PAK3

p21 (RAC1) activated kinase 3

Basic information

Region (hg38): X:110944285-111227361

Previous symbols: [ "MRX30", "MRX47" ]

Links

ENSG00000077264 ∙ NCBI:5063 ∙ OMIM:300142 ∙ HGNC:8592 ∙ Uniprot:O75914 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• non-syndromic X-linked intellectual disability (Supportive), mode of inheritance: XL
• intellectual disability, X-linked 30 (Definitive), mode of inheritance: XL
• X-linked syndromic intellectual disability (Definitive), mode of inheritance: XL
• intellectual disability, X-linked 30 (Definitive), mode of inheritance: XLR
• intellectual disability, X-linked 30 (Moderate), mode of inheritance: XL
• intellectual disability, X-linked 30 (Strong), mode of inheritance: XL

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, X-linked 30	XL	General	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	Craniofacial; Neurologic	8826460; 9332663; 9731525; 10946356; 12884430; 17853471; 18523455

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the PAK3 gene.

• not provided (2 variants)
• Intellectual disability, X-linked 30 (1 variants)
• Microcephaly;Intellectual disability (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the PAK3 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			2	19	8	29
missense	2	3	55	6		66
nonsense	1	3				4
start loss						0
frameshift	1	1	1			3
inframe indel			1			1
splice donor/acceptor (+/-2bp)		2	1			3
splice region		1	4	1		6
non coding			8	11	25	44
Total	4	9	68	36	33

Variants in PAK3

This is a list of pathogenic ClinVar variants found in the PAK3 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
X-111013898-G-C		Intellectual disability, X-linked 30	Uncertain significance (Jun 23, 2021)
X-111096276-G-A		Intellectual disability, X-linked 30	Benign (Jan 12, 2018)
X-111096295-G-C		Intellectual disability, X-linked 30	Conflicting classifications of pathogenicity (Jul 01, 2023)
X-111096298-G-T		Intellectual disability, X-linked 30	Uncertain significance (Jan 13, 2018)
X-111097586-G-C		Intellectual disability, X-linked 30	Uncertain significance (Jan 13, 2018)
X-111103174-G-A		Intellectual disability, X-linked 30	Uncertain significance (Jan 12, 2018)
X-111103271-A-G		Intellectual disability, X-linked 30	Benign (Jan 13, 2018)
X-111123089-T-C		Intellectual disability, X-linked 30	Benign (Jan 13, 2018)
X-111123112-C-T		Intellectual disability, X-linked 30	Benign (Nov 29, 2022)
X-111123113-G-A		not specified • Intellectual disability, X-linked 30 • Inborn genetic diseases	Benign/Likely benign (Oct 03, 2023)
X-111123120-A-G			Uncertain significance (Nov 05, 2023)
X-111123124-T-G			Uncertain significance (Apr 29, 2022)
X-111123128-G-A		Intellectual disability, X-linked 30	Uncertain significance (Nov 29, 2022)
X-111123139-G-A			Benign (May 31, 2023)
X-111123162-G-C		Intellectual disability, X-linked 30	Uncertain significance (May 20, 2023)
X-111123171-G-A		not specified	Uncertain significance (Mar 14, 2016)
X-111123185-C-T			Uncertain significance (Oct 22, 2021)
X-111123204-C-T			Uncertain significance (Oct 22, 2014)
X-111123248-C-T			Uncertain significance (Dec 06, 2021)
X-111123264-G-T		Inborn genetic diseases	Uncertain significance (Oct 24, 2018)
X-111123295-C-T			Likely benign (Sep 06, 2022)
X-111123532-A-T			Benign (Jun 19, 2021)
X-111142080-A-C			Likely benign (Aug 09, 2023)
X-111142095-G-A		Intellectual disability, X-linked 30	Likely pathogenic (Apr 20, 2023)
X-111142119-C-T		Intellectual disability, X-linked 30	Pathogenic (Aug 14, 2000)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
PAK3	protein_coding	protein_coding	ENST00000360648	16	283077

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.987	0.0128	125582	1	1	125584	0.00000796

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.53	69	215	0.321	0.0000156	3806
Missense in Polyphen		15	109.9	0.13648		1865
Synonymous	0.319	70	73.5	0.953	0.00000525	1091
Loss of Function	3.95	2	22.0	0.0910	0.00000160	408

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.00	0.00
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000123	0.00000881
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.000221	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell migration, or cell cycle regulation. Plays a role in dendrite spine morphogenesis as well as synapse formation and plasticity. Acts as downstream effector of the small GTPases CDC42 and RAC1. Activation by the binding of active CDC42 and RAC1 results in a conformational change and a subsequent autophosphorylation on several serine and/or threonine residues. Phosphorylates MAPK4 and MAPK6 and activates the downstream target MAPKAPK5, a regulator of F-actin polymerization and cell migration. Additionally, phosphorylates TNNI3/troponin I to modulate calcium sensitivity and relaxation kinetics of thin myofilaments. May also be involved in early neuronal development. {ECO:0000269|PubMed:21177870}.
• Disease: DISEASE: Mental retardation, X-linked 30 (MRX30) [MIM:300558]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non- syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. {ECO:0000269|PubMed:10946356, ECO:0000269|PubMed:12884430, ECO:0000269|PubMed:9731525}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: 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);Axon guidance - Homo sapiens (human);Ras signaling pathway - Homo sapiens (human);Integrin-mediated Cell Adhesion;Focal Adhesion;MET in type 1 papillary renal cell carcinoma;Ras Signaling;Regulation of Actin Cytoskeleton;G13 Signaling Pathway;Developmental Biology;Signal Transduction;VEGFA-VEGFR2 Pathway;Generation of second messenger molecules;MAPK6/MAPK4 signaling;TCR signaling;CD28 dependent Vav1 pathway;CD28 co-stimulation;Costimulation by the CD28 family;CD209 (DC-SIGN) signaling;C-type lectin receptors (CLRs);EPH-Ephrin signaling;Innate Immune System;Immune System;Ephrin signaling;Adaptive Immune System;Activation of RAC1;RHO GTPases activate PAKs;RHO GTPase Effectors;Signaling by Rho GTPases;agrin in postsynaptic differentiation;Sema3A PAK dependent Axon repulsion;MAPK family signaling cascades;Semaphorin interactions;Signaling by ROBO receptors;Signaling by VEGF;Axon guidance;Signaling by Receptor Tyrosine Kinases;Regulation of p38-alpha and p38-beta;VEGFR2 mediated vascular permeability (Consensus)

Intolerance Scores

• loftool: 0.173
• rvis_EVS: -0.41
• rvis_percentile_EVS: 26.23

Haploinsufficiency Scores

• pHI: 0.480
• hipred: Y
• hipred_score: 0.729
• ghis: 0.536

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.768

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Pak3
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan)

Gene ontology

• Biological process: MAPK cascade;activation of MAPK activity;stimulatory C-type lectin receptor signaling pathway;axonogenesis;positive regulation of fibroblast migration;dendrite development;cell migration;signal transduction by protein phosphorylation;regulation of actin filament polymerization;stress-activated protein kinase signaling cascade;T cell costimulation;activation of protein kinase activity;regulation of MAPK cascade;positive regulation of neuron apoptotic process;ephrin receptor signaling pathway;regulation of axonogenesis;synapse organization;T cell receptor signaling pathway;dendritic spine morphogenesis;positive regulation of dendritic spine morphogenesis;cellular response to organic cyclic compound;positive regulation of DNA biosynthetic process
• Cellular component: cytoplasm;endosome;cytosol;plasma membrane;postsynaptic density;glutamatergic synapse
• Molecular function: protein serine/threonine kinase activity;MAP kinase kinase activity;protein binding;ATP binding;SH3 domain binding;metal ion binding;Rac GTPase binding