PAK2

Chr 3AD

p21 (RAC1) activated kinase 2

Also known as: KNO2, PAK65, PAKgamma

NCBI Gene: 5062 ENSG00000180370 UniProt: Q13177 OMIM: 605022

PAK2 encodes a serine/threonine protein kinase that regulates cytoskeleton organization, cell motility, cell cycle progression, and apoptosis by acting as a downstream effector of the small GTPases CDC42 and RAC1. Mutations cause Knobloch syndrome 2, which follows autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating that proper PAK2 function is essential for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The p21 activated kinases (PAK) are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. The PAK proteins are a family of serine/threonine kinases that serve as targets for the small GTP binding proteins, CDC42 and RAC1, and have been implicated in a wide range of biological activities. The protein encoded by this gene is activated by proteolytic cleavage during caspase-mediated apoptosis, and may play a role in regulating the apoptotic events in the dying cell. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.321 OMIM phenotype

Clinical Summary— PAK2

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 49 VUS of 79 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.32LOEUF

pLI 0.972

Z-score 4.27

OE 0.14 (0.07–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.40Z-score

OE missense 0.43 (0.37–0.50)

122 obs / 283.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.14 (0.07–0.32)

0≤0.351.4

Missense OE?0.43 (0.37–0.50)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 4 / 28.6Missense obs/exp: 122 / 283.0Syn Z: -0.06

This gene — mechanism propensity

0.4785th %ile

GOF

0.5954th %ile

LOF

0.67top 25%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.32

Literature Evidence

LOF3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 15918153 ↗

ClinVar Variant Classifications

79 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

Likely Pathogenic2

VUS49

Likely Benign4

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	2	0	2
VUS	1	48	0	49
Likely Benign	0	2	2	4
Benign	0	0	0	0
Total	1	53	2	56

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

88 pathogenic / likely-pathogenic (of 113) ClinVar copy-number / structural variants overlap PAK2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →