PAK1

Chr 11AD

p21 (RAC1) activated kinase 1

Also known as: IDDMSSD, PAKalpha, alpha-PAK, p65-PAK

NCBI Gene: 5058 ENSG00000149269 UniProt: Q13153 OMIM: 602590

This gene encodes a serine/threonine protein kinase that regulates cytoskeleton dynamics, cell adhesion, migration, and synaptic function by linking Rho GTPases to downstream signaling pathways. Mutations cause autosomal dominant intellectual developmental disorder with macrocephaly, seizures, and speech delay. The gene shows tolerance to loss-of-function variants (pLI 0.001, LOEUF 0.563), suggesting the pathogenic variants may act through other mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a family member of serine/threonine p21-activating kinases, known as PAK proteins. These proteins are critical effectors that link RhoGTPases to cytoskeleton reorganization and nuclear signaling, and they serve as targets for the small GTP binding proteins Cdc42 and Rac. This specific family member regulates cell motility and morphology. Mutations in this gene have been associated with macrocephaly, seizures, and speech delay. Overexpression of this gene is also reported in many cancer types, and particularly in breast cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2020]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder with macrocephaly, seizures, and speech delayMIM #618158

Clinical highlights

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

169

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.56

LOEUF

GOF*

Mechanism· G2P

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