Is HRAS p.Arg68Leu (c.203G>T) pathogenic?

HRAS p.Arg68Leu (c.203G>T) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-04). AlphaMissense: likely pathogenic (0.9913); Absent from gnomAD v4.1; Associated with Costello syndrome.

What condition is associated with HRAS p.Arg68Leu (c.203G>T)?

HRAS p.Arg68Leu (c.203G>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Arg68Leu (c.203G>T) in the general population?

HRAS p.Arg68Leu (c.203G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HRAS p.Arg68Leu (c.203G>T)?

AlphaMissense predicts likely pathogenic (score 0.9913) — an in-silico prediction, not a clinical call.

HRAS p.Arg68Leu

c.203G>T · rs730880461 · VCV1021434

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9913 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.9913	likely pathogenic
REVEL	0.818	moderately pathogenic-leaning
SaProt	LLR -13.99	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 5.8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.65	unconstrained · MANE · 435 bp · p 0.0016 · regional, not allelic
Overall
CADD	23.7	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.Arg68Leu
Coding: c.203G>T
MANE Select: NM_005343
dbSNP: rs730880461
Type: single nucleotide variant
Location: chr11:533853 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 68: 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.Arg68Gln Uncertain significance ★★ ⚠ same residue
HRAS p.Arg68= Likely benign ★ same residue
HRAS p.Arg68_Asp69insGlyGlnGluGluTyrSerAlaMetArg 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

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-arg68leu (accessed [today's date]).

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