Is MRAS p.Ala145Val (c.434C>T) pathogenic?

MRAS p.Ala145Val (c.434C>T) is classified Uncertain significance in MRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-11). AlphaMissense: likely pathogenic (0.9718); Very rare (popmax 0.00223%, eas).

How common is MRAS p.Ala145Val (c.434C>T) in the general population?

MRAS p.Ala145Val (c.434C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about MRAS p.Ala145Val (c.434C>T)?

AlphaMissense predicts likely pathogenic (score 0.9718) — an in-silico prediction, not a clinical call.

MRAS p.Ala145Val

c.434C>T · VCV3625001

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9718	likely pathogenic
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -15.41	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 7.4	GERP 0.95, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 29 kb · p 1.4e-09 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,878 alleles

Filtering AF 0.000429% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000312%

Overall 0.000682% 11/1,614,008 alleles · very rare exomes 11/1,461,814 · genomes 0/152,194 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,878
European (non-Finnish)	0.000847%	117,997

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.Ala145Val
Coding: c.434C>T
MANE Select: NM_001085049
Type: single nucleotide variant
Location: chr3:138398555 (GRCh38)
Gene constraint: LOEUF 0.444 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 86.61 · 11 PDB
Residue 145: an α-helix

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

Similar variants

MRAS p.Ala145Glu Uncertain significance ★ ⚠ same residue
MRAS p.Ala145= 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
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-ala145val (accessed [today's date]).

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