Is HRAS p.Thr158= (c.474G>C) pathogenic?

HRAS p.Thr158= (c.474G>C) is classified Likely benign in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-09). Very rare (popmax 0.000342%); Associated with Costello syndrome.

What condition is associated with HRAS p.Thr158= (c.474G>C)?

HRAS p.Thr158= (c.474G>C) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Thr158= (c.474G>C) in the general population?

HRAS p.Thr158= (c.474G>C) is very rare (popmax 0.000342%) (gnomAD).

HRAS p.Thr158=

c.474G>C · rs747269683 · VCV2884864

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000342%)

Conditions

Costello syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -3.7
Overall
CADD	0.501	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000342%

Overall 0.000342% 5/1,460,714 alleles · very rare

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.Thr158=
Coding: c.474G>C
MANE Select: NM_005343
dbSNP: rs747269683
Type: single nucleotide variant
Location: chr11:532732 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 158: 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.Thr158Met Uncertain significance ★★ ⚠ same residue
HRAS p.Thr158Arg Uncertain significance ★ same residue
HRAS p.Thr158Lys Uncertain significance ★ same residue
HRAS p.Thr158fs Conflicting classifications of pathogenicity ★ same residue
HRAS p.Ser158Ala Likely benign ★ 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-thr158 (accessed [today's date]).

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