Is HRAS p.Val125= (c.375G>C) pathogenic?

HRAS p.Val125= (c.375G>C) is classified Likely benign in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). Absent from gnomAD v4.1; Associated with Costello syndrome.

What condition is associated with HRAS p.Val125= (c.375G>C)?

HRAS p.Val125= (c.375G>C) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Val125= (c.375G>C) in the general population?

HRAS p.Val125= (c.375G>C) is absent from gnomAD v4.1 (gnomAD).

HRAS p.Val125=

c.375G>C · rs1851243465 · VCV1089010

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Costello syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.34 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.38	GERP -3.7, phastCons 0.99
Overall
CADD	11.6	PHRED · no single calibrated threshold — expert panels disagree

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: HRAS
Protein: p.Val125=
Coding: c.375G>C
MANE Select: NM_005343
dbSNP: rs1851243465
Type: single nucleotide variant
Location: chr11:533528 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB

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

Disease context

Costello syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

HRAS p.Val125Ala Uncertain significance ★ ⚠ same residue
HRAS p.Val125fs Uncertain significance ★ same residue
HRAS p.Ala59Thr Likely pathogenic ★★★ same condition
HRAS p.Gly12Ser Pathogenic ★★★ same condition
HRAS p.Gly13Cys Pathogenic ★★★ same condition
HRAS p.Lys117Arg Pathogenic ★★★ same condition
HRAS p.Thr58Ile Pathogenic ★★★ same condition
HRAS p.Gly138Ser 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/hras-p-val125 (accessed [today's date]).

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