Is HRAS p.Ser136= (c.408C>T) pathogenic?

HRAS p.Ser136= (c.408C>T) is classified Likely benign in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-22). Absent from gnomAD v4.1; Associated with Costello syndrome.

What condition is associated with HRAS p.Ser136= (c.408C>T)?

HRAS p.Ser136= (c.408C>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Ser136= (c.408C>T) in the general population?

HRAS p.Ser136= (c.408C>T) is absent from gnomAD v4.1 (gnomAD).

HRAS p.Ser136=

c.408C>T · rs2133986691 · VCV1655381

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

Costello syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.92 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	GERP -3.7, phastCons 1
Overall
CADD	7.618	PHRED · no single calibrated threshold — expert panels disagree

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.Ser136=
Coding: c.408C>T
MANE Select: NM_005343
dbSNP: rs2133986691
Type: single nucleotide variant
Location: chr11:533495 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 136: 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.Ser136Asn Uncertain significance ★ ⚠ same residue
HRAS p.Ser136Gly Uncertain significance ★ ⚠ same residue
HRAS p.Ser136Thr Uncertain significance ★ ⚠ same residue
HRAS p.Ser136fs 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

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-ser136 (accessed [today's date]).

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