GeneBe

PAK1

protein-coding

p21 (RAC1) activated kinase 1

Gene summary

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]

MANE transcript

NM_002576.5

Inheritance

AD

ClinVar variants

P:26U:107B:22

Top phenotype

Intellectual developmental disorder with macrocephaly, seizures, and speech delay

gnomAD constraint

pLI —, LoF o/e 0.34

Max pathogenic AF

—

Genomic locus

chr11:77,322,017-77,474,635

External References & Databases

Ensembl (ENSG00000149269)NCBI Gene (5058)OMIM (602590)HGNC:8590GenCCUniProt (Q13153)AlphaFoldClinVar (PAK1)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~152.6 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual developmental disorder with macrocephaly, seizures, and speech delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032568

Submitter: G2P

intellectual developmental disorder with macrocephaly, seizures, and speech delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032568

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder with macrocephaly, seizures, and speech delayMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032568

Submitter: Ambry Genetics

intellectual developmental disorder with macrocephaly, seizures, and speech delaySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0032568

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Intellectual developmental disorder with macrocephaly, seizures, and speech delayAD

Manifestation: Craniofacial; Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 30290153Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAK1 variants in ClinVar

10 Conditions Cataloged
not providedTotal: 81
Intellectual developmental disorder with macrocephaly, seizures, and speech delayTotal: 39
Inborn genetic diseasesTotal: 36
not specifiedTotal: 13
PAK1-related disorderTotal: 13
See casesTotal: 2
Neurodevelopmental disorderTotal: 1
Neurodevelopmental disorder with behavioral abnormalities, absent speech, and hypotoniaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002576.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
4
clinvar
14
clinvar
3
clinvar
 21
missense
2
clinvar
23
clinvar
92
clinvar
5
clinvar
 122
nonsense
2
clinvar
 2
start loss
0
frameshift
1
clinvar
3
clinvar
 4
splice donor/acceptor (+/-2bp)
6
clinvar
 6
Total224107193155

Highest pathogenic variant AF is 0.00000867736

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 156 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002576.5RefSeqNP_002567.314MANE Select
ENST00000356341.8EnsemblENSP00000348696.414MANE Select
NM_001128620.2RefSeqNP_001122092.115Standard
NM_001376268.1RefSeqNP_001363197.115Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
pak1Danio rerio

Structure: melanocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Focal adhesion - Homo sapiens (human)
  • T cell receptor signaling pathway - Homo sapiens (human)
  • Fc gamma R-mediated phagocytosis - Homo sapiens (human)
  • Renal cell carcinoma - Homo sapiens (human)
  • ErbB signaling pathway - Homo sapiens (human)

Biological Process

  • MAPK cascade
  • response to hypoxia
  • positive regulation of protein phosphorylation
  • stimulatory C-type lectin receptor signaling pathway
  • protein phosphorylation

Molecular Function

  • protein kinase activity
  • protein serine/threonine kinase activity
  • protein binding
  • collagen binding
  • ATP binding

Cellular Component

  • ruffle
  • cytoplasm
  • cytosol
  • actin filament
  • plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000278568
Coding exons
15
Length
152929
Individuals with no LoFs
125735
Homozygous LoFs
0
Heterozygous LoFs
13
Defined
125748
p
0.0000517
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense4.001133120.3620.00001663635
Missense (PolyPhen)30138.540.216541612
Synonymous0.2411081110.9710.000005801043
Loss of Function3.481132.40.3400.00000175377

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish0.000140.00014rare
European (Non-Finnish)0.0000350.000035rare
South Asian0.0000650.000065rare
Other0.000160.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Protein kinase involved in intracellular signaling pathways downstream of integrins and receptor-type kinases that plays an important role in cytoskeleton dynamics, in cell adhesion, migration, proliferation, apoptosis, mitosis, and in vesicle-mediated transport processes. Can directly phosphorylate BAD and protects cells against apoptosis. Activated by interaction with CDC42 and RAC1. Functions as GTPase effector that links the Rho-related GTPases CDC42 and RAC1 to the JNK MAP kinase pathway. Phosphorylates and activates MAP2K1, and thereby mediates activation of downstream MAP kinases. Involved in the reorganization of the actin cytoskeleton, actin stress fibers and of focal adhesion complexes. Phosphorylates the tubulin chaperone TBCB and thereby plays a role in the regulation of microtubule biogenesis and organization of the tubulin cytoskeleton. Plays a role in the regulation of insulin secretion in response to elevated glucose levels. Part of a ternary complex that contains PAK1, DVL1 and MUSK that is important for MUSK-dependent regulation of AChR clustering during the formation of the neuromuscular junction (NMJ). Activity is inhibited in cells undergoing apoptosis, potentially due to binding of CDC2L1 and CDC2L2. Phosphorylates MYL9/MLC2. Phosphorylates RAF1 at 'Ser-338' and 'Ser-339' resulting in: activation of RAF1, stimulation of RAF1 translocation to mitochondria, phosphorylation of BAD by RAF1, and RAF1 binding to BCL2. Phosphorylates SNAI1 at 'Ser-246' promoting its transcriptional repressor activity by increasing its accumulation in the nucleus. In podocytes, promotes NR3C2 nuclear localization. Required for atypical chemokine receptor ACKR2- induced phosphorylation of LIMK1 and cofilin (CFL1) and for the up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In synapses, seems to mediate the regulation of F- actin cluster formation performed by SHANK3, maybe through CFL1 phosphorylation and inactivation. Plays a role in RUFY3-mediated facilitating gastric cancer cells migration and invasion (PubMed:25766321). {ECO:0000269|PubMed:10551809, ECO:0000269|PubMed:11733498, ECO:0000269|PubMed:12624090, ECO:0000269|PubMed:12876277, ECO:0000269|PubMed:14585966, ECO:0000269|PubMed:15611088, ECO:0000269|PubMed:15831477, ECO:0000269|PubMed:15833848, ECO:0000269|PubMed:16278681, ECO:0000269|PubMed:17726028, ECO:0000269|PubMed:17989089, ECO:0000269|PubMed:22669945, ECO:0000269|PubMed:23633677, ECO:0000269|PubMed:25766321, ECO:0000269|PubMed:8805275, ECO:0000269|PubMed:9032240, ECO:0000269|PubMed:9395435, ECO:0000269|PubMed:9528787}.;

Recessive Scores

pRec
0.346

Intolerance Scores

LoFtool
0.494
RVIS EVS
-0.6
RVIS percentile EVS
17.75

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.999

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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