Is PAK3 p.Trp428Arg (c.1282T>A) pathogenic?

PAK3 p.Trp428Arg (c.1282T>A) is classified Likely pathogenic in PAK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-12-10). AlphaMissense: likely pathogenic (1); Absent from gnomAD v4.1; Associated with intellectual disability, X-linked 30.

What condition is associated with PAK3 p.Trp428Arg (c.1282T>A)?

PAK3 p.Trp428Arg (c.1282T>A) is associated with intellectual disability, X-linked 30 (ClinVar).

How common is PAK3 p.Trp428Arg (c.1282T>A) in the general population?

PAK3 p.Trp428Arg (c.1282T>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK3 p.Trp428Arg (c.1282T>A)?

AlphaMissense predicts likely pathogenic (score 1) — an in-silico prediction, not a clinical call.

PAK3 p.Trp428Arg

c.1282T>A · rs1603378331 · VCV633605

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

1 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

intellectual disability, X-linked 30

Computational evidence

Protein change
AlphaMissense	1	likely pathogenic ✓ concordant with ClinVar · top 1% in PAK3
REVEL	0.776	moderately pathogenic-leaning
SaProt	LLR -15.49	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 2.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 90 kb · p 0.00047 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM W443R vs ClinVar W428R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PAK3
Protein: p.Trp428Arg
Coding: c.1282T>A
MANE Select: NM_002578
dbSNP: rs1603378331
Type: single nucleotide variant
Location: chrX:111196515 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 443 UniProt numbering: the dh domain; an α-helix

Full PAK3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

intellectual disability, X-linked 30 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAK3 p.Arg100Ter Pathogenic/Likely pathogenic ★★ same condition
PAK3 p.Arg436Ter Pathogenic/Likely pathogenic ★★ same condition
PAK3 p.Glu356Ter Pathogenic/Likely pathogenic ★★ same condition
PAK3 p.Arg493Cys Uncertain significance ★★ ⚠ same condition
PAK3 p.Gly262= Uncertain significance ★★ same condition
PAK3 p.Gly335Asp Uncertain significance ★★ ⚠ same condition
PAK3 c.431-26A>G Benign ★★ same condition
PAK3 p.Ala161= Benign/Likely benign ★★ same condition

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/pak3-p-trp428arg (accessed [today's date]).

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