Is PAK3 p.Val443Phe (c.1327G>T) pathogenic?

PAK3 p.Val443Phe (c.1327G>T) is classified Uncertain significance in PAK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-23). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1.

How common is PAK3 p.Val443Phe (c.1327G>T) in the general population?

PAK3 p.Val443Phe (c.1327G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PAK3 p.Val443Phe (c.1327G>T)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

PAK3 p.Val443Phe

c.1327G>T · VCV3391468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic · top 1% in PAK3
REVEL	0.648	pathogenic-leaning
SaProt	LLR -15.38	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 90 kb · p 0.00047 · regional, not allelic
Overall
CADD	32.0	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 V458F vs ClinVar V443F) — 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.Val443Phe
Coding: c.1327G>T
MANE Select: NM_002578
Type: single nucleotide variant
Location: chrX:111196560 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB

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

Similar variants

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PAK3 p.Glu356Ter Pathogenic/Likely pathogenic ★★ same type
PAK3 c.830+6T>A Uncertain significance ★★ same type
PAK3 p.Ala490Thr Uncertain significance ★★ ⚠ same type
PAK3 p.Arg493Cys Uncertain significance ★★ ⚠ same type
PAK3 p.Arg498Cys Uncertain significance ★★ ⚠ same type
PAK3 p.Asn185Thr 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/pak3-p-val443phe (accessed [today's date]).

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