MTHFS

Chr 15AR

methenyltetrahydrofolate synthetase

Also known as: HsT19268, NEDMEHM

NCBI Gene: 10588ENSG00000136371UniProt: P49914

The protein encoded by this gene is an enzyme that catalyzes the conversion of 5-formyltetrahydrofolate to 5,10-methenyltetrahydrofolate, a precursor of reduced folates involved in 1-carbon metabolism. An increased activity of the encoded protein can result in an increased folate turnover rate and folate depletion. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Jun 2011]

Primary Disease Associations & Inheritance

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelinationMIM #618367
AR
81
ClinVar variants
25
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MTHFS
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 33 VUS of 81 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.55LOEUF
pLI 0.000
Z-score 0.50
OE 0.80 (0.44–1.55)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.55Z-score
OE missense 0.85 (0.72–1.01)
97 obs / 113.6 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.80 (0.44–1.55)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.72–1.01)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.08
0≤1.21.6
LoF obs/exp: 6 / 7.5Missense obs/exp: 97 / 113.6Syn Z: -0.44

ClinVar Variant Classifications

81 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic21
Likely Pathogenic4
VUS33
Likely Benign16
Benign5
Conflicting2
21
Pathogenic
4
Likely Pathogenic
33
VUS
16
Likely Benign
5
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
19
0
21
Likely Pathogenic
1
0
3
0
4
VUS
0
24
8
1
33
Likely Benign
0
3
5
8
16
Benign
0
4
0
1
5
Conflicting
—2
Total232351081

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

View in ClinVar →

Protein Context — Lollipop Plot

MTHFS · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neurodevelopmental disorder with microcephaly, epilepsy, and hypomyelination

MIM #618367

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MTHFS
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Bacterial conversion of folinic acid is required for antifolate resistance.
Ogwang S et al.·J Biol Chem
2011
Cloning and characterization of methenyltetrahydrofolate synthetase from Saccharomyces cerevisiae.
Holmes WB et al.·J Biol Chem
2002
The 5-formyltetrahydrofolate futile cycle reduces pathway stochasticity in an extended hybrid-stochastic model of folate-mediated one-carbon metabolism.
Misselbeck K et al.·Sci Rep
2019Functional
A SHMT1 variant decreases the risk of nonsyndromic cleft lip with or without cleft palate in Chile.
Salamanca C et al.·Oral Dis
2020
COVID-19 Mimics Pulmonary Dysfunction in Muscular Dystrophy as a Post-Acute Syndrome in Patients.
Tyagi SC et al.·Int J Mol Sci
2022Review
Low serum concentrations of Irisin are associated with increased risk of hip fracture in Chinese older women.
Yan J et al.·Joint Bone Spine
2018
Construction and validation of a folate metabolism-related gene signature for predicting prognosis in HNSCC.
Wang L et al.·J Cancer Res Clin Oncol
2024
Prognostic significance of folate metabolism polymorphisms for lung cancer.
Matakidou A et al.·Br J Cancer
2007
A female case of 5,10-methenyltetrahydrofolate synthetase deficiency with novel neuro-imaging abnormalities.
Cavusoglu D et al.·Brain Dev
2022Case report
Fine mapping of the keratoconus with cataract locus on chromosome 15q and candidate gene analysis.
Dash DP et al.·Mol Vis
2006
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools