Is KRAS p.Asp153Val (c.458A>T) pathogenic?

KRAS p.Asp153Val (c.458A>T) is classified Pathogenic in KRAS (ClinVar, Expert panel, 18 submitters; last evaluated 2024-12-03). Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with KRAS p.Asp153Val (c.458A>T)?

KRAS p.Asp153Val (c.458A>T) is associated with RASopathy, urinary bladder cancer, lung carcinoma (ClinVar).

How common is KRAS p.Asp153Val (c.458A>T) in the general population?

KRAS p.Asp153Val (c.458A>T) is absent from gnomAD v4.1 (gnomAD).

KRAS p.Asp153Val

c.458A>T · rs104894360 · VCV12587

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 18 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Pathogenic for RASopathy. Applied ACMG criteria (verbatim):

PS2_VeryStrong PM2_Supporting PS3_Moderate PS4 PP2 PP3

Curation rationale (ClinGen, verbatim)

The c.458A>T variant in the KRAS gene is a missense variant predicted to cause substitution of asparagine by valine at amino acid 153 (p.Asp153Val). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.791 supporting a deleterious impact to KRAS function (PP3). The variant is located in the KRAS gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2). This variant has been reported in at least 6 individuals with four confirmed de novo occurrences with clinical features of a RASopathy (PS4, PS2_VeryStrong; PMIDs: 16474405, 16474404, 21062266, 21871821, 24703799, 16773572). In vitro functional studies showed that this variant enhanced RAS/MEK/ERK activation (PS3_Moderate; PMID: 17875937, 20949621). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4, PS3_Moderate, PM2_Supporting, PP2, PP3 (Specification Version 2.3, 12/3/2024)

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

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.791	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 16 kb · p 0.056 · regional, not allelic
Overall
CADD	27.7	PHRED · no single calibrated threshold — expert panels disagree

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: KRAS
Protein: p.Asp153Val
Coding: c.458A>T
MANE Select: NM_004985
dbSNP: rs104894360
Type: single nucleotide variant
Location: chr12:25209904 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB
Residue 153: an α-helix; a UniProt-annotated variant site (in cfc2 and ns3; exhibits only minor alterations in its in vitro biochemical behavior compared to wild-type protein)

Full KRAS 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 lung carcinoma exocrine pancreatic carcinoma arteriovenous malformations of the brain hereditary diffuse gastric adenocarcinoma linear nevus sebaceous syndrome Noonan syndrome 1 Noonan syndrome 3 autoimmune lymphoproliferative syndrome type 4 cardiofaciocutaneous syndrome 2 cardiofaciocutaneous syndrome hereditary breast carcinoma acute myeloid leukemia Noonan syndrome

Similar variants

KRAS p.Asp153Gly Pathogenic/Likely pathogenic ★★ same residue
KRAS p.Asp153His Likely pathogenic ★ same residue
KRAS p.Glu153Ala Likely pathogenic same residue
KRAS p.Gln22Arg Pathogenic ★★★ same condition
KRAS p.Gly60Arg Pathogenic ★★★ same condition
KRAS p.Lys5Asn Pathogenic ★★★ same condition
KRAS p.Pro34Leu Pathogenic ★★★ same condition
KRAS p.Ser65Ile 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/kras-p-asp153val (accessed [today's date]).

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