PAK1

Chr 11

p21 (RAC1) activated kinase 1

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

NCBI Gene: 5058 ENSG00000149269 UniProt: Q13153

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 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 ResearchGenerating clinical summary…

GOFmechanismLOEUF 0.56

Clinical Summary— PAK1

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

25 unique Pathogenic / Likely Pathogenic· 98 VUS of 165 total submissions

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GeneReview available — PAK1

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.56LOEUF

pLI 0.001

Z-score 3.48

OE 0.34 (0.21–0.56)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

4.00Z-score

OE missense 0.36 (0.31–0.42)

113 obs / 312.0 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.34 (0.21–0.56)

0≤0.351.4

Missense OE?0.36 (0.31–0.42)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 11 / 32.4Missense obs/exp: 113 / 312.0Syn Z: 0.24

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongPAK1-related neurodevelopmental disorderGOFAD

This gene — mechanism propensity

0.80top 25%

GOF

0.78top 25%

LOF

0.2970th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation · 96% of P/LP are missense

DNprediction above median · 1 literature citation

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

DNFurthermore, sublethal doses of IPA3 or ectopic expression of dominant-negative PAK1 sensitized Ras-mutated cells to GDC-0897 and AZD6244, which otherwise have reduced efficiency against cells with activated Ras.1

GOFActivating Mutations in PAK1, Encoding p21-Activated Kinase 1, Cause a Neurodevelopmental Disorder2

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

References

ClinVar Variant Classifications

165 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic23

VUS98

Likely Benign16

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	2	0	0	2
Likely Pathogenic	1	22	0	0	23
VUS	9	81	8	0	98
Likely Benign	0	5	1	10	16
Benign	0	1	2	3	6
Conflicting	—				1
Total	10	111	11	13	146

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 11) ClinVar copy-number / structural variants overlap PAK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →