MTHFR

Chr 1ARAD

methylenetetrahydrofolate reductase

NCBI Gene: 4524 ENSG00000177000 UniProt: P42898

The protein encoded by this gene catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate for homocysteine remethylation to methionine. Genetic variation in this gene influences susceptibility to occlusive vascular disease, neural tube defects, colon cancer and acute leukemia, and mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

{Neural tube defects, susceptibility to}MIM #601634

{Schizophrenia, susceptibility to}MIM #181500

{Thromboembolism, susceptibility to}MIM #188050

{Vascular disease, susceptibility to}

Homocystinuria due to MTHFR deficiencyMIM #236250

UniProtIschemic stroke

Active trials

196

Pathogenic / LP

795

ClinVar variants

310

Pubs (1 yr)

0.9

Missense Z

0.92

LOEUF

Clinical Summary— MTHFR

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Gene-Disease Validity (ClinGen)

homocystinuria due to methylene tetrahydrofolate reductase deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

196 Pathogenic / Likely Pathogenic· 178 VUS of 795 total submissions

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — MTHFR

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint

0.92LOEUF

pLI 0.000

Z-score 1.90

OE 0.63 (0.45–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint

0.90Z-score

OE missense 0.87 (0.80–0.95)

342 obs / 391.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.63 (0.45–0.92)

0≤0.351.4

Missense OE0.87 (0.80–0.95)

0≤0.61.4

Synonymous OE1.14

0≤1.21.6

LoF obs/exp: 20 / 31.5Missense obs/exp: 342 / 391.9Syn Z: -1.37

Badonyi & Marsh 2024 ↗

0.6745th %ile

GOF

0.5169th %ile

LOF

0.2582th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

795 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic93

Likely Pathogenic103

VUS178

Likely Benign349

Benign36

Conflicting36

Pathogenic

103

Likely Pathogenic

178

VUS

349

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	34	13	45	1	93
Likely Pathogenic	42	30	28	3	103
VUS	0	145	32	1	178
Likely Benign	0	8	123	218	349
Benign	0	4	28	4	36
Conflicting	—				36
Total	76	200	256	227	795

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

MTHFR · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

MTHFR-related methylenetetrahydrofolate deductase deficiency

definitive

ARLoss Of FunctionAbsent Gene Product

Dev. Disorders

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

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GeneReview available — MTHFR

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Hyperhomocysteinemia

Evaluation of a Genetically Determined Personalized Approach in Prescribing Biologically Active Substances in Patients With Elevated Blood Homocysteine Levels.

RECRUITING

NCT06264570Phase NAS.LAB (SOLOWAYS)Started 2023-10-23

B-TMG supplementationB-SAM supplementationB-TMG placebo

Hereditary Dysfibrinogenemia

Genomics of Fibrin Clot Structure in Patients With Constitutional Dysfibrinogenemia

ACTIVE NOT RECRUITING

NCT05233384University Hospital, Clermont-FerrandStarted 2022-07-28

Blood test

Silent Myocardial IschemiaAcute Myocardial Infarction

Silent Myocardial Ischemia in Patients Undergoing Non-oncological Abdominal Surgeries

RECRUITING

NCT06536686University Medical Centre LjubljanaStarted 2024-07-01