Is PAK3 p.Arg493Cys (c.1477C>T) pathogenic?

PAK3 p.Arg493Cys (c.1477C>T) is classified Uncertain significance in PAK3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-09). AlphaMissense: likely benign (0.1581); Very rare (popmax 0.00177%, sas); Associated with intellectual disability, X-linked 30.

What condition is associated with PAK3 p.Arg493Cys (c.1477C>T)?

PAK3 p.Arg493Cys (c.1477C>T) is associated with intellectual disability, X-linked 30 (ClinVar).

How common is PAK3 p.Arg493Cys (c.1477C>T) in the general population?

PAK3 p.Arg493Cys (c.1477C>T) is very rare (popmax 0.00177%, sas) (gnomAD).

What do computational predictors say about PAK3 p.Arg493Cys (c.1477C>T)?

AlphaMissense predicts likely benign (score 0.1581) — an in-silico prediction, not a clinical call.

PAK3 p.Arg493Cys

c.1477C>T · rs2094880920 · VCV3251597

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1581 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00177%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

intellectual disability, X-linked 30

Computational evidence

Protein change
AlphaMissense	0.1581	likely benign
REVEL	0.553	indeterminate
SaProt	LLR -13.49	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.81	unconstrained · MANE · 81 kb · p 2.6e-07 · regional, not allelic
Overall
CADD	29.9	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 R508C vs ClinVar R493C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00177% South Asian · 1/56,435 alleles

Overall 0.000186% 2/1,075,208 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00177%	56,435
European (non-Finnish)	0.000114%	874,546

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: PAK3
Protein: p.Arg493Cys
Coding: c.1477C>T
MANE Select: NM_001354046 · reported on NM_002578
dbSNP: rs2094880920
Type: single nucleotide variant
Location: chrX:111216490 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 493: the ph domain

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.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
PAK3 p.Arg506= 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-arg493cys (accessed [today's date]).

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