Is HRAS p.Val109Met (c.325G>A) pathogenic?

HRAS p.Val109Met (c.325G>A) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely pathogenic (0.9206); Very rare (popmax 0.00223%, eas); Associated with Costello syndrome.

What condition is associated with HRAS p.Val109Met (c.325G>A)?

HRAS p.Val109Met (c.325G>A) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Val109Met (c.325G>A) in the general population?

HRAS p.Val109Met (c.325G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about HRAS p.Val109Met (c.325G>A)?

AlphaMissense predicts likely pathogenic (score 0.9206) — an in-silico prediction, not a clinical call.

HRAS p.Val109Met

c.325G>A · rs1342261234 · VCV1403670

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9206 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.9206	likely pathogenic
REVEL	0.701	pathogenic-leaning
SaProt	LLR -13.76	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	23.3	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 · 1/44,886 alleles

Overall 0.000137% 2/1,461,542 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,886
European (non-Finnish)	8.47e-05%	1,179,988

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: HRAS
Protein: p.Val109Met
Coding: c.325G>A
MANE Select: NM_005343
dbSNP: rs1342261234
Type: single nucleotide variant
Location: chr11:533578 (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.Val109Leu Uncertain significance ★ ⚠ same residue
HRAS p.Val109Ala 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-val109met (accessed [today's date]).

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