Is HRAS p.Val45Ile (c.133G>A) pathogenic?

HRAS p.Val45Ile (c.133G>A) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-22). AlphaMissense: likely benign (0.1526); Very rare (popmax 0.0011%, sas); Associated with Costello syndrome.

What condition is associated with HRAS p.Val45Ile (c.133G>A)?

HRAS p.Val45Ile (c.133G>A) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Val45Ile (c.133G>A) in the general population?

HRAS p.Val45Ile (c.133G>A) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about HRAS p.Val45Ile (c.133G>A)?

AlphaMissense predicts likely benign (score 0.1526) — an in-silico prediction, not a clinical call.

HRAS p.Val45Ile

c.133G>A · rs1564789708 · VCV842180

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1526 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.1526	likely benign
REVEL	0.301	indeterminate
SaProt	LLR -11.05	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 435 bp · p 0.0016 · regional, not allelic
Overall
CADD	23.2	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 0.0011% South Asian · 1/91,078 alleles

Overall 6.85e-05% 1/1,460,154 alleles · very rare

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.Val45Ile
Coding: c.133G>A
MANE Select: NM_005343
dbSNP: rs1564789708
Type: single nucleotide variant
Location: chr11:533923 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 45: a β-strand

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.Val45Asp Uncertain significance ★★ ⚠ same residue
HRAS p.Val45= Likely benign ★★ 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-val45ile (accessed [today's date]).

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