Is MTHFD1 p.Pro277Arg (c.830C>G) pathogenic?

MTHFD1 p.Pro277Arg (c.830C>G) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-19). AlphaMissense: likely pathogenic (0.7601); Very rare (popmax 0.00167%, amr).

How common is MTHFD1 p.Pro277Arg (c.830C>G) in the general population?

MTHFD1 p.Pro277Arg (c.830C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about MTHFD1 p.Pro277Arg (c.830C>G)?

AlphaMissense predicts likely pathogenic (score 0.7601) — an in-silico prediction, not a clinical call.

MTHFD1 p.Pro277Arg

c.830C>G · rs2550500774 · VCV2124328

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7601 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7601	likely pathogenic
REVEL	0.727	pathogenic-leaning
SaProt	LLR -15.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00167% Admixed American · 1/60,026 alleles

Overall 6.2e-05% 1/1,614,158 alleles · very rare exomes 1/1,461,890 · genomes 0/152,268 · joint denominator

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.Pro277Arg
Coding: c.830C>G
MANE Select: NM_005956
dbSNP: rs2550500774
Type: single nucleotide variant
Location: chr14:64424906 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 277: 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 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
MTHFD1 p.Arg293Cys 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-pro277arg (accessed [today's date]).

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