Is MRAS p.Val91Ala (c.272T>C) pathogenic?

MRAS p.Val91Ala (c.272T>C) is classified Uncertain significance in MRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-10). AlphaMissense: likely pathogenic (0.9288); Very rare (popmax 0.000169%, nfe).

How common is MRAS p.Val91Ala (c.272T>C) in the general population?

MRAS p.Val91Ala (c.272T>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about MRAS p.Val91Ala (c.272T>C)?

AlphaMissense predicts likely pathogenic (score 0.9288) — an in-silico prediction, not a clinical call.

MRAS p.Val91Ala

c.272T>C · VCV3695138

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9288 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9288	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -11.58	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.5	GERP 2.5, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 29 kb · p 1.4e-09 · regional, not allelic
Overall
CADD	28.9	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 0.000169% European (non-Finnish) · 2/1,180,016 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,152 alleles · very rare exomes 2/1,461,862 · genomes 0/152,290 · 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: MRAS
Protein: p.Val91Ala
Coding: c.272T>C
MANE Select: NM_001085049
Type: single nucleotide variant
Location: chr3:138397402 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 11 PDB
Residue 91: a β-strand

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

Similar variants

MRAS p.Val91Ile Uncertain significance ★★ ⚠ same residue
MRAS p.Val91Leu Uncertain significance ★ ⚠ same residue
MRAS p.Val91= Likely benign ★ same residue
MRAS p.Gln71Arg Likely pathogenic ★★★ same type
MRAS p.Gly23Arg Likely pathogenic ★★★ same type
MRAS p.Gly23Val Likely pathogenic ★★★ same type
MRAS p.Thr68Ile Likely pathogenic ★★★ same type
MRAS p.Gln59= Benign ★★★ 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/mras-p-val91ala (accessed [today's date]).

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