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Primary topic: sulfur transsulfuration pathway

Sulfur and Transsulfuration Pathway: When Homocysteine Is Not the Whole Story

This pathway matters when homocysteine starts the conversation but downstream sulfur handling may be the real bottleneck.

What this pathway does

The transsulfuration pathway moves homocysteine toward cysteine, glutathione support, and sulfur buffering. It sits directly between methylation and redox resilience.

Why it matters

It matters because sulfur pressure can hide inside generic methylation talk even when glutathione and detox-related support are the real next steps.

What creates pressure on this pathway

  • slower conversion of homocysteine into downstream sulfur metabolites
  • reduced glutathione-building support once sulfur leaves methylation

Validation markers to consider

  • homocysteine
  • cysteine / sulfate context
  • glutathione support

Genes and SNPs connected to this pathway

This is about one of the body's cleanup routes. It helps deal with alcohol, inflammation, illness, hard training, and normal body waste.

Study rows support the SNP/gene claim. The pathway connection comes from the curated gene-to-pathway map.

What may run higher

Alcohol, illness, inflammation, or hard workouts may overload your cleanup system faster.

What may work more slowly

Your cleanup system may work more slowly.

What to check next

Check recovery after alcohol, illness, hard training, plus homocysteine, GGT, ALT, AST, hs-CRP, and oxidative-stress markers if available.

5mapped genes
8mapped SNPs
16SNP/gene claims
9report eligible
CBS3 SNPs - 3 claimsShow SNPsOpen gene page
rs1219649621 claims - 3 study rows

enzyme activity - TT or compound-heterozygous CBS deficiency context

CBS transsulfuration activity tendency

Strong

rs121964962 T on the genomic plus strand, corresponding to CBS c.919G>A / p.Gly307Ser, is associated with lower cystathionine beta-synthase activity and reduced homocysteine-to-cystathionine transsulfuration flux in recessive or compound-heterozygous deficiency contexts.

CBS rs121964962 T is staged as a recessive pathogenic CBS deficiency allele relevant to sulfur / transsulfuration scoring.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 117clinical curation - directClinVar maps rs121964962 to CBS c.919G>A / p.Gly307Ser, classifies it as pathogenic for homocystinuria, and includes submitter evidence that homozygous or compound-heterozygous affected individuals have absent or near-absent CBS enzyme activity.GeneReviews CBS deficiencyclinical curation - directGeneReviews supports CBS deficiency as autosomal recessive homocystinuria, with diagnosis by biallelic CBS pathogenic variants and monitoring by plasma total homocysteine, methionine, and amino-acid markers.PMCID PMC7560719clinical curation - directThe checked classical homocystinuria cohort source describes CBS as catalyzing homocysteine plus serine to cystathionine, with CBS deficiency producing high homocysteine and methionine and low cystathionine and cysteine; it identifies G307S as a recurrent global CBS deficiency allele.
rs289348911 claims - 2 study rows

enzyme activity - TT or compound-heterozygous CBS deficiency context

CBS transsulfuration activity tendency

Strong

rs28934891 T (forward-genomic; CBS c.1330G>A / p.Asp444Asn transcript context) is associated with lower CBS transsulfuration activity tendency and homocysteine/methionine biomarker disruption in recessive or compound-heterozygous CBS deficiency contexts.

CBS rs28934891 T is staged as the forward-genomic rare pathogenic CBS deficiency allele affecting transsulfuration entry from homocysteine toward cystathionine.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar RCV000000149clinical curation - directClinVar maps rs28934891 to CBS c.1330G>A / p.Asp444Asn, reports observations in homocystinuria, and cites experimental studies showing that the missense change affects CBS function.GeneReviews CBS deficiencyclinical curation - directGeneReviews supports CBS deficiency as a transsulfuration disorder with biochemical monitoring centered on homocysteine, methionine, cystathionine, cysteine, and treatment responsiveness.
rs57429051 claims - 2 study rows

enzyme activity - GG

CBS transsulfuration activity tendency

Strong

rs5742905 GG, the genomic plus-strand representation of CBS c.833T>C / p.Ile278Thr, is associated with lower cystathionine beta-synthase activity and reduced homocysteine-to-cystathionine transsulfuration flux.

CBS rs5742905 G is staged as a recessive pathogenic CBS deficiency allele relevant to sulfur / transsulfuration scoring.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 120clinical curation - directClinVar maps rs5742905 to CBS c.833T>C / p.Ile278Thr, classifies the variant as pathogenic, and includes submitter evidence that the allele acts recessively in homocystinuria with reduced enzymatic activity evidence.GeneReviews CBS deficiencyclinical curation - directGeneReviews supports CBS deficiency as impaired transsulfuration in which CBS catalyzes homocysteine plus serine to cystathionine, with deficiency leading to homocysteine and methionine accumulation and low cysteine.
GCLC1 SNPs - 3 claimsShow SNPsOpen gene page
rs178839013 claims - 3 study rows

expression - AA

GCLC gene expression

Moderate

rs17883901 AA is associated with reduced GCLC gene expression.

GCLC rs17883901 is scored as a lower GCLC expression tendency for A-containing genotypes, strongest for AA.

Likely effectLower gene expression signal
Signal sizeModerate signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
PubMed 12598062functional assay - directKoide et al. studied a promoter polymorphism in GCLC and reported lower promoter activity, about 50% to 60% of the comparison allele, in response to H2O2 in human endothelial cells. Because GCLC encodes the catalytic subunit of glutamate-cysteine ligase, this supports a lower expression tendency for the lower-promoter-activity genotype pattern.

expression - AG

GCLC gene expression

Moderate

rs17883901 AG is associated with reduced GCLC gene expression.

GCLC rs17883901 is scored as a lower GCLC expression tendency for A-containing genotypes, strongest for AA.

Likely effectLower gene expression signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
PubMed 12598062functional assay - directKoide et al. studied a promoter polymorphism in GCLC and reported lower promoter activity, about 50% to 60% of the comparison allele, in response to H2O2 in human endothelial cells. Because GCLC encodes the catalytic subunit of glutamate-cysteine ligase, this supports a lower expression tendency for the lower-promoter-activity genotype pattern.

expression - GG

GCLC gene expression

Not used for pathway scoring

rs17883901 GG has no scored directional claim for GCLC gene expression.

GCLC rs17883901 is scored as a lower GCLC expression tendency for A-containing genotypes, strongest for AA.

Likely effectNo clear expression signal
Signal sizeMinimal signal
Evidence supportVery limited support
Report useEvidence only, not scored
Show study evidence
PubMed 12598062functional assay - directKoide et al. studied a promoter polymorphism in GCLC and reported lower promoter activity, about 50% to 60% of the comparison allele, in response to H2O2 in human endothelial cells. Because GCLC encodes the catalytic subunit of glutamate-cysteine ligase, this supports a lower expression tendency for the lower-promoter-activity genotype pattern.
MTHFR2 SNPs - 6 claimsShow SNPsOpen gene page
rs18011313 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.
rs18011333 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.
CTH1 SNPs - 3 claimsShow SNPsOpen gene page
rs10217373 claims - 6 study rows

enzyme activity - TT

CTH enzyme activity

Moderate

rs1021737 TT is associated with reduced CTH enzyme activity.

CTH rs1021737 is scored as a lower cystathionine gamma-lyase activity tendency for T-containing genotypes, strongest for TT and more conservative for GT.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportModerate support
Report useIncluded in pathway scoring
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data place rs1021737 in CTH, the cystathionine gamma-lyase gene. CTH encodes an enzyme involved in sulfur amino acid metabolism and hydrogen sulfide production.PubMed 34061822functional assay - directThe PubMed record for Sueiro-Olivares and colleagues reports that recombinant CTH carrying rs1021737 S403I had significantly reduced enzymatic activity compared with the reference enzyme, measured by relative hydrogen sulfide production. The figure caption also reports TT human macrophage data compared with GG and GT.

enzyme activity - GT

CTH enzyme activity

Not used for pathway scoring

rs1021737 GT is associated with reduced CTH enzyme activity.

CTH rs1021737 is scored as a lower cystathionine gamma-lyase activity tendency for T-containing genotypes, strongest for TT and more conservative for GT.

Likely effectLower enzyme activity signal
Signal sizeSmall signal
Evidence supportModerate support
Report useEvidence only, not scored
Show study evidence
NCBI RefSNP recordidentity only - unknownNCBI RefSNP data place rs1021737 in CTH, the cystathionine gamma-lyase gene. CTH encodes an enzyme involved in sulfur amino acid metabolism and hydrogen sulfide production.PubMed 34061822functional assay - directThe PubMed record for Sueiro-Olivares and colleagues reports that recombinant CTH carrying rs1021737 S403I had significantly reduced enzymatic activity compared with the reference enzyme, measured by relative hydrogen sulfide production. The figure caption also reports TT human macrophage data compared with GG and GT.

enzyme activity - GG

CTH enzyme activity

Not used for pathway scoring

rs1021737 GG has no scored directional claim for CTH enzyme activity.

CTH rs1021737 is scored as a lower cystathionine gamma-lyase activity tendency for T-containing genotypes, strongest for TT and more conservative for GT.

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 place rs1021737 in CTH, the cystathionine gamma-lyase gene. CTH encodes an enzyme involved in sulfur amino acid metabolism and hydrogen sulfide production.PubMed 34061822functional assay - directThe PubMed record for Sueiro-Olivares and colleagues reports that recombinant CTH carrying rs1021737 S403I had significantly reduced enzymatic activity compared with the reference enzyme, measured by relative hydrogen sulfide production. The figure caption also reports TT human macrophage data compared with GG and GT.
SUOX1 SNPs - 1 claimsShow SNPsOpen gene page
rs7575591681 claims - 3 study rows

enzyme activity - AA or compound-heterozygous SUOX deficiency context

Sulfite oxidase activity tendency

Strong

rs757559168 A / SUOX c.1084G>A / p.Gly362Ser is associated with lower sulfite oxidase activity and impaired sulfite clearance in recessive or compound-heterozygous isolated sulfite oxidase deficiency contexts.

SUOX rs757559168 A is staged as a pathogenic isolated sulfite oxidase deficiency allele affecting sulfur amino-acid catabolism.

Likely effectLower enzyme activity signal
Signal sizeModerate signal
Evidence supportStrong support
Report useIncluded in pathway scoring
Show study evidence
ClinVar Variation 992188clinical curation - directClinVar maps rs757559168 to SUOX c.1084G>A / p.Gly362Ser with pathogenic assertions for isolated sulfite oxidase deficiency.GARD isolated sulfite oxidase deficiencyclinical curation - directGARD supports isolated sulfite oxidase deficiency as an inherited SUOX-linked condition affecting sulfite oxidation and sulfur-metabolite handling.PMCID PMC8077164review - directThe checked review supports SUOX as the molybdenum-dependent enzyme oxidizing sulfite and describes sulfur-metabolite abnormalities in isolated sulfite oxidase deficiency.

Where DNA analysis helps

DNA helps separate methylation pressure from sulfur outflow pressure so the follow-up markers are chosen more carefully.

Example interpretation

Sulfur handling may deserve its own follow-up when homocysteine pressure overlaps with weaker glutathione support.

Suggested validation: homocysteine plus downstream sulfur context.

What to do next

  • validate homocysteine together with downstream sulfur context
  • compare CBS, CTH, and SUOX before assuming methylation is the only issue

Related pages

CBS

CBS gene methylation

CTH

CTH gene DNA analysis

Brain fog

brain fog metabolism causes

Homocysteine and sulfur flow

Homocysteine and sulfur flow DNA follow-up

Can DNA predict metabolism?

can DNA predict metabolism

23andMe vs Metastate metabolism report

23andMe vs Metastate metabolism report

Get the full report

Use your DNA file to see which pathways may be worth validating first.