PAK1

Chr 11AD

p21 (RAC1) activated kinase 1

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

NCBI Gene: 5058ENSG00000149269UniProt: Q13153

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]

Primary Disease Associations & Inheritance

Intellectual developmental disorder with macrocephaly, seizures, and speech delayMIM #618158
AD
152
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— PAK1
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 98 VUS of 152 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Missense constrained — critical functional residues
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
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?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.34 (0.21–0.56)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.36 (0.31–0.42)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.97
0≤1.21.6
LoF obs/exp: 11 / 32.4Missense obs/exp: 113 / 312.0Syn Z: 0.24

ClinVar Variant Classifications

152 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic23
VUS98
Likely Benign16
Benign5
Conflicting1
9
Pathogenic
23
Likely Pathogenic
98
VUS
16
Likely Benign
5
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
7
0
9
Likely Pathogenic
1
22
0
0
23
VUS
6
80
11
1
98
Likely Benign
0
5
2
9
16
Benign
0
0
2
3
5
Conflicting
—1
Total71092213152

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

View 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.

Gene2Phenotype Curations

PAK1-related neurodevelopmental disorder

strong
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

MIM #618158

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — PAK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Targeting PAK1.
Semenova G et al.·Biochem Soc Trans
2017Review
NDRG1 regulates Filopodia-induced Colorectal Cancer invasiveness via modulating CDC42 activity.
Aikemu B et al.·Int J Biol Sci
2021
Cdc42GAP deficiency contributes to the Alzheimer's disease phenotype.
Zhu M et al.·Brain
2023
Gadd45g insufficiency drives the pathogenesis of myeloproliferative neoplasms.
Zhang P et al.·Nat Commun
2024
RHOA(L57V) drives the development of diffuse gastric cancer through IGF1R-PAK1-YAP1 signaling.
Schaefer A et al.·Sci Signal
2023
PAK1 inhibitor NVS-PAK1-1 preserves dendritic spines in amyloid/tau exposed neurons and 5xFAD mice.
Yang T et al.·Alzheimers Dement
2025
Phosphoproteomics identifies determinants of PAK inhibitor sensitivity in leukaemia cells.
Casado P et al.·Cell Commun Signal
2025
Increased Fascin1 and Pak1 Expressions Enhance Age-Associated B-Cell Actin Cytoskeleton Remodeling and Motility.
Fujiwara M et al.·Cell Biochem Funct
2025Functional
PAK1 and PAK2 in cell metabolism regulation.
Kořánová T et al.·J Cell Biochem
2022
PAK1, PAK1Δ15, and PAK2: similarities, differences and mutual interactions.
Grebeňová D et al.·Sci Rep
2019
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Phosphatidylinositol 4,5-bisphosphate mediates Arl4D self-interaction to promote Pak1 signaling.
Chang TW et al.·Proc Natl Acad Sci U S A
2026
Endothelial TBK1 Deficiency Inhibits Endothelial-to-Mesenchymal Transition and Atherogenesis Through Suppressing PAK1/ERK1/2 Signaling.
Pu Y et al.·Circ Res
2026
RETRACTION: Diallyl Disulfide Downregulating RhoGDI2 Induces Differentiation and Inhibit Invasion Via the Rac1/Pak1/LIMK1 Pathway in Human Leukemia HL-60 Cells.
·Environ Toxicol
2026
PAK1 (p21-Activated Kinase 1) and Its Role in Neurodevelopmental Disorders-New Case Report and a Comprehensive Review.
Blek N et al.·Int J Mol Sci
2025🔓 Open AccessReview
Computational identification of potential PAK1 inhibitors for anti-cancer therapy: an e-pharmacophore guided virtual screening study.
Muthuvairam Subbulakshmi M et al.·SAR QSAR Environ Res
2025
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools