Is HRAS p.Thr35fs (c.102del) pathogenic?

HRAS p.Thr35fs (c.102del) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-22). Associated with Costello syndrome.

What condition is associated with HRAS p.Thr35fs (c.102del)?

HRAS p.Thr35fs (c.102del) is associated with Costello syndrome (ClinVar).

HRAS p.Thr35fs

c.102del · VCV4737610

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Costello syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 2 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: HRAS
Protein: p.Thr35fs
Coding: c.102del
MANE Select: NM_005343
Type: Deletion
Location: chr11:534221 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 35: an α-helix; a binding site

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.Thr35= Likely benign ★ same residue
HRAS p.Leu163fs Pathogenic/Likely pathogenic ★★ same condition
HRAS p.Gly60fs Uncertain significance ★★ same condition
HRAS c.110_111+5del Uncertain significance ★ same condition
HRAS c.112-59_*6-51del Uncertain significance ★ same condition
HRAS c.450+6del Uncertain significance ★ same condition
HRAS p.Arg149fs Uncertain significance ★ same condition
HRAS p.Arg161_Lys170del 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-thr35fs (accessed [today's date]).

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