acid. The PubMed abstract states that heterozygous or homozygous mutation status correlated with reduced enzyme activity and increased thermolability in lymphocyte extracts, and that homozygous individuals had significantly elevated plasma homocysteine. This supports a negative enzyme-activity direction for A-containing genotypes, with a larger magnitude for AA than AG.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
enzyme activity - GG
MTHFR enzyme activity
rs1801133 GG has no scored directional claim for MTHFR enzyme activity.
MTHFR rs1801133 is scored as a lower-activity tendency, with stronger scoring for the two-copy genotype than the one-copy genotype.
Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordidentity only - unknownClinVar Variation ID 3520 identifies rs1801133 as MTHFR NM_005957.5:c.665C>T, protein p.Ala222Val, also named MTHFR 677C-T / ALA222VAL. The canonical SPDI shown by ClinVar is NC_000001.11:11796320:G:A, so this file uses the dbSNP/GRCh38 forward-strand genotype letters G and A. ClinVar condition classifications are mixed and include benign, uncertain, conflicting, and drug-response contexts, so this record is limited to enzyme-activity tendency rather than disease interpretation.PubMed 7647779functional assay - directFrosst et al. 1995 reported a common MTHFR mutation that changes a conserved amino acid. The PubMed abstract states that heterozygous or homozygous mutation status correlated with reduced enzyme activity and increased thermolability in lymphocyte extracts, and that homozygous individuals had significantly elevated plasma homocysteine. This supports a negative enzyme-activity direction for A-containing genotypes, with a larger magnitude for AA than AG.PubMed 23288205clinical curation - close proxyThe 2013 ACMG practice guideline says MTHFR polymorphism testing has minimal clinical utility in routine thrombophilia evaluation and discusses disproven or weak disease-risk associations. This supports conservative certainty and prevents using this genotype-effect row as a diagnosis, disease-risk estimate, or treatment rule.
MTR2 SNPs - 2 claimsShow SNPs
Open gene pagers11314501 claims - 3 study rows
biomarker tendency - AA
MTR-mediated homocysteine remethylation
rs1131450 AA is associated with lower MTR-mediated homocysteine remethylation capacity.
MTR rs1131450 AA is scored as a lower MTR/remethylation tendency based on functional reporter data and homocysteine-related biomarkers.
Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP places rs1131450 on chromosome 1 and lists G and A alleles on the current preferred genomic placement. This supports using A-containing genotype labels for the MTR G>A source claim, but does not itself assign effect direction.Scientific Reports 2016 MTR functional variant studyfunctional assay - directQu et al. reported rs1131450 G>A in the MTR 3 prime UTR. In luciferase assays, the A-allele construct showed lower reporter activity than the G construct in LNCaP and PC3 cells. The same paper notes that prostate tissue qPCR did not show a direct mRNA-expression association for rs1131450, so this evidence supports a conservative lower MTR pathway-function tendency rather than a high-certainty expression claim.Scientific Reports 2016 plasma homocysteine analysisbiomarker association - close proxyThe same study measured plasma homocysteine in 201 prostate cancer patients and 210 matched controls. For rs1131450 G>A, AA carriers had the highest plasma homocysteine concentration, approximately 1.5-fold higher than GG carriers in the case cohort, control cohort, and combined analysis. Because MTR remethylates homocysteine to methionine, this is close metabolic biomarker support for lower MTR-mediated remethylation capacity in AA.
rs22755651 claims - 3 study rows
biomarker tendency - GT
Plasma total homocysteine tendency
rs2275565 GT carries one T allele in MTR and is associated with lower plasma total homocysteine tendency.
MTR rs2275565 GT is staged as a modest lower-homocysteine biomarker genotype within the B12-dependent remethylation route.
Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs2275565 as a chromosome 1 MTR-region variant. This row supports variant identity only and does not assign biomarker direction.PubMed 23824729gwas - directvan Meurs et al. reported rs2275565 near MTR among known loci associated with plasma total homocysteine. The coded T allele frequency was 0.21, with beta -0.0542 SD per allele, SE 0.009, and P = 1.96e-10 for total homocysteine.GWAS Catalog association 34418gwas - directGWAS Catalog records rs2275565-T for homocysteine measurement, mapped to MTR, with beta direction decrease, beta 0.0542, SE 0.009, and P = 2e-10. This independently confirms allele orientation in a curated association record.
CBS1 SNPs - 1 claimsShow SNPs
Open gene pagers2347091 claims - 3 study rows
biomarker tendency - CT
Plasma total homocysteine tendency
rs234709 CT carries one T allele near CBS and is associated with lower plasma total homocysteine tendency.
CBS rs234709 CT is staged as a modest lower-homocysteine biomarker genotype within methylation outflow context.
Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs234709 as a chromosome 21 CBS-region variant. This row supports variant identity only and does not assign biomarker direction.PubMed 23824729gwas - directvan Meurs et al. reported rs234709 near CBS among known loci associated with plasma total homocysteine. The coded T allele frequency was 0.45, with beta -0.0718 SD per allele, SE 0.007, and P = 3.90e-24 for total homocysteine.GWAS Catalog association 34423gwas - directGWAS Catalog records rs234709-T for homocysteine measurement, mapped to CBS, with beta direction decrease, beta 0.0718, SE 0.007, and P = 4e-24. This supports the T allele as a lower-homocysteine biomarker allele.
DMGDH1 SNPs - 1 claimsShow SNPs
Open gene pagers2483861 claims - 2 study rows
biomarker tendency - C
circulating dimethylglycine tendency
rs248386 C at the DMGDH locus is associated with higher circulating dimethylglycine tendency.
DMGDH rs248386 is staged as a methylation/choline-support metabolite-QTL for dimethylglycine.
Likely effectHigher biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
PMCID PMC3973158gwas - directThe checked community metabolomics GWAS reports rs248386 at DMGDH associated with dimethylglycine, with C/A allele coding and positive beta for the coded allele.PMCID PMC4962516gwas - directThe checked exome-array metabolomics source confirms rs248386 as the common DMGDH dimethylglycine association signal and shows it remains independent from a rare DMGDH coding signal.
TCN11 SNPs - 1 claimsShow SNPs
Open gene pagers343242191 claims - 4 study rows
biomarker tendency - AC
Circulating vitamin B12 tendency
rs34324219 AC carries one A allele in TCN1 and is associated with lower circulating vitamin B12 tendency.
TCN1 rs34324219 AC is staged as a lower circulating-B12 carrier-context genotype, not as a direct cellular B12-use measurement.
Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs34324219 as a TCN1-region variant. This row supports variant identity only and does not assign B12 biomarker direction.PubMed 25147783gwas - directKeene et al. reported rs34324219 A in TCN1 associated with vitamin B12 measurement in the VISP ischemic stroke population. GWAS Catalog records the association as A with beta direction decrease and P about 5e-11, supporting A as a lower circulating B12 allele.GWAS Catalog association 44386gwas - directGWAS Catalog association 44386 records rs34324219-A, mapped to TCN1, for vitamin B12 measurement with beta direction decrease. This supports the exact effect allele and B12 biomarker direction.PubMed 23754956gwas - directGrarup et al. reported rs34324219 as the strongest TCN1-locus serum B12 signal in the Icelandic data and described it as a D301Y missense variant. Public association summaries report the C allele as B12-increasing at this biallelic A/C locus, which supports A as the lower-B12 allele by contrast.
TCN21 SNPs - 1 claimsShow SNPs
Open gene pagers11316031 claims - 4 study rows
biomarker tendency - TT
Vitamin B12 status tendency
rs1131603 TT carries two T alleles in TCN2 and is associated with lower vitamin B12 status tendency.
TCN2 rs1131603 TT is staged as a lower vitamin-B12-status genotype within B12 transport and remethylation context.
Likely effectLower biomarker tendency
Signal sizeSmall signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP identifies rs1131603 as a chromosome 22 TCN2-region variant with T/C alleles. This row supports variant identity only and does not assign B12-status direction.PubMed 23754956gwas - directGrarup et al. reported rs1131603 at TCN2 as a serum vitamin B12 locus. Public summaries of the study report the C allele as B12-increasing with beta about 0.19 and strong genome-wide significance; at this C/T biallelic locus, that supports T as lower B12 status relative to C.GWAS Catalog association 106202384gwas - directGWAS Catalog records rs1131603-C for vitamin B12 measurement at genome-wide significance. Because C is the vitamin B12-increasing allele in this C/T locus, this supports T as the lower B12-status allele by contrast.GWAS Catalog association 163385781gwas - close proxyGWAS Catalog records rs1131603-T for vitamin B12 deficiency with beta direction increase, beta 0.3565, SE 0.04763, and P = 5e-25. For the B12-status target, higher B12-deficiency liability supports a lower B12-status direction for T.
Where DNA analysis helps
DNA interpretation helps prioritize whether methylation deserves attention before broad supplement strategies are used.
Example interpretation
Your methylation pathway may have less reserve than expected because folate-processing and remethylation signals cluster together.
Suggested validation: homocysteine.
What to do next
- validate homocysteine before assuming methyl donors are needed
- look at folate and B12 support together rather than separately
- compare methylation genes as a system, not as isolated SNPs