Is MTHFD1 p.Pro247Arg (c.740C>G) pathogenic?

MTHFD1 p.Pro247Arg (c.740C>G) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely benign (0.0905); Rare (popmax 0.116%, afr).

How common is MTHFD1 p.Pro247Arg (c.740C>G) in the general population?

MTHFD1 p.Pro247Arg (c.740C>G) is rare (popmax 0.116%, afr) (gnomAD).

What do computational predictors say about MTHFD1 p.Pro247Arg (c.740C>G)?

AlphaMissense predicts likely benign (score 0.0905) — an in-silico prediction, not a clinical call.

MTHFD1 p.Pro247Arg

c.740C>G · rs150205662 · VCV1510847

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0905 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.116%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0905	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -9.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.8	GERP 1.2, phastCons 0.25
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	17.18	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 0.116% African / African-American · 87/74,996 alleles

Filtering AF 0.0963% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.089%

Overall 0.00861% 139/1,613,978 alleles · rare exomes 89/1,461,768 · genomes 50/152,210 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.116%	862
Middle Eastern	0.0826%	1,211
Remaining individualsnot grpmax-eligible	0.0448%	2,232
Admixed American	0.0183%	5,451
South Asian	0.0022%	45,517
European (non-Finnish)	0.000508%	196,667

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.Pro247Arg
Coding: c.740C>G
MANE Select: NM_005956
dbSNP: rs150205662
Type: single nucleotide variant
Location: chr14:64424816 (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.Pro247Ser 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-pro247arg (accessed [today's date]).

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