PAK1
Chr 11ADp21 (RAC1) activated kinase 1
Also known as: IDDMSSD, PAKalpha, alpha-PAK, p65-PAK
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.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
PAK1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools