Is MTHFD1 p.Pro247Ser (c.739C>T) pathogenic?

MTHFD1 p.Pro247Ser (c.739C>T) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-27). AlphaMissense: likely benign (0.0929); Very rare (popmax 0.00441%, nfe).

How common is MTHFD1 p.Pro247Ser (c.739C>T) in the general population?

MTHFD1 p.Pro247Ser (c.739C>T) is very rare (popmax 0.00441%, nfe) (gnomAD).

What do computational predictors say about MTHFD1 p.Pro247Ser (c.739C>T)?

AlphaMissense predicts likely benign (score 0.0929) — an in-silico prediction, not a clinical call.

MTHFD1 p.Pro247Ser

c.739C>T · rs758410301 · VCV1435268

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0929 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00441%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0929	likely benign
REVEL	0.041	moderately benign-leaning
SaProt	LLR -8.46	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.024	GERP -3.3, phastCons 0.003
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	13.65	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00441% European (non-Finnish) · 52/1,180,034 alleles

Filtering AF 0.00342% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0031%

Overall 0.00335% 54/1,613,938 alleles · very rare exomes 48/1,461,770 · genomes 6/152,168 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00441%	22,693
African / African-American	0.00267%	37,456

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: MTHFD1
Protein: p.Pro247Ser
Coding: c.739C>T
MANE Select: NM_005956
dbSNP: rs758410301
Type: single nucleotide variant
Location: chr14:64424815 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 247: a UniProt-annotated variant site (in cimah); the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region; an α-helix

Full MTHFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTHFD1 p.Pro247Arg Uncertain significance ★ ⚠ same residue
MTHFD1 c.727+1G>A Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Arg173Cys Pathogenic/Likely pathogenic ★★ same type
MTHFD1 p.Gln100Ter Likely pathogenic ★★ same type
MTHFD1 p.Glu225Ter Pathogenic ★★ same type
MTHFD1 p.Ser49Phe Pathogenic/Likely pathogenic ★★ same type
MTHFD1 c.186+5C>T Uncertain significance ★★ same type
MTHFD1 p.Arg173His Uncertain significance ★★ ⚠ same type

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mthfd1-p-pro247ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown