Is KRAS p.Gln22Arg (c.65A>G) pathogenic?

KRAS p.Gln22Arg (c.65A>G) is classified Pathogenic in KRAS (ClinVar, Expert panel, 13 submitters; last evaluated 2024-12-03). AlphaMissense: likely pathogenic (0.9015); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with KRAS p.Gln22Arg (c.65A>G)?

KRAS p.Gln22Arg (c.65A>G) is associated with RASopathy, gastric cancer, urinary bladder cancer (ClinVar).

How common is KRAS p.Gln22Arg (c.65A>G) in the general population?

KRAS p.Gln22Arg (c.65A>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about KRAS p.Gln22Arg (c.65A>G)?

AlphaMissense predicts likely pathogenic (score 0.9015) — an in-silico prediction, not a clinical call.

KRAS p.Gln22Arg

c.65A>G · rs727503110 · VCV40452

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.9015 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Pathogenic for RASopathy. Applied ACMG criteria (verbatim):

PM6_VeryStrong PM2_Supporting PS3_Supporting PS4 PP2 PP3

Curation rationale (ClinGen, verbatim)

The c.65A>G variant in the KRAS gene is a missense variant predicted to cause substitution of glutamine by arginine at amino acid 22 (p.Glln22Arg). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.749 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 several individuals with clinical features of a RASopathy, with 2 unconfirmed de novo occurrences (PS4, PM6_VeryStrong; GeneDx, Partners LMM, HudsonAlpha Institute for Biotechnology, Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago, ARUP Laboratories, Molecular Genetics and Genomics; ClinVar: SCV000207881.10; SCV000198473.4; SCV001870321.1; SCV000678231.1; SCV000604082.1). In vitro functional studies showed that this variant enhanced ERK activation (PS3_Supporting; PMID: 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: PM6_VeryStrong, PS4, PS3_Supporting, 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
AlphaMissense	0.9015	likely pathogenic ✓ concordant with ClinVar
REVEL	0.749	pathogenic-leaning
SaProt	LLR -11.77	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 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 20 kb · p 1.6e-16 · regional, not allelic
Overall
CADD	26.4	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: KRAS
Protein: p.Gln22Arg
Coding: c.65A>G
MANE Select: NM_004985
dbSNP: rs727503110
Type: single nucleotide variant
Location: chr12:25245320 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB
Residue 22: a UniProt-annotated variant site (in cfc2; exhibits an increase in intrinsic and guanine nucleotide exchange factor catalyzed nucleotide exchange in combination with an impaired gtpase-activating protein-stimulated gtp hydrolysis but functional in interaction with effectors); a UniProt-annotated variant site (in ns3; impairs gtpase-activating protein stimulated gtp hydrolysis with unaffected intrinsic functions and a virtually functional effector interaction); an α-helix

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: gastric cancer urinary bladder cancer arteriovenous malformations of the brain linear nevus sebaceous syndrome lung cancer Toriello-Lacassie-Droste syndrome Noonan syndrome 3 autoimmune lymphoproliferative syndrome type 4 cardiofaciocutaneous syndrome 2 familial pancreatic carcinoma hereditary breast carcinoma acute myeloid leukemia Noonan syndrome

Similar variants

KRAS p.Gln22Glu Pathogenic ★★ same residue
KRAS p.Gln22Lys Pathogenic/Likely pathogenic ★★ same residue
KRAS p.Gln22= Likely benign ★★ same residue
KRAS p.Gln22Leu Likely pathogenic ★ same residue
KRAS p.Gln22Pro Uncertain significance ⚠ same residue
KRAS p.Asp153Val Pathogenic ★★★ same condition
KRAS p.Gly60Arg Pathogenic ★★★ same condition
KRAS p.Lys5Asn 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-gln22arg (accessed [today's date]).

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