Is MRAS p.Pro180Ala (c.538C>G) pathogenic?

MRAS p.Pro180Ala (c.538C>G) is classified Uncertain significance in MRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-28). AlphaMissense: likely benign (0.1386); Absent from gnomAD v4.1.

How common is MRAS p.Pro180Ala (c.538C>G) in the general population?

MRAS p.Pro180Ala (c.538C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MRAS p.Pro180Ala (c.538C>G)?

AlphaMissense predicts likely benign (score 0.1386) — an in-silico prediction, not a clinical call.

MRAS p.Pro180Ala

c.538C>G · rs2474169596 · VCV2118744

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1386 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1386	likely benign
REVEL	0.323	indeterminate
SaProt	LLR -14.19	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 2.2, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 29 kb · p 1.4e-09 · regional, not allelic
Overall
CADD	23.3	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MRAS
Protein: p.Pro180Ala
Coding: c.538C>G
MANE Select: NM_001085049
dbSNP: rs2474169596
Type: single nucleotide variant
Location: chr3:138402180 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 11 PDB

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

Similar variants

MRAS p.Pro180= Benign/Likely benign ★★ same residue
MRAS p.Pro180Leu Uncertain significance ★ ⚠ 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
MRAS p.Pro151= 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-pro180ala (accessed [today's date]).

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