Is HRAS p.Pro169fs (c.500dup) pathogenic?

HRAS p.Pro169fs (c.500dup) is classified Conflicting classifications of pathogenicity in HRAS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-01). Very rare (popmax 0.00764%, nfe); Associated with congenital fibrosis of extraocular muscles.

What condition is associated with HRAS p.Pro169fs (c.500dup)?

HRAS p.Pro169fs (c.500dup) is associated with congenital fibrosis of extraocular muscles, Costello syndrome (ClinVar).

How common is HRAS p.Pro169fs (c.500dup) in the general population?

HRAS p.Pro169fs (c.500dup) is very rare (popmax 0.00764%, nfe) (gnomAD).

How is Congenital fibrosis of extraocular muscles inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

HRAS p.Pro169fs

c.500dup · rs35613389 · VCV522672

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00764%, nfe)

Conditions

congenital fibrosis of extraocular muscles

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP 0.98, phastCons 0.67
Overall
CADD	19.05	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00764% European (non-Finnish) · 90/1,178,650 alleles

Filtering AF 0.00632% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00585%

Overall 0.00631% 101/1,600,628 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00764%	13,096
Admixed American	0.0067%	14,932
Remaining individualsnot grpmax-eligible	0.00643%	15,543
East Asian	0.00447%	22,350
South Asian	0.0011%	90,772

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.Pro169fs
Coding: c.500dup
MANE Select: NM_005343 · reported on NM_176795
dbSNP: rs35613389
Type: Duplication
Location: chr11:533308 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 169: the 'hypervariable region' region

Full HRAS gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital fibrosis of extraocular muscles — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Costello syndrome

For Congenital fibrosis of extraocular muscles (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: Neonatal
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

HRAS p.Arg169Trp Uncertain significance ★★ same residue
HRAS p.Arg169Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
HRAS p.Arg169Leu Uncertain significance ★ ⚠ same residue
HRAS p.Glu63_Asp69dup Likely pathogenic ★★ same condition
HRAS p.Glu37fs Uncertain significance ★★ same condition
HRAS p.Arg73_Thr74insAspGlnTyrMetArg Likely pathogenic ★ same condition
HRAS p.Asp57_Gln61dup Likely pathogenic ★ same condition
HRAS p.Glu62_Arg68dup 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-pro169fs (accessed [today's date]).

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