Is MRAS p.Pro12Arg (c.35C>G) pathogenic?

MRAS p.Pro12Arg (c.35C>G) is classified Uncertain significance in MRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-14). AlphaMissense: ambiguous (0.5554); Very rare (popmax 0.00123%, sas); Associated with Inborn genetic diseases.

What condition is associated with MRAS p.Pro12Arg (c.35C>G)?

MRAS p.Pro12Arg (c.35C>G) is associated with Inborn genetic diseases (ClinVar).

How common is MRAS p.Pro12Arg (c.35C>G) in the general population?

MRAS p.Pro12Arg (c.35C>G) is very rare (popmax 0.00123%, sas) (gnomAD).

What do computational predictors say about MRAS p.Pro12Arg (c.35C>G)?

AlphaMissense predicts ambiguous (score 0.5554) — an in-silico prediction, not a clinical call.

MRAS p.Pro12Arg

c.35C>G · VCV3912831

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5554 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5554	ambiguous
REVEL	0.443	indeterminate
SaProt	LLR -6.75	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.4	GERP 7.1, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 96 bp · p 0.02 · regional, not allelic
Overall
CADD	23.5	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

Grpmax group 0.00123% South Asian · 1/81,388 alleles

Overall 6.45e-05% 1/1,550,506 alleles · very rare exomes 1/1,398,188 · genomes 0/152,318 · 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.Pro12Arg
Coding: c.35C>G
MANE Select: NM_001085049
Type: single nucleotide variant
Location: chr3:138372918 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MRAS p.Pro12Ser Uncertain significance ★★ same residue
MRAS p.Pro12= Likely benign ★ same residue
MRAS p.Ala167Gly Uncertain significance ★★ ⚠ same condition
MRAS p.Arg105Cys Uncertain significance ★★ ⚠ same condition
MRAS p.Arg193Gln Uncertain significance ★★ ⚠ same condition
MRAS p.Asn10Ser Uncertain significance ★★ ⚠ same condition
MRAS p.Asn126Lys Uncertain significance ★★ ⚠ same condition
MRAS p.Asn126Ser Uncertain significance ★★ ⚠ same condition

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-pro12arg (accessed [today's date]).

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