Is HRAS p.Pro140Ser (c.418C>T) pathogenic?

HRAS p.Pro140Ser (c.418C>T) is classified Conflicting classifications of pathogenicity in HRAS (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2026-05-23). AlphaMissense: ambiguous (0.5183); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with HRAS p.Pro140Ser (c.418C>T)?

HRAS p.Pro140Ser (c.418C>T) is associated with Cardiovascular phenotype, Costello syndrome (ClinVar).

How common is HRAS p.Pro140Ser (c.418C>T) in the general population?

HRAS p.Pro140Ser (c.418C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about HRAS p.Pro140Ser (c.418C>T)?

AlphaMissense predicts ambiguous (score 0.5183) — an in-silico prediction, not a clinical call.

HRAS p.Pro140Ser

c.418C>T · rs144001095 · VCV177861

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5183 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5183	ambiguous
REVEL	0.592	indeterminate
SaProt	LLR -10.29	damaging
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.4	GERP 1.9, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,164 bp · p 0.94 · regional, not allelic
Overall
CADD	23.1	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 0.0011% South Asian · 1/91,080 alleles

Overall 0.000274% 4/1,461,284 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
South Asiangrpmax	0.0011%	91,080
European (non-Finnish)	8.47e-05%	1,179,972

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro140Ser
Coding: c.418C>T
MANE Select: NM_198075 · reported on NM_005343
dbSNP: rs144001095
Type: single nucleotide variant
Location: chr11:533485 (GRCh38)

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

Disease context

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

Also linked: Costello syndrome

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-pro140ser (accessed [today's date]).

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