Is PAK3 p.Pro441Thr (c.1321C>A) pathogenic?

PAK3 p.Pro441Thr (c.1321C>A) is classified Uncertain significance in PAK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-09). AlphaMissense: likely pathogenic (0.8594); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with PAK3 p.Pro441Thr (c.1321C>A)?

PAK3 p.Pro441Thr (c.1321C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PAK3 p.Pro441Thr (c.1321C>A) in the general population?

PAK3 p.Pro441Thr (c.1321C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK3 p.Pro441Thr (c.1321C>A)?

AlphaMissense predicts likely pathogenic (score 0.8594) — an in-silico prediction, not a clinical call.

PAK3 p.Pro441Thr

c.1321C>A · VCV4833245

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8594 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8594	likely pathogenic
REVEL	0.438	indeterminate
SaProt	LLR -11.99	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	Δ0.59	donor gain · deltas
Pangolin	Δ0.61	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 6	GERP 2.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 90 kb · p 0.00047 · 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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P456T vs ClinVar P441T) — 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.Pro441Thr
Coding: c.1321C>A
MANE Select: NM_002578
Type: single nucleotide variant
Location: chrX:111196554 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 456 UniProt numbering: a turn

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PAK3 p.Pro441Leu Uncertain significance ★ ⚠ same residue
PAK3 p.Pro441= Likely benign ★★ same residue
PAK3 p.Arg436Ter Pathogenic/Likely pathogenic ★★ same condition
PAK3 c.830+6T>A Uncertain significance ★★ same condition
PAK3 c.276+2659T>C Benign/Likely benign ★★ same condition
PAK3 p.Ala161= Benign/Likely benign ★★ same condition
PAK3 p.Asn236Ser Likely benign ★★ same condition
PAK3 p.Gly4Ser 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-pro441thr (accessed [today's date]).

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