Is HRAS p.Arg161His (c.482G>A) pathogenic?

HRAS p.Arg161His (c.482G>A) is classified Uncertain significance in HRAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-10). AlphaMissense: likely pathogenic (0.8199); Very rare (popmax 0.00668%, eas); Associated with Cardiovascular phenotype.

What condition is associated with HRAS p.Arg161His (c.482G>A)?

HRAS p.Arg161His (c.482G>A) is associated with Cardiovascular phenotype, Costello syndrome (ClinVar).

How common is HRAS p.Arg161His (c.482G>A) in the general population?

HRAS p.Arg161His (c.482G>A) is very rare (popmax 0.00668%, eas) (gnomAD).

What do computational predictors say about HRAS p.Arg161His (c.482G>A)?

AlphaMissense predicts likely pathogenic (score 0.8199) — an in-silico prediction, not a clinical call.

HRAS p.Arg161His

c.482G>A · rs748729430 · VCV517437

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.8199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00668%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8199	likely pathogenic
REVEL	0.596	indeterminate
SaProt	LLR -13.96	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	24.6	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 0.00668% East Asian · 3/44,894 alleles

Filtering AF 0.00177% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000744% 12/1,612,994 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00668%	14,965
Remaining individualsnot grpmax-eligible	0.0032%	31,234
European (non-Finnish)	0.000593%	168,572

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.Arg161His
Coding: c.482G>A
MANE Select: NM_005343
dbSNP: rs748729430
Type: single nucleotide variant
Location: chr11:532724 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 161: an α-helix

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Costello syndrome

Similar variants

HRAS p.Arg161Cys Uncertain significance ★★ ⚠ same residue
HRAS p.Gly161Arg Conflicting classifications of pathogenicity ★ same residue
HRAS p.Arg161= Likely benign ★ same residue
HRAS p.Arg161_Lys170del Uncertain significance ★ same residue
HRAS p.Arg161Gly Uncertain significance ★ ⚠ same residue
HRAS p.Ala59Thr Likely pathogenic ★★★ same condition
HRAS p.Gly12Ser Pathogenic ★★★ same condition
HRAS p.Gly13Cys 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-arg161his (accessed [today's date]).

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