Is KRAS p.Gln25Arg (c.74A>G) pathogenic?

KRAS p.Gln25Arg (c.74A>G) is classified Uncertain significance in KRAS (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.8662); Very rare (popmax 8.48e-05%, nfe).

How common is KRAS p.Gln25Arg (c.74A>G) in the general population?

KRAS p.Gln25Arg (c.74A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about KRAS p.Gln25Arg (c.74A>G)?

AlphaMissense predicts likely pathogenic (score 0.8662) — an in-silico prediction, not a clinical call.

KRAS p.Gln25Arg

c.74A>G · rs2135805919 · VCV1050562

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8662 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8662	likely pathogenic
REVEL	0.689	pathogenic-leaning
SaProt	LLR -12.88	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	26.8	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 8.48e-05% European (non-Finnish) · 1/1,178,968 alleles

Overall 6.85e-05% 1/1,459,966 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: KRAS
Protein: p.Gln25Arg
Coding: c.74A>G
MANE Select: NM_004985
dbSNP: rs2135805919
Type: single nucleotide variant
Location: chr12:25245311 (GRCh38)
Gene constraint: LOEUF 0.264 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 91.65 · 549 PDB
Residue 25: an α-helix

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

Similar variants

KRAS p.Gln25= Likely benign ★ same residue
KRAS p.Gln25Leu Uncertain significance ⚠ same residue
KRAS p.Gln25_Asn26del Uncertain significance same residue
KRAS p.Asp153Val Pathogenic ★★★ same type
KRAS p.Gln22Arg Pathogenic ★★★ same type
KRAS p.Gly60Arg Pathogenic ★★★ same type
KRAS p.Lys5Asn Pathogenic ★★★ same type
KRAS p.Pro34Leu Pathogenic ★★★ same type

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-gln25arg (accessed [today's date]).

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