Is HRAS p.Ala155Val (c.464C>T) pathogenic?

HRAS p.Ala155Val (c.464C>T) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-31). AlphaMissense: likely pathogenic (0.8655); Very rare (popmax 8.47e-05%, nfe); Associated with Costello syndrome.

What condition is associated with HRAS p.Ala155Val (c.464C>T)?

HRAS p.Ala155Val (c.464C>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Ala155Val (c.464C>T) in the general population?

HRAS p.Ala155Val (c.464C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about HRAS p.Ala155Val (c.464C>T)?

AlphaMissense predicts likely pathogenic (score 0.8655) — an in-silico prediction, not a clinical call.

HRAS p.Ala155Val

c.464C>T · rs1269551105 · VCV964643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.8655	likely pathogenic
REVEL	0.542	indeterminate
SaProt	LLR -14.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	24.0	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 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 0.000137% 2/1,460,468 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00159%	62,708
European (non-Finnish)grpmax	8.47e-05%	1,179,997

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala155Val
Coding: c.464C>T
MANE Select: NM_005343
dbSNP: rs1269551105
Type: single nucleotide variant
Location: chr11:532742 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 155: 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.Ala155Ser 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
HRAS p.Ile93Val 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-ala155val (accessed [today's date]).

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