Is HRAS p.Ala146Pro (c.436G>C) pathogenic?

HRAS p.Ala146Pro (c.436G>C) is classified Likely pathogenic in HRAS (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-20). AlphaMissense: likely pathogenic (0.9966); Absent from gnomAD v4.1; Associated with HRAS-related disorders.

What condition is associated with HRAS p.Ala146Pro (c.436G>C)?

HRAS p.Ala146Pro (c.436G>C) is associated with HRAS-related disorders (ClinVar).

How common is HRAS p.Ala146Pro (c.436G>C) in the general population?

HRAS p.Ala146Pro (c.436G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about HRAS p.Ala146Pro (c.436G>C)?

AlphaMissense predicts likely pathogenic (score 0.9966) — an in-silico prediction, not a clinical call.

HRAS p.Ala146Pro

c.436G>C · rs104894231 · VCV4910043

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9966 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

HRAS-related disorders

Computational evidence

Protein change
AlphaMissense	0.9966	likely pathogenic ✓ concordant with ClinVar
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -14.59	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 7.5	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	23.8	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: HRAS
Protein: p.Ala146Pro
Coding: c.436G>C
MANE Select: NM_005343
dbSNP: rs104894231
Type: single nucleotide variant
Location: chr11:533467 (GRCh38)
Gene constraint: LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 92.50 · 256 PDB
Residue 146: a binding site; a UniProt-annotated variant site (in cstlo); a turn

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

Disease context

HRAS-related disorders

Similar variants

HRAS p.Ala146Val Likely pathogenic ★★ same residue
HRAS p.Ala146= Likely benign ★ same residue
HRAS p.Ala146Thr Pathogenic same residue
HRAS p.Gln22Lys Pathogenic/Likely pathogenic ★★ same condition
HRAS p.Gly12Ala Pathogenic ★★ same condition
HRAS p.Gly12Cys Pathogenic ★★ same condition
HRAS p.Gly13Arg Pathogenic/Likely pathogenic ★★ same condition
HRAS p.Gly60Ser Likely 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-ala146pro (accessed [today's date]).

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