MTHFSD

Chr 16

methenyltetrahydrofolate synthetase domain containing

NCBI Gene: 64779 ENSG00000103248 UniProt: Q2M296 OMIM: 616820

The MTHFSD protein enables RNA binding activity and is predicted to function in the cytoplasm. This gene is not highly constrained against loss-of-function variants (LOEUF 1.705), and no established Mendelian diseases have been definitively associated with MTHFSD mutations in current clinical databases.

OMIM ResearchSummary from RefSeq

Enables RNA binding activity. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOEUF 1.71

Clinical Summary— MTHFSD

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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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ClinVar Variants

2 unique Pathogenic / Likely Pathogenic· 75 VUS of 91 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.71LOEUF

pLI 0.000

Z-score -0.50

OE 1.14 (0.77–1.71)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.98Z-score

OE missense 1.19 (1.07–1.33)

245 obs / 205.3 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.14 (0.77–1.71)

0≤0.351.4

Missense OE?1.19 (1.07–1.33)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 16 / 14.0Missense obs/exp: 245 / 205.3Syn Z: -0.21

ClinVar Variant Classifications

91 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

VUS75

Likely Benign4

Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Total
Pathogenic	0	0	2	2
Likely Pathogenic	0	0	0	0
VUS	1	73	1	75
Likely Benign	0	4	0	4
Benign	0	0	0	0
Total	1	77	3	81

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

View in ClinVar →

44 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap MTHFSD — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →