Is PAK3 p.Ser209Phe (c.626C>T) pathogenic?

PAK3 p.Ser209Phe (c.626C>T) is classified Uncertain significance in PAK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-25). AlphaMissense: likely benign (0.2992); Very rare (popmax 0.00296%, eas); Associated with Inborn genetic diseases.

What condition is associated with PAK3 p.Ser209Phe (c.626C>T)?

PAK3 p.Ser209Phe (c.626C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PAK3 p.Ser209Phe (c.626C>T) in the general population?

PAK3 p.Ser209Phe (c.626C>T) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about PAK3 p.Ser209Phe (c.626C>T)?

AlphaMissense predicts likely benign (score 0.2992) — an in-silico prediction, not a clinical call.

PAK3 p.Ser209Phe

c.626C>T · rs2094216905 · VCV1752540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2992 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2992	likely benign
REVEL	0.255	benign-leaning
SaProt	LLR -9.91	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.1	GERP 2, phastCons 1
Regional constraint	o/e 1.31	unconstrained · MANE · 90 kb · p 0.00047 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 S224F vs ClinVar S209F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00296% East Asian · 1/33,790 alleles

Overall 8.3e-05% 1/1,205,252 alleles · very rare exomes 1/1,092,112 · genomes 0/113,140 · 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: PAK3
Protein: p.Ser209Phe
Coding: c.626C>T
MANE Select: NM_002578
dbSNP: rs2094216905
Type: single nucleotide variant
Location: chrX:111163587 (GRCh38)
Structure: AlphaFold pLDDT 66.31 · 4 PDB
Residue 224 UniProt numbering: the sh3 domain; a β-strand

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.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
PAK3 p.Leu395= Benign ★★ same condition
PAK3 p.Ser224Tyr 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-ser209phe (accessed [today's date]).

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