PAK3

Chr X

p21 (RAC1) activated kinase 3

Also known as: ARA, MRX30, MRX47, OPHN3, PAK-3, PAK3beta, XLID30, bPAK

NCBI Gene: 5063 ENSG00000077264 UniProt: O75914

PAK3 encodes a serine/threonine kinase that regulates cytoskeletal reorganization, dendritic spine morphogenesis, and synaptic plasticity by acting downstream of CDC42 and RAC1. Mutations cause X-linked intellectual developmental disorder with inheritance following an X-linked recessive pattern. The gene is highly constrained against loss-of-function variants, indicating that complete loss of protein function is likely not tolerated.

ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a serine-threonine kinase and forms an activated complex with GTP-bound RAS-like (P21), CDC2 and RAC1. This protein may be necessary for dendritic development and for the rapid cytoskeletal reorganization in dendritic spines associated with synaptic plasticity. Defects in this gene are the cause of a non-syndromic form of X-linked intellectual disability. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2017]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.29

Clinical Summary— PAK3

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

28 unique Pathogenic / Likely Pathogenic· 124 VUS of 296 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.29LOEUF

pLI 0.987

Z-score 3.95

OE 0.09 (0.04–0.29)

Highly constrained

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

Missense Constraint?

3.53Z-score

OE missense 0.32 (0.26–0.39)

69 obs / 214.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.09 (0.04–0.29)

0≤0.351.4

Missense OE?0.32 (0.26–0.39)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 2 / 22.0Missense obs/exp: 69 / 214.7Syn Z: 0.32

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitivePAK3-related intellectual developmental disorderLOFXLR

definitivePAK3-related agenesis of the corpus callosumGOFXLR

This gene — mechanism propensity

0.4884th %ile

GOF

0.6248th %ile

LOF

0.65top 25%

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

LOFprediction above median · 57% of P/LP variants are LoF · LOEUF 0.29 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

296 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic23

VUS124

Likely Benign39

Benign33

Conflicting5

Pathogenic

Likely Pathogenic

124

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	1	0	5
Likely Pathogenic	13	8	2	0	23
VUS	3	103	16	2	124
Likely Benign	0	7	11	21	39
Benign	0	0	25	8	33
Conflicting	—				5
Total	19	119	55	31	229

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

View in ClinVar →

94 pathogenic / likely-pathogenic (of 104) ClinVar copy-number / structural variants overlap PAK3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →