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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

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

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · homocystinuria due to methylene tetrahydrofolate reductase deficiency · AR · ClinGen 2019

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.92

LOEUF

LOF

Mechanism· G2P

📖

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 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

Background carrier burden — how many people carry a rare variant somewhere in MTHFR?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 57

921 rare PASS variants

Rare truncating (LoF)

1 in 1,200

155 rare PASS variants

Rare synonymous (reference)

1 in 100

406 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MTHFR. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 76	1 in 1,100
South Asian	~43k	1 in 45	1 in 910
Remaining (unassigned)	~30k	1 in 43	1 in 2,700
European (Finnish)	~27k	1 in 240	≈ 1 in 8,700
Admixed American	~22k	1 in 46	1 in 700
African / African American	~21k	1 in 43	1 in 490
East Asian	~20k	1 in 63	1 in 3,300
Ashkenazi Jewish	~13k	1 in 350	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 50	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 11 coding exons well covered in gnomAD exomes and genomes.? see exons ↓

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

📖

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

Blood PressurePregnancy

Optimal Nutrition for Prevention of Hypertension in Pregnancy

ACTIVE NOT RECRUITING

NCT04723836Phase NAUniversity of UlsterStarted 2017-03-01

Riboflavin (5mg)5-methyltetrahydrofolate (400µg)Placebo

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

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