Is PAK2 p.Asp229Val (c.686A>T) pathogenic?

PAK2 p.Asp229Val (c.686A>T) is classified Uncertain significance in PAK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.9886); Very rare (popmax 8.61e-05%, nfe).

How common is PAK2 p.Asp229Val (c.686A>T) in the general population?

PAK2 p.Asp229Val (c.686A>T) is very rare (popmax 8.61e-05%, nfe) (gnomAD).

What do computational predictors say about PAK2 p.Asp229Val (c.686A>T)?

AlphaMissense predicts likely pathogenic (score 0.9886) — an in-silico prediction, not a clinical call.

PAK2 p.Asp229Val

c.686A>T · VCV3927382

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9886 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.61e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9886	likely pathogenic
REVEL	0.635	indeterminate
SaProt	LLR -14.30	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>G here scores Δ0.82 · evaluated, not missing
Constraint at this position
Conservation	phyloP 11	GERP 2.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 5.6e-05 · regional, not allelic
Overall
CADD	26.5	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 8.61e-05% European (non-Finnish) · 1/1,161,782 alleles

Overall 6.27e-05% 1/1,593,696 alleles · very rare exomes 1/1,441,354 · genomes 0/152,342 · joint denominator

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.Asp229Val
Coding: c.686A>T
MANE Select: NM_002577
Type: single nucleotide variant
Location: chr3:196807891 (GRCh38)
Gene constraint: LOEUF 0.662 · pLI 0.83 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 75.06 · 9 PDB

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-asp229val (accessed [today's date]).

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