Is HRAS p.Ser136fs (c.401_402insAAGACCTCGC) pathogenic?

HRAS p.Ser136fs (c.401402insAAGACCTCGC) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-23). Very rare (popmax 8.47e-05%, nfe); Associated with Costello syndrome.

What condition is associated with HRAS p.Ser136fs (c.401_402insAAGACCTCGC)?

HRAS p.Ser136fs (c.401_402insAAGACCTCGC) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Ser136fs (c.401_402insAAGACCTCGC) in the general population?

HRAS p.Ser136fs (c.401_402insAAGACCTCGC) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

HRAS p.Ser136fs

c.401_402insAAGACCTCGC · rs780297433 · VCV2036547

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

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 4 of 6
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.2	GERP -0.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,982 alleles

Overall 6.84e-05% 1/1,461,342 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.Ser136fs
Coding: c.401_402insAAGACCTCGC
MANE Select: NM_005343
dbSNP: rs780297433
Type: Insertion
Location: chr11:533501 (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.Ser136= Likely benign ★ 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-ser136fs (accessed [today's date]).

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