Is HRAS p.Ser65Arg (c.195C>G) pathogenic?

HRAS p.Ser65Arg (c.195C>G) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-20). AlphaMissense: likely pathogenic (0.9896); Absent from gnomAD v4.1.

How common is HRAS p.Ser65Arg (c.195C>G) in the general population?

HRAS p.Ser65Arg (c.195C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HRAS p.Ser65Arg (c.195C>G)?

AlphaMissense predicts likely pathogenic (score 0.9896) — an in-silico prediction, not a clinical call.

HRAS p.Ser65Arg

c.195C>G · VCV3361451

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9896 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9896	likely pathogenic
REVEL	0.54	indeterminate
SaProt	LLR -13.02	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 -2.8	GERP -3.1
Regional constraint	o/e 0.65	unconstrained · MANE · 435 bp · p 0.0016 · regional, not allelic
Overall
CADD	17.6	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HRAS
Protein: p.Ser65Arg
Coding: c.195C>G
MANE Select: NM_005343
Type: single nucleotide variant
Location: chr11:533861 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB

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

Similar variants

HRAS p.Ser65Asn Uncertain significance ★★ ⚠ same residue
HRAS p.Ser65= Likely benign ★ same residue
HRAS p.Ala59Thr Likely pathogenic ★★★ same type
HRAS p.Gly12Ser Pathogenic ★★★ same type
HRAS p.Gly13Cys Pathogenic ★★★ same type
HRAS p.Lys117Arg Pathogenic ★★★ same type
HRAS p.Thr58Ile Pathogenic ★★★ same type
HRAS p.Gly138Ser Uncertain significance ★★★ ⚠ same type

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-ser65arg (accessed [today's date]).

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