Is PAK5 p.Arg656Trp (c.1966C>T) pathogenic?

PAK5 p.Arg656Trp (c.1966C>T) is classified Uncertain significance in PAK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.9911); Very rare (popmax 0.00223%, eas).

How common is PAK5 p.Arg656Trp (c.1966C>T) in the general population?

PAK5 p.Arg656Trp (c.1966C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about PAK5 p.Arg656Trp (c.1966C>T)?

AlphaMissense predicts likely pathogenic (score 0.9911) — an in-silico prediction, not a clinical call.

PAK5 p.Arg656Trp

c.1966C>T · VCV3927404

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9911 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9911	likely pathogenic
REVEL	0.62	indeterminate
SaProt	LLR -18.26	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,217 bp · p 0.8 · regional, not allelic
Overall
CADD	33.0	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 0.00223% East Asian · 1/44,882 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000806% 13/1,613,794 alleles · very rare exomes 12/1,461,696 · genomes 1/152,098 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,882
European (non-Finnish)	0.00102%	98,323

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: PAK5
Protein: p.Arg656Trp
Coding: c.1966C>T
MANE Select: NM_177990
Type: single nucleotide variant
Location: chr20:9542624 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 2 PDB
Residue 656: the protein kinase domain; an α-helix

Full PAK5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PAK5 p.Leu490= Benign ★★ same type
PAK5 p.Leu603= Benign ★★ same type
PAK5 p.Lys216= Benign ★★ same type
PAK5 p.Tyr333= Benign ★★ same type
PAK5 p.Ala120Gly Uncertain significance ★ ⚠ same type
PAK5 p.Ala120Val Uncertain significance ★ ⚠ same type
PAK5 p.Ala251Val Uncertain significance ★ ⚠ same type
PAK5 p.Ala303Thr 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/pak5-p-arg656trp (accessed [today's date]).

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