MTHFR

Chr 1ARAD

methylenetetrahydrofolate reductase

NCBI Gene: 4524 ENSG00000177000 UniProt: P42898 OMIM: 607093

The protein catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a co-substrate required for homocysteine remethylation to methionine. Mutations cause homocystinuria due to MTHFR deficiency with autosomal recessive inheritance, while certain variants increase susceptibility to neural tube defects, thromboembolism, and vascular disease. Loss-of-function mutations result in enzyme deficiency leading to elevated homocysteine levels and disrupted methionine metabolism.

OMIM ResearchSummary from RefSeq, OMIM, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismAR/ADLOEUF 0.925 OMIM phenotypes

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

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Population Constraint (gnomAD)

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

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Clinical Trials

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

Explore recent and relevant literature in Research Assistant →

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 OE?0.63 (0.45–0.92)

0≤0.351.4

Missense OE?0.87 (0.80–0.95)

0≤0.61.4

Synonymous OE?1.14

0≤1.21.6

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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveMTHFR-related methylenetetrahydrofolate deductase deficiencyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6745th %ile

GOF

0.5169th %ile

LOF

0.2582th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

MTHFR · protein map & ClinVar variants

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

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Pancreatic Cancer

Pancreatic Cancer Genetics

RECRUITING

NCT01102569Columbia UniversityStarted 2008-01

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

Overweight and ObesityLupus Erythematosus

Methyl-donor Nutrient Supplementation and Methylation Profile in Lupus Patients With Obesity

ENROLLING BY INVITATION

NCT05097365Phase NAUniversity of Sao PauloStarted 2022-01-01

Vitamin B12 + folic acid supplementationPlacebo supplementation

Blood PressurePregnancy

Optimal Nutrition for Prevention of Hypertension in Pregnancy

ACTIVE NOT RECRUITING

NCT04723836Phase NAUniversity of UlsterStarted 2017-03-01