Is MRAS p.Pro12Ser (c.34C>T) pathogenic?

MRAS p.Pro12Ser (c.34C>T) is classified Uncertain significance in MRAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-30). AlphaMissense: ambiguous (0.4396); Very rare (popmax 0.00142%, afr); Associated with Inborn genetic diseases.

What condition is associated with MRAS p.Pro12Ser (c.34C>T)?

MRAS p.Pro12Ser (c.34C>T) is associated with Inborn genetic diseases (ClinVar).

How common is MRAS p.Pro12Ser (c.34C>T) in the general population?

MRAS p.Pro12Ser (c.34C>T) is very rare (popmax 0.00142%, afr) (gnomAD).

What do computational predictors say about MRAS p.Pro12Ser (c.34C>T)?

AlphaMissense predicts ambiguous (score 0.4396) — an in-silico prediction, not a clinical call.

MRAS p.Pro12Ser

c.34C>T · VCV3874285

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00142%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4396	ambiguous
REVEL	0.434	indeterminate
SaProt	LLR -9.73	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	25.0	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 0.00142% African / African-American · 1/70,418 alleles

Overall 0.000129% 2/1,550,612 alleles · very rare exomes 2/1,398,304 · genomes 0/152,308 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00142%	70,418
European (non-Finnish)	8.65e-05%	1,155,536

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.Pro12Ser
Coding: c.34C>T
MANE Select: NM_001085049
Type: single nucleotide variant
Location: chr3:138372917 (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.Pro12Arg 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-pro12ser (accessed [today's date]).

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