Is HRAS p.Ile93= (c.279C>T) pathogenic?

HRAS p.Ile93= (c.279C>T) is classified Likely benign in HRAS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-07). Ultra-rare (popmax 0.0165%, mid); Associated with Costello syndrome.

What condition is associated with HRAS p.Ile93= (c.279C>T)?

HRAS p.Ile93= (c.279C>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Ile93= (c.279C>T) in the general population?

HRAS p.Ile93= (c.279C>T) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

HRAS p.Ile93=

c.279C>T · rs2133989886 · VCV1109487

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Conditions

Costello syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 1.3	GERP -3.7, phastCons 1
Overall
CADD	5.881	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0165% Middle Eastern · 1/6,062 alleles

Overall 0.000186% 3/1,613,310 alleles · ultra-rare exomes 3/1,461,046 · genomes 0/152,264 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0165%	6,062
East Asian	0.00223%	44,874
European (non-Finnish)	8.47e-05%	1,179,993

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.Ile93=
Coding: c.279C>T
MANE Select: NM_005343
dbSNP: rs2133989886
Type: single nucleotide variant
Location: chr11:533777 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 93: 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.Ile93Val Uncertain significance ★★★ ⚠ same residue
HRAS p.Ile93Thr 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
HRAS p.Gly138Ser Uncertain significance ★★★ ⚠ 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-ile93 (accessed [today's date]).

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