What is the MTRR gene?
MTRR helps regenerate the active B12 form used by methionine synthase. That makes it part of the remethylation system that keeps homocysteine moving back toward methionine instead of accumulating under pressure.
How MTRR affects metabolism
If MTRR-related recycling is less efficient, methylation support may rely on a weaker B12 handoff cycle. That can make homocysteine, methylmalonic acid, and broader one-carbon balance more important to validate directly.
What happens when MTRR is altered
Altered MTRR function does not prove deficiency, but it increases the value of checking functional markers instead of assuming B12 handling is fine because intake looks adequate.
Curated SNP evidence for MTRR
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.
Evidence-backed report connection
MTRR currently has 3 curated SNPs, 9 claim-level scores, and 0 claims eligible for pathway scoring.
Open the sample reportrs1532268MTRR supporting signal3 claims · 15 study rows
enzyme activity · TT
MTRR enzyme activity
rs1532268 TT is associated with reduced MTRR enzyme activity.
MTRR rs1532268 is scored as a low-certainty tendency signal for MTRR activity. The current evidence is weaker than for established functional SNPs, so this should remain a minor supporting signal.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportLimited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar RCV000405120 identifies rs1532268 as MTRR NM_002454.3:c.524C>T, p.Ser175Leu, with GRCh38 location chr5:7878066 and a missense molecular consequence. The same record reports a benign classification for intracellular cobalamin metabolism from one submitter, so this source supports identity and missense status but not a clinical pathogenic claim.NCBI RefSNP recordidentity only · unknownNCBI RefSNP data checked for rs1532268 identify MTRR as the annotated gene and include c.524C>T transcript annotations with Ser-to-Leu protein substitutions in MTRR products. The RefSNP record is multiallelic, but the curated rows here cover the common C/T missense allele pair supported by ClinVar and literature.PubMed 34667917other · directMolecular-dynamics work on rs1532268 describes the variant as a nonsynonymous MTRR Ser-to-Leu change and reports altered FAD and NAD binding-domain structure, restricted ligand binding, and potential impairment of the NADP(H) to FAD to FMN electron-transfer path. This is mechanistic modeling rather than a direct wet-lab enzyme-activity measurement, so certainty is low.Evidence 4functional assay · loose proxyOlteanu et al. studied MTRR polymorphic variants including I22/L175 and M22/S175. The abstract reports less effective methionine synthase activation for these polymorphic variants and suggests altered affinity for methionine synthase as a likely mechanism. Because the study compared haplotypic protein backgrounds rather than isolated rs1532268 genotypes, it only weakly supports a T-allele activity tendency.PubMed 35579185other · mismatchA meta-analysis of rs1532268 and gastric cancer notes inconsistent prior findings and reports only a small pooled association under allele and dominant models, with no relationship in stratified White or Asian analyses. This disease-association evidence is indirect for enzyme activity and is used only as a caveat.
enzyme activity · CT
MTRR enzyme activity
rs1532268 CT is associated with reduced MTRR enzyme activity.
MTRR rs1532268 is scored as a low-certainty tendency signal for MTRR activity. The current evidence is weaker than for established functional SNPs, so this should remain a minor supporting signal.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar RCV000405120 identifies rs1532268 as MTRR NM_002454.3:c.524C>T, p.Ser175Leu, with GRCh38 location chr5:7878066 and a missense molecular consequence. The same record reports a benign classification for intracellular cobalamin metabolism from one submitter, so this source supports identity and missense status but not a clinical pathogenic claim.NCBI RefSNP recordidentity only · unknownNCBI RefSNP data checked for rs1532268 identify MTRR as the annotated gene and include c.524C>T transcript annotations with Ser-to-Leu protein substitutions in MTRR products. The RefSNP record is multiallelic, but the curated rows here cover the common C/T missense allele pair supported by ClinVar and literature.PubMed 34667917other · directMolecular-dynamics work on rs1532268 describes the variant as a nonsynonymous MTRR Ser-to-Leu change and reports altered FAD and NAD binding-domain structure, restricted ligand binding, and potential impairment of the NADP(H) to FAD to FMN electron-transfer path. This is mechanistic modeling rather than a direct wet-lab enzyme-activity measurement, so certainty is low.Evidence 4functional assay · loose proxyOlteanu et al. studied MTRR polymorphic variants including I22/L175 and M22/S175. The abstract reports less effective methionine synthase activation for these polymorphic variants and suggests altered affinity for methionine synthase as a likely mechanism. Because the study compared haplotypic protein backgrounds rather than isolated rs1532268 genotypes, it only weakly supports a T-allele activity tendency.PubMed 35579185other · mismatchA meta-analysis of rs1532268 and gastric cancer notes inconsistent prior findings and reports only a small pooled association under allele and dominant models, with no relationship in stratified White or Asian analyses. This disease-association evidence is indirect for enzyme activity and is used only as a caveat.
enzyme activity · CC
MTRR enzyme activity
rs1532268 CC has no scored directional claim for MTRR enzyme activity.
MTRR rs1532268 is scored as a low-certainty tendency signal for MTRR activity. The current evidence is weaker than for established functional SNPs, so this should remain a minor supporting signal.
Likely effectNo clear enzyme signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
ClinVar recordclinical curation · close proxyClinVar RCV000405120 identifies rs1532268 as MTRR NM_002454.3:c.524C>T, p.Ser175Leu, with GRCh38 location chr5:7878066 and a missense molecular consequence. The same record reports a benign classification for intracellular cobalamin metabolism from one submitter, so this source supports identity and missense status but not a clinical pathogenic claim.NCBI RefSNP recordidentity only · unknownNCBI RefSNP data checked for rs1532268 identify MTRR as the annotated gene and include c.524C>T transcript annotations with Ser-to-Leu protein substitutions in MTRR products. The RefSNP record is multiallelic, but the curated rows here cover the common C/T missense allele pair supported by ClinVar and literature.PubMed 34667917other · directMolecular-dynamics work on rs1532268 describes the variant as a nonsynonymous MTRR Ser-to-Leu change and reports altered FAD and NAD binding-domain structure, restricted ligand binding, and potential impairment of the NADP(H) to FAD to FMN electron-transfer path. This is mechanistic modeling rather than a direct wet-lab enzyme-activity measurement, so certainty is low.Evidence 4functional assay · loose proxyOlteanu et al. studied MTRR polymorphic variants including I22/L175 and M22/S175. The abstract reports less effective methionine synthase activation for these polymorphic variants and suggests altered affinity for methionine synthase as a likely mechanism. Because the study compared haplotypic protein backgrounds rather than isolated rs1532268 genotypes, it only weakly supports a T-allele activity tendency.PubMed 35579185other · mismatchA meta-analysis of rs1532268 and gastric cancer notes inconsistent prior findings and reports only a small pooled association under allele and dominant models, with no relationship in stratified White or Asian analyses. This disease-association evidence is indirect for enzyme activity and is used only as a caveat.
rs162036MTRR supporting signal3 claims · 12 study rows
biomarker tendency · AG
MTRR biomarker tendency
rs162036 AG is associated with increased MTRR biomarker tendency.
MTRR rs162036 is scored as a weak biomarker-response tendency, not as a direct MTRR enzyme-activity result.
Likely effectHigher biomarker tendency
Signal sizeSmall signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
Evidence 1identity only · unknownNCBI dbSNP build 157 identifies rs162036 as an A>G SNV at chr5:7885846 on GRCh38.p14, with MTRR consequence annotated as missense. The HGVS aliases include NM_002454.3:c.1049A>G and protein change p.Lys350Arg, supporting MTRR as the gene and A/G as the genotype-letter set used here.ClinVar recordclinical curation · loose proxyClinVar Variation ID 138291 identifies NM_002454.3(MTRR):c.1049A>G (p.Lys350Arg), location 5:7885846 on GRCh38, and aggregate germline classification benign/likely benign. This supports a non-disease interpretation and argues against treating the G allele as a high-confidence pathogenic or strongly deleterious functional allele.Evidence 3biomarker association · close proxyIn a hyperhomocysteinaemia folate-treatment study, rs162036 AG and AG+GG genotypes were less frequent in treatment failures than successes. Compared with AA, AG and AG+GG were reported as favoring folic acid therapy response, with OR 0.56 and 0.63 for treatment failure respectively, while the G allele alone was not significantly different from A. This supports a weak positive biomarker-response tendency for AG, and a lower-certainty positive tendency for GG because the specific GG-only estimate was not the main supported result.Evidence 4biomarker association · close proxyA later prospective cohort of 230 hyperhomocysteinaemia patients reported that MTRR rs162036 was associated with folate treatment response with P = 0.048, but the accessible abstract does not provide genotype-specific effect direction or a direct enzyme-activity measurement. This supports only low-to-moderate certainty for a biomarker/treatment-response tendency.
biomarker tendency · GG
MTRR biomarker tendency
rs162036 GG is associated with increased MTRR biomarker tendency.
MTRR rs162036 is scored as a weak biomarker-response tendency, not as a direct MTRR enzyme-activity result.
Likely effectHigher biomarker tendency
Signal sizeSmall signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
Evidence 1identity only · unknownNCBI dbSNP build 157 identifies rs162036 as an A>G SNV at chr5:7885846 on GRCh38.p14, with MTRR consequence annotated as missense. The HGVS aliases include NM_002454.3:c.1049A>G and protein change p.Lys350Arg, supporting MTRR as the gene and A/G as the genotype-letter set used here.ClinVar recordclinical curation · loose proxyClinVar Variation ID 138291 identifies NM_002454.3(MTRR):c.1049A>G (p.Lys350Arg), location 5:7885846 on GRCh38, and aggregate germline classification benign/likely benign. This supports a non-disease interpretation and argues against treating the G allele as a high-confidence pathogenic or strongly deleterious functional allele.Evidence 3biomarker association · close proxyIn a hyperhomocysteinaemia folate-treatment study, rs162036 AG and AG+GG genotypes were less frequent in treatment failures than successes. Compared with AA, AG and AG+GG were reported as favoring folic acid therapy response, with OR 0.56 and 0.63 for treatment failure respectively, while the G allele alone was not significantly different from A. This supports a weak positive biomarker-response tendency for AG, and a lower-certainty positive tendency for GG because the specific GG-only estimate was not the main supported result.Evidence 4biomarker association · close proxyA later prospective cohort of 230 hyperhomocysteinaemia patients reported that MTRR rs162036 was associated with folate treatment response with P = 0.048, but the accessible abstract does not provide genotype-specific effect direction or a direct enzyme-activity measurement. This supports only low-to-moderate certainty for a biomarker/treatment-response tendency.
biomarker tendency · AA
MTRR biomarker tendency
rs162036 AA has no scored directional claim for MTRR biomarker tendency.
MTRR rs162036 is scored as a weak biomarker-response tendency, not as a direct MTRR enzyme-activity result.
Likely effectNo clear biomarker tendency
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
Evidence 1identity only · unknownNCBI dbSNP build 157 identifies rs162036 as an A>G SNV at chr5:7885846 on GRCh38.p14, with MTRR consequence annotated as missense. The HGVS aliases include NM_002454.3:c.1049A>G and protein change p.Lys350Arg, supporting MTRR as the gene and A/G as the genotype-letter set used here.ClinVar recordclinical curation · loose proxyClinVar Variation ID 138291 identifies NM_002454.3(MTRR):c.1049A>G (p.Lys350Arg), location 5:7885846 on GRCh38, and aggregate germline classification benign/likely benign. This supports a non-disease interpretation and argues against treating the G allele as a high-confidence pathogenic or strongly deleterious functional allele.Evidence 3biomarker association · close proxyIn a hyperhomocysteinaemia folate-treatment study, rs162036 AG and AG+GG genotypes were less frequent in treatment failures than successes. Compared with AA, AG and AG+GG were reported as favoring folic acid therapy response, with OR 0.56 and 0.63 for treatment failure respectively, while the G allele alone was not significantly different from A. This supports a weak positive biomarker-response tendency for AG, and a lower-certainty positive tendency for GG because the specific GG-only estimate was not the main supported result.Evidence 4biomarker association · close proxyA later prospective cohort of 230 hyperhomocysteinaemia patients reported that MTRR rs162036 was associated with folate treatment response with P = 0.048, but the accessible abstract does not provide genotype-specific effect direction or a direct enzyme-activity measurement. This supports only low-to-moderate certainty for a biomarker/treatment-response tendency.
rs1801394A66G3 claims · 12 study rows
enzyme activity · GG
MTRR enzyme activity
rs1801394 GG is associated with reduced MTRR enzyme activity.
MTRR rs1801394 is scored as a moderate-low certainty lower-activity tendency.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportLimited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only · unknownNCBI RefSNP data checked for rs1801394 identify MTRR as the annotated gene and the A/G alleles at this locus. MTRR transcript annotations include c.66A>G with an Ile-to-Met protein substitution at residue 22 in multiple transcript products.Evidence 2functional assay · loose proxyOlteanu et al. characterized common human methionine synthase reductase variants. The abstract states that MTRR reactivates oxidized methionine synthase, that M22/S175 is a genetic determinant of plasma homocysteine levels, and that biochemical penalties in the polymorphic variants likely involve altered affinity for methionine synthase rather than NADPH reduction kinetics. This supports a conservative lower MTRR-to-methionine-synthase reactivation model for the G-containing genotypes.PubMed 11472746biomarker association · directGaughan et al. reported an MTRR A66G association with plasma total homocysteine, but the reported genotype pattern does not support a simple G-allele lower-enzyme-activity direction. It is treated as non-supporting for this exact claim.PubMed 11006889biomarker association · directBrown et al. screened MTRR 66A>G in a coronary angiography cohort and found no difference in fasting plasma homocysteine, serum folate, or vitamin B12 among genotypes, so this row is not scored as supporting lower activity.
enzyme activity · AG
MTRR enzyme activity
rs1801394 AG is associated with reduced MTRR enzyme activity.
MTRR rs1801394 is scored as a moderate-low certainty lower-activity tendency.
Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportLimited support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only · unknownNCBI RefSNP data checked for rs1801394 identify MTRR as the annotated gene and the A/G alleles at this locus. MTRR transcript annotations include c.66A>G with an Ile-to-Met protein substitution at residue 22 in multiple transcript products.Evidence 2functional assay · loose proxyOlteanu et al. characterized common human methionine synthase reductase variants. The abstract states that MTRR reactivates oxidized methionine synthase, that M22/S175 is a genetic determinant of plasma homocysteine levels, and that biochemical penalties in the polymorphic variants likely involve altered affinity for methionine synthase rather than NADPH reduction kinetics. This supports a conservative lower MTRR-to-methionine-synthase reactivation model for the G-containing genotypes.PubMed 11472746biomarker association · directGaughan et al. reported an MTRR A66G association with plasma total homocysteine, but the reported genotype pattern does not support a simple G-allele lower-enzyme-activity direction. It is treated as non-supporting for this exact claim.PubMed 11006889biomarker association · directBrown et al. screened MTRR 66A>G in a coronary angiography cohort and found no difference in fasting plasma homocysteine, serum folate, or vitamin B12 among genotypes, so this row is not scored as supporting lower activity.
enzyme activity · AA
MTRR enzyme activity
rs1801394 AA has no scored directional claim for MTRR enzyme activity.
MTRR rs1801394 is scored as a moderate-low certainty lower-activity tendency.
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 checked for rs1801394 identify MTRR as the annotated gene and the A/G alleles at this locus. MTRR transcript annotations include c.66A>G with an Ile-to-Met protein substitution at residue 22 in multiple transcript products.Evidence 2functional assay · loose proxyOlteanu et al. characterized common human methionine synthase reductase variants. The abstract states that MTRR reactivates oxidized methionine synthase, that M22/S175 is a genetic determinant of plasma homocysteine levels, and that biochemical penalties in the polymorphic variants likely involve altered affinity for methionine synthase rather than NADPH reduction kinetics. This supports a conservative lower MTRR-to-methionine-synthase reactivation model for the G-containing genotypes.PubMed 11472746biomarker association · directGaughan et al. reported that MTRR A66G significantly influenced plasma total homocysteine in 601 Northern-Irish men, but the abstract emphasizes a genotype-phenotype association rather than a direct enzyme assay and reports the 66AA genotype as higher in homocysteine ranking than 66GG. This conflicts with a simple G-allele-only biomarker model and lowers certainty.PubMed 11006889biomarker association · directBrown et al. screened MTRR 66A>G in a coronary angiography cohort and found no difference in fasting plasma homocysteine, serum folate, or vitamin B12 among the three genotypes. This supports treating the enzyme-activity row as a weak functional tendency, not a deterministic biomarker call.
Common symptoms people report
- fatigue or brain fog with unclear B12 context
- homocysteine concerns despite reasonable intake
- slower recovery when methylation support looks strained
- neurological or energy questions that do not fit a simple folate-only explanation
Biomarkers to validate
Methylmalonic acid
Useful for checking whether B12 support is functionally sufficient inside cells.
Homocysteine
Adds practical context for whether remethylation support appears pressured.
Holotranscobalamin
Helpful when transport and recycling questions overlap.
Where DNA analysis helps
DNA analysis can show whether B12 recycling deserves attention inside a methylation review. The value is in prioritizing the right follow-up markers, not diagnosing dysfunction from genetics alone.
Example Insight
Your B12 recycling pathway may contribute to methylation pressure even when intake alone does not look obviously low.
Suggested validation: methylmalonic acid plus homocysteine.
What to do next
- Check homocysteine and methylmalonic acid before assuming B12 recycling is limiting.
- Compare MTRR with TCN2, MTHFR, and BHMT when methylation support looks uneven.
- Use functional markers before escalating supplement strategy.
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