Is HRAS p.Pro174Ser (c.520C>T) pathogenic?

HRAS p.Pro174Ser (c.520C>T) is classified Benign in HRAS (ClinVar, Expert panel, 11 submitters; last evaluated 2017-04-18). AlphaMissense: likely benign (0.0683); Rare (popmax 0.122%, amr); Associated with RASopathy.

What condition is associated with HRAS p.Pro174Ser (c.520C>T)?

HRAS p.Pro174Ser (c.520C>T) is associated with RASopathy, urinary bladder cancer, nevus, epidermal (ClinVar).

How common is HRAS p.Pro174Ser (c.520C>T) in the general population?

HRAS p.Pro174Ser (c.520C>T) is rare (popmax 0.122%, amr) (gnomAD).

What do computational predictors say about HRAS p.Pro174Ser (c.520C>T)?

AlphaMissense predicts likely benign (score 0.0683) — an in-silico prediction, not a clinical call.

HRAS p.Pro174Ser

c.520C>T · rs397517144 · VCV40448

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.0683 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.122%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.520C>T (p.Pro174Ser) variant in the HRAS gene is 0.115% (20/11482) of Latino chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.0683	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -8.87	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 6.4, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	19.27	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 0.122% Admixed American · 73/60,008 alleles

Filtering AF 0.0992% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.091%

Overall 0.00459% 74/1,613,046 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.122%	822
European (non-Finnish)	8.47e-05%	1,179,993

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.Pro174Ser
Coding: c.520C>T
MANE Select: NM_005343
dbSNP: rs397517144
Type: single nucleotide variant
Location: chr11:532686 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 174: the 'hypervariable region' region

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

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: urinary bladder cancer nevus, epidermal linear nevus sebaceous syndrome thyroid cancer, nonmedullary, 2 Costello syndrome hereditary neoplastic syndrome large congenital melanocytic nevus

Similar variants

HRAS p.Pro174His 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
HRAS p.Thr58Ile Pathogenic ★★★ same condition
HRAS p.Gly138Ser Uncertain significance ★★★ ⚠ same condition
HRAS p.Ile93Val Uncertain significance ★★★ ⚠ 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-pro174ser (accessed [today's date]).

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