Is HRAS p.Arg169Trp (c.505C>T) pathogenic?

HRAS p.Arg169Trp (c.505C>T) is classified Uncertain significance in HRAS (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-25). AlphaMissense: ambiguous (0.3701); Very rare (popmax 0.00559%, nfe); Associated with thyroid cancer, nonmedullary, 2.

What condition is associated with HRAS p.Arg169Trp (c.505C>T)?

HRAS p.Arg169Trp (c.505C>T) is associated with thyroid cancer, nonmedullary, 2, urinary bladder cancer, nevus, epidermal (ClinVar).

How common is HRAS p.Arg169Trp (c.505C>T) in the general population?

HRAS p.Arg169Trp (c.505C>T) is very rare (popmax 0.00559%, nfe) (gnomAD).

What do computational predictors say about HRAS p.Arg169Trp (c.505C>T)?

AlphaMissense predicts ambiguous (score 0.3701) — an in-silico prediction, not a clinical call.

HRAS p.Arg169Trp

Q: How is Familial papillary or follicular thyroid carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.505C>T · rs151229168 · VCV177918

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3701 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00559%, nfe)

Conditions

thyroid cancer, nonmedullary, 2

Computational evidence

Protein change
AlphaMissense	0.3701	ambiguous
REVEL	0.357	indeterminate
SaProt	LLR -13.26	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 5.5, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	23.7	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

Grpmax group 0.00559% European (non-Finnish) · 66/1,179,972 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00422% 68/1,613,016 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00559%	17,878
Remaining individualsnot grpmax-eligible	0.0016%	62,462
South Asian	0.0011%	91,092

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.Arg169Trp
Coding: c.505C>T
MANE Select: NM_005343
dbSNP: rs151229168
Type: single nucleotide variant
Location: chr11:532701 (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

thyroid cancer, nonmedullary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: urinary bladder cancer nevus, epidermal linear nevus sebaceous syndrome Costello syndrome large congenital melanocytic nevus

For Familial papillary or follicular thyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult

Similar variants

HRAS p.Arg169Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
HRAS p.Arg169Leu Uncertain significance ★ ⚠ same residue
HRAS p.Pro169fs Conflicting classifications of pathogenicity ★ 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
HRAS p.Thr58Ile 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-arg169trp (accessed [today's date]).

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