Is HRAS p.Arg164Pro (c.491G>C) pathogenic?

HRAS p.Arg164Pro (c.491G>C) is classified Uncertain significance in HRAS (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-05-01). AlphaMissense: likely pathogenic (0.9978); Very rare (popmax 0.005%, amr); Associated with linear nevus sebaceous syndrome.

What condition is associated with HRAS p.Arg164Pro (c.491G>C)?

HRAS p.Arg164Pro (c.491G>C) is associated with linear nevus sebaceous syndrome, urinary bladder cancer, nevus, epidermal (ClinVar).

How common is HRAS p.Arg164Pro (c.491G>C) in the general population?

HRAS p.Arg164Pro (c.491G>C) is very rare (popmax 0.005%, amr) (gnomAD).

How is Linear nevus sebaceus syndrome inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about HRAS p.Arg164Pro (c.491G>C)?

AlphaMissense predicts likely pathogenic (score 0.9978) — an in-silico prediction, not a clinical call.

HRAS p.Arg164Pro

c.491G>C · rs753977266 · VCV850426

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

linear nevus sebaceous syndrome

Computational evidence

Protein change
AlphaMissense	0.9978	likely pathogenic
REVEL	0.716	pathogenic-leaning
SaProt	LLR -18.11	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 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	25.4	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 0.005% Admixed American · 3/60,004 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000372% 6/1,613,062 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	20,001
European (non-Finnish)	0.000254%	393,337

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.Arg164Pro
Coding: c.491G>C
MANE Select: NM_005343
dbSNP: rs753977266
Type: single nucleotide variant
Location: chr11:532715 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 164: an α-helix

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

Disease context

linear nevus sebaceous syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: urinary bladder cancer nevus, epidermal thyroid cancer, nonmedullary, 2 Costello syndrome large congenital melanocytic nevus

For Linear nevus sebaceus syndrome (Orphanet):

Inheritance: Not applicable
Onset: Childhood, Infancy, Neonatal

Similar variants

HRAS p.Arg164Trp Uncertain significance ★★ ⚠ same residue
HRAS p.Arg164= Likely benign ★★ same residue
HRAS p.Arg164Gln Conflicting classifications of pathogenicity ★ ⚠ 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-arg164pro (accessed [today's date]).

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