Is HRAS p.Asp154Val (c.461A>T) pathogenic?

HRAS p.Asp154Val (c.461A>T) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-11). AlphaMissense: ambiguous (0.5239); Very rare (popmax 0.00667%, amr); Associated with Costello syndrome.

What condition is associated with HRAS p.Asp154Val (c.461A>T)?

HRAS p.Asp154Val (c.461A>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Asp154Val (c.461A>T) in the general population?

HRAS p.Asp154Val (c.461A>T) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about HRAS p.Asp154Val (c.461A>T)?

AlphaMissense predicts ambiguous (score 0.5239) — an in-silico prediction, not a clinical call.

HRAS p.Asp154Val

c.461A>T · rs1434040739 · VCV578573

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5239 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.5239	ambiguous
REVEL	0.588	indeterminate
SaProt	LLR -13.00	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	23.7	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 0.00667% Admixed American · 4/60,010 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000248% 4/1,612,700 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.Asp154Val
Coding: c.461A>T
MANE Select: NM_005343
dbSNP: rs1434040739
Type: single nucleotide variant
Location: chr11:532745 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 154: an α-helix

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.Asp154= Likely benign ★★ same residue
HRAS p.Asp154Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
HRAS p.Asp154Tyr 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

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-asp154val (accessed [today's date]).

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