Is PAK2 p.Val269Ile (c.805G>A) pathogenic?

PAK2 p.Val269Ile (c.805G>A) is classified Uncertain significance in PAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-02). AlphaMissense: likely benign (0.0703); Very rare (popmax 0.00447%, eas).

How common is PAK2 p.Val269Ile (c.805G>A) in the general population?

PAK2 p.Val269Ile (c.805G>A) is very rare (popmax 0.00447%, eas) (gnomAD).

What do computational predictors say about PAK2 p.Val269Ile (c.805G>A)?

AlphaMissense predicts likely benign (score 0.0703) — an in-silico prediction, not a clinical call.

PAK2 p.Val269Ile

c.805G>A · VCV4564071

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00447%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0703	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -7.22	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 2.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	20.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00447% East Asian · 2/44,760 alleles

Filtering AF 0.000741% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000277%

Overall 0.000567% 9/1,588,540 alleles · very rare exomes 6/1,436,350 · genomes 3/152,190 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00447%	22,380
Admixed American	0.00167%	59,910
Remaining individualsnot grpmax-eligible	0.00162%	61,614
African / African-American	0.00134%	74,530
European (non-Finnish)	0.000346%	289,263

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: PAK2
Protein: p.Val269Ile
Coding: c.805G>A
MANE Select: NM_002577
Type: single nucleotide variant
Location: chr3:196812250 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI 0.83 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 9 PDB
Residue 269: the protein kinase domain; a turn

Full PAK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAK2 p.Asp425Asn Likely pathogenic ★ same type
PAK2 p.Gln279Pro Likely pathogenic ★ same type
PAK2 p.Ala347Thr Uncertain significance ★ same type
PAK2 p.Ala90Gly Uncertain significance ★ same type
PAK2 p.Arg104Gln Uncertain significance ★ ⚠ same type
PAK2 p.Arg186Leu Uncertain significance ★ ⚠ same type
PAK2 p.Arg350Gly Uncertain significance ★ ⚠ same type
PAK2 p.Arg524His Uncertain significance ★ ⚠ 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/pak2-p-val269ile (accessed [today's date]).

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