Is PAK5 p.Arg662Ser (c.1986A>C) pathogenic?

PAK5 p.Arg662Ser (c.1986A>C) is classified Uncertain significance in PAK5 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-24). AlphaMissense: likely pathogenic (0.5744); Ultra-rare (popmax 0.0165%, mid).

How common is PAK5 p.Arg662Ser (c.1986A>C) in the general population?

PAK5 p.Arg662Ser (c.1986A>C) is ultra-rare (popmax 0.0165%, mid) (gnomAD).

What do computational predictors say about PAK5 p.Arg662Ser (c.1986A>C)?

AlphaMissense predicts likely pathogenic (score 0.5744) — an in-silico prediction, not a clinical call.

PAK5 p.Arg662Ser

c.1986A>C · VCV4564096

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5744 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0165%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5744	likely pathogenic
REVEL	0.288	benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.5	GERP -1.9, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 3,217 bp · p 0.8 · regional, not allelic
Overall
CADD	25.7	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

Grpmax group 0.0165% Middle Eastern · 1/6,060 alleles

Overall 6.2e-05% 1/1,614,012 alleles · ultra-rare exomes 1/1,461,852 · genomes 0/152,160 · 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: PAK5
Protein: p.Arg662Ser
Coding: c.1986A>C
MANE Select: NM_177990
Type: single nucleotide variant
Location: chr20:9542604 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 63.09 · 2 PDB
Residue 662: the protein kinase domain

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-arg662ser (accessed [today's date]).

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