Is HRAS p.Pro110Leu (c.329C>T) pathogenic?

HRAS p.Pro110Leu (c.329C>T) is classified Uncertain significance in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-14). AlphaMissense: likely pathogenic (0.9907); Very rare (popmax 0.000169%, nfe); Associated with Costello syndrome.

What condition is associated with HRAS p.Pro110Leu (c.329C>T)?

HRAS p.Pro110Leu (c.329C>T) is associated with Costello syndrome (ClinVar).

How common is HRAS p.Pro110Leu (c.329C>T) in the general population?

HRAS p.Pro110Leu (c.329C>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about HRAS p.Pro110Leu (c.329C>T)?

AlphaMissense predicts likely pathogenic (score 0.9907) — an in-silico prediction, not a clinical call.

HRAS p.Pro110Leu

c.329C>T · rs1204223913 · VCV1063136

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Costello syndrome

Computational evidence

Protein change
AlphaMissense	0.9907	likely pathogenic
REVEL	0.837	moderately pathogenic-leaning
SaProt	LLR -17.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,006 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,613,752 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.Pro110Leu
Coding: c.329C>T
MANE Select: NM_005343
dbSNP: rs1204223913
Type: single nucleotide variant
Location: chr11:533574 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB

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.Pro110= 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
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-pro110leu (accessed [today's date]).

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