Is HRAS p.Ser136Thr (c.407G>C) pathogenic?

HRAS p.Ser136Thr (c.407G>C) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-27). AlphaMissense: likely benign (0.0904); Absent from gnomAD v4.1; Associated with Costello syndrome.

What condition is associated with HRAS p.Ser136Thr (c.407G>C)?

HRAS p.Ser136Thr (c.407G>C) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Ser136Thr (c.407G>C) in the general population?

HRAS p.Ser136Thr (c.407G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HRAS p.Ser136Thr (c.407G>C)?

AlphaMissense predicts likely benign (score 0.0904) — an in-silico prediction, not a clinical call.

HRAS p.Ser136Thr

c.407G>C · rs748289593 · VCV2705867

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0904 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.0904	likely benign
REVEL	0.313	indeterminate
SaProt	LLR -10.18	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
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 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

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.Ser136Thr
Coding: c.407G>C
MANE Select: NM_005343
dbSNP: rs748289593
Type: single nucleotide variant
Location: chr11:533496 (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.Ser136= Likely benign ★ 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-ser136thr (accessed [today's date]).

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