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Primary topic: MTHFR gene metabolism

MTHFR Gene and Metabolism: What It Means for Your Body

MTHFR sits inside the folate cycle and helps produce methyl groups used across detoxification, neurotransmitter balance, and homocysteine handling.

What is the MTHFR gene?

The MTHFR enzyme helps convert folate into a form your body can use for methylation. That matters because methylation supports homocysteine recycling, DNA maintenance, neurotransmitter chemistry, and many routine cellular processes.

How MTHFR affects metabolism

When MTHFR-related capacity is lower, folate handling can become less efficient. That may show up as slower methylation support, more pressure on compensatory remethylation pathways, and a greater need to validate whether homocysteine or B vitamin status is actually affected.

What happens when MTHFR is altered

Altered MTHFR function does not guarantee a problem, but it can reduce how efficiently the pathway runs. The practical question is whether the reduced pathway efficiency is large enough to matter in your physiology under real conditions.

Curated SNP evidence for MTHFR

These SNPs come from the approved study-level evidence model. Each claim is scored from curated study rows, then gated before it can influence pathway scoring.

B12 transport Choline support Estrogen metabolism Methylation Sulfur / transsulfuration

Evidence-backed report connection

MTHFR currently has 4 curated SNPs, 12 claim-level scores, and 2 claims eligible for pathway scoring.

Open the sample report
rs1801131A1298C3 claims · 9 study rows

enzyme activity · GG

MTHFR enzyme activity

Moderate

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

Not used for pathway scoring

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

Not used for pathway scoring

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.
rs1801133C677T3 claims · 9 study rows

enzyme activity · AA

MTHFR enzyme activity

Moderate

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

Not used for pathway scoring

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

Not used for pathway scoring

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.
rs2066470MTHFR regulatory signal3 claims · 9 study rows

unknown · AA

MTHFR unscored target

Not used for pathway scoring

rs2066470 AA has no scored directional claim for MTHFR unscored target.

MTHFR rs2066470 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar VCV000292246 identifies rs2066470 as NM_005957.5(MTHFR):c.117C>T, NP_005948.3:p.Pro39=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11802999:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, which supports not assigning a direct enzyme-activity decrease from this variant alone.Evidence 2identity only · unknownNCBI dbSNP maps rs2066470 to MTHFR transcript variant 2 as NM_005957.5:c.117C>T and protein NP_005948.3:p.Pro39=, with synonymous-variant annotation. dbSNP also lists a rarer G>C allele at this site; this curation models the commonly discussed A/G genotype set only.Evidence 3other · loose proxyZhong et al. 2022 reported an association between rs2066470 AA versus GG and congenital heart disease risk in a Han Chinese case-control study, and reported rs2066470 interaction with maternal folic acid use. The study did not directly measure MTHFR enzyme activity, expression, homocysteine, or folate biomarkers by genotype, so it is not converted here into a directional metabolomic effect.

unknown · AG

MTHFR unscored target

Not used for pathway scoring

rs2066470 AG has no scored directional claim for MTHFR unscored target.

MTHFR rs2066470 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar VCV000292246 identifies rs2066470 as NM_005957.5(MTHFR):c.117C>T, NP_005948.3:p.Pro39=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11802999:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, which supports not assigning a direct enzyme-activity decrease from this variant alone.Evidence 2identity only · unknownNCBI dbSNP maps rs2066470 to MTHFR transcript variant 2 as NM_005957.5:c.117C>T and protein NP_005948.3:p.Pro39=, with synonymous-variant annotation. dbSNP also lists a rarer G>C allele at this site; this curation models the commonly discussed A/G genotype set only.Evidence 3other · loose proxyZhong et al. 2022 reported an association between rs2066470 AA versus GG and congenital heart disease risk in a Han Chinese case-control study, and reported rs2066470 interaction with maternal folic acid use. The study did not directly measure MTHFR enzyme activity, expression, homocysteine, or folate biomarkers by genotype, so it is not converted here into a directional metabolomic effect.

unknown · GG

MTHFR unscored target

Not used for pathway scoring

rs2066470 GG has no scored directional claim for MTHFR unscored target.

MTHFR rs2066470 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar VCV000292246 identifies rs2066470 as NM_005957.5(MTHFR):c.117C>T, NP_005948.3:p.Pro39=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11802999:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, which supports not assigning a direct enzyme-activity decrease from this variant alone.Evidence 2identity only · unknownNCBI dbSNP maps rs2066470 to MTHFR transcript variant 2 as NM_005957.5:c.117C>T and protein NP_005948.3:p.Pro39=, with synonymous-variant annotation. dbSNP also lists a rarer G>C allele at this site; this curation models the commonly discussed A/G genotype set only.Evidence 3other · loose proxyZhong et al. 2022 reported an association between rs2066470 AA versus GG and congenital heart disease risk in a Han Chinese case-control study, and reported rs2066470 interaction with maternal folic acid use. The study did not directly measure MTHFR enzyme activity, expression, homocysteine, or folate biomarkers by genotype, so it is not converted here into a directional metabolomic effect.
rs4846051MTHFR supporting signal3 claims · 9 study rows

unknown · AA

MTHFR unscored target

Not used for pathway scoring

rs4846051 AA has no scored directional claim for MTHFR unscored target.

MTHFR rs4846051 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · loose proxyClinVar VCV000167306 identifies rs4846051 as NM_005957.5(MTHFR):c.1305C>T, NP_005948.3:p.Phe435=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11794399:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, supporting no curated direct functional effect from this variant alone.PMC12264804other · loose proxyBeydoun et al. 2019 studied one-carbon metabolism gene polymorphisms and cognitive trajectory in African-American HANDLS participants and reported rs4846051(A1317G, G>A) associations with cognitive-change measures. This is an observational cognitive-outcome association, not direct evidence for MTHFR enzyme activity, expression, folate status, or homocysteine tendency by rs4846051 genotype.PMC1798268other · loose proxyHughes et al. 2006 reported that rs4846051 allele frequencies differed by ancestry in rheumatoid arthritis cohorts and that rs4846051 was not associated with methotrexate response overall; a toxicity-score association in African-American participants was described as preliminary. This does not provide a direct genotype-to-metabolic-target effect suitable for enzyme or biomarker scoring.

unknown · AG

MTHFR unscored target

Not used for pathway scoring

rs4846051 AG has no scored directional claim for MTHFR unscored target.

MTHFR rs4846051 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · loose proxyClinVar VCV000167306 identifies rs4846051 as NM_005957.5(MTHFR):c.1305C>T, NP_005948.3:p.Phe435=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11794399:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, supporting no curated direct functional effect from this variant alone.PMC12264804other · loose proxyBeydoun et al. 2019 studied one-carbon metabolism gene polymorphisms and cognitive trajectory in African-American HANDLS participants and reported rs4846051(A1317G, G>A) associations with cognitive-change measures. This is an observational cognitive-outcome association, not direct evidence for MTHFR enzyme activity, expression, folate status, or homocysteine tendency by rs4846051 genotype.PMC1798268other · loose proxyHughes et al. 2006 reported that rs4846051 allele frequencies differed by ancestry in rheumatoid arthritis cohorts and that rs4846051 was not associated with methotrexate response overall; a toxicity-score association in African-American participants was described as preliminary. This does not provide a direct genotype-to-metabolic-target effect suitable for enzyme or biomarker scoring.

unknown · GG

MTHFR unscored target

Not used for pathway scoring

rs4846051 GG has no scored directional claim for MTHFR unscored target.

MTHFR rs4846051 is currently not scored for a metabolic effect because the curated evidence does not support a clear genotype-level activity, transport, expression, or biomarker direction.

Likely effectNo clear DNA signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · loose proxyClinVar VCV000167306 identifies rs4846051 as NM_005957.5(MTHFR):c.1305C>T, NP_005948.3:p.Phe435=, a synonymous MTHFR variant with canonical SPDI NC_000001.11:11794399:G:A. The aggregate germline classification is benign with multiple submitters and no conflicts, supporting no curated direct functional effect from this variant alone.PMC12264804other · loose proxyBeydoun et al. 2019 studied one-carbon metabolism gene polymorphisms and cognitive trajectory in African-American HANDLS participants and reported rs4846051(A1317G, G>A) associations with cognitive-change measures. This is an observational cognitive-outcome association, not direct evidence for MTHFR enzyme activity, expression, folate status, or homocysteine tendency by rs4846051 genotype.PMC1798268other · loose proxyHughes et al. 2006 reported that rs4846051 allele frequencies differed by ancestry in rheumatoid arthritis cohorts and that rs4846051 was not associated with methotrexate response overall; a toxicity-score association in African-American participants was described as preliminary. This does not provide a direct genotype-to-metabolic-target effect suitable for enzyme or biomarker scoring.

Common symptoms people report

  • brain fog or low mental sharpness
  • fatigue that feels disproportionate to workload
  • poor response to folate or B-complex supplements
  • higher concern around homocysteine or methylation balance

Biomarkers to validate

Homocysteine

Useful for checking whether methylation support is actually under strain.

Serum folate or red blood cell folate

Helps assess folate availability alongside pathway interpretation.

Vitamin B12

Helps separate folate-cycle pressure from a broader methylation support issue.

Where DNA analysis helps

DNA helps identify whether the folate and methylation pathway is worth validating first. It does not diagnose dysfunction on its own, but it can help prioritize which markers to check before guessing on interventions.

Example Insight

Your methylation pathway may show reduced efficiency due to variants affecting folate processing.

Suggested validation: homocysteine levels.

What to do next

  • Review homocysteine and B vitamin markers before making assumptions.
  • Use folate-related nutrition and supplement decisions only after checking whether the pathway is actually pressured.
  • Compare MTHFR with related methylation genes such as COMT, CBS, and BHMT.

Upload your DNA file and receive a structured metabolic pathway analysis with prioritized insights and suggested validation markers.

Get My DNA Report

Related pages

COMT

COMT gene metabolism

CBS

CBS gene methylation

Holotranscobalamin

holotranscobalamin and B12 transport

Homocysteine

homocysteine and methylation

B12 transport and recycling pathway

B12 transport and recycling pathway

Methylation pathway

methylation pathway explained

Is DNA metabolism analysis worth it?

is DNA metabolism analysis worth it

DNA nutrition analysis report

DNA nutrition analysis report

Related symptom angle

Brain fog metabolism causes

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