PAK4

protein-coding

p21 (RAC1) activated kinase 4

Gene summary

PAK proteins, a family of serine/threonine p21-activating kinases, include PAK1, PAK2, PAK3 and PAK4. PAK proteins are critical effectors that link Rho GTPases to cytoskeleton reorganization and nuclear signaling. They serve as targets for the small GTP binding proteins Cdc42 and Rac and have been implicated in a wide range of biological activities. PAK4 interacts specifically with the GTP-bound form of Cdc42Hs and weakly activates the JNK family of MAP kinases. PAK4 is a mediator of filopodia formation and may play a role in the reorganization of the actin cytoskeleton. Multiple alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

MANE transcript

NM_005884.5

Inheritance

—

ClinVar variants

U:119B:7

Top phenotype

Prostate cancer

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr19:39,125,770-39,182,816

External References & Databases

Ensembl (ENSG00000130669)

Transcript & Mutation Effects

hg38 • Region Span ~57.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PAK4 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 110

not providedTotal: 7

Prostate cancerTotal: 1

Hereditary breast ovarian cancer syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_005884.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	3 clinvar		5
missense			114 clinvar	3 clinvar	1 clinvar	118
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	0	0	119	6	1	126

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 156 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_005884.5	RefSeq	NP_005875.1	8	MANE Select
ENST00000360442.8	Ensembl	ENSP00000353625.3	8	MANE Select
NM_001014831.3	RefSeq	NP_001014831.1	8	Standard
NM_001014832.2	RefSeq	NP_001014832.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
pak4	Danio rerio	Structure: myeloid leukocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

pak4

Danio rerio

Structure: myeloid leukocyte

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)
Renal cell carcinoma - Homo sapiens (human)
ErbB signaling pathway - Homo sapiens (human)
Regulation of actin cytoskeleton - Homo sapiens (human)

Biological Process

regulation of cell growth
apoptotic process
cytoskeleton organization
cell cycle
signal transduction

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
protein binding
ATP binding
Rac GTPase binding

Cellular Component

cytoplasm
Golgi apparatus
cell-cell adherens junction
focal adhesion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000593690
Coding exons: 8
Length: 57047
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125745
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.590	366	399	0.917	0.0000284	3710
Missense (PolyPhen)		128	161.98	0.79021		1445
Synonymous	-0.420	189	182	1.04	0.0000136	1303
Loss of Function	2.35	11	23.2	0.474	0.00000141	225

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000059	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000046	0.000044	rare
South Asian	0.000098	0.000098	rare
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, growth, proliferation or cell survival. Activation by various effectors including growth factor receptors or active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates and inactivates the protein phosphatase SSH1, leading to increased inhibitory phosphorylation of the actin binding/depolymerizing factor cofilin. Decreased cofilin activity may lead to stabilization of actin filaments. Phosphorylates LIMK1, a kinase that also inhibits the activity of cofilin. Phosphorylates integrin beta5/ITGB5 and thus regulates cell motility. Phosphorylates ARHGEF2 and activates the downstream target RHOA that plays a role in the regulation of assembly of focal adhesions and actin stress fibers. Stimulates cell survival by phosphorylating the BCL2 antagonist of cell death BAD. Alternatively, inhibits apoptosis by preventing caspase-8 binding to death domain receptors in a kinase independent manner. Plays a role in cell-cycle progression by controlling levels of the cell-cycle regulatory protein CDKN1A and by phosphorylating RAN. {ECO:0000269|PubMed:11278822, ECO:0000269|PubMed:11313478, ECO:0000269|PubMed:14560027, ECO:0000269|PubMed:15660133, ECO:0000269|PubMed:20507994, ECO:0000269|PubMed:20631255, ECO:0000269|PubMed:20805321, ECO:0000269|PubMed:26607847}.;

Recessive Scores

pRec: 0.300

Intolerance Scores

LoFtool: 0.236
RVIS EVS: -0.49
RVIS percentile EVS: 22.65

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium