MTHFR

Chr 1

methylenetetrahydrofolate reductase

NCBI Gene: 4524ENSG00000177000UniProt: 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]

GeneReviewsResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtHomocystinuria due to deficiency of N(5,10)-methylenetetrahydrofolate reductase activity
UniProtIschemic stroke
UniProtNeural tube defects, folate-sensitive
UniProtSchizophrenia

Clinical highlights

Gene-disease validity (ClinGen)
homocystinuria due to methylene tetrahydrofolate reductase deficiency · ARDefinitivesufficient evidence for diagnostic panels
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.
6
Active trials
415
Pubs (1 yr)
—
P/LP submissions
—
P/LP missense
0.92
LOEUF
LOF
Mechanism· G2P
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GeneReview available — MTHFR
Authoritative clinical overview · Recommended first read
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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

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