Human Gene Module / Chromosome 3 / PAK2

PAK2p21 (RAC1) activated kinase 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
2 / 6
Rare Variants / Common Variants
5 / 0
Aliases
PAK2, PAK65,  PAKgamma
Associated Syndromes
3q29 microdeletion syndrome
Chromosome Band
3q29
Associated Disorders
DD/NDD, ID, EPS
Relevance to Autism

Pak2 +/- mice were found to exhibit reduced spine density, defective long-term potentiation, impaired actin polymerization, and autism-related behaviors, including increased stereotypic behavior and reduced social interactions (Wang et al., 2018); in the same report, a rare de novo nonsense variant and inherited damaging missense variants in the PAK2 gene were identified in Han Chinese ASD probands. PAK2 resides within the 1.5-Mb region on chromosome 3q29 that defines the 3q29 microdeletion syndrome (OMIM 609425) and may contribute to the phenotypes observed in affected individuals, including autism/autistic features and schizophrenia in some individuals (Willatt et al., 2015; Mulle et al., 2010; Quintero-Rivera et al., 2010).

Molecular Function

The PAK2 gene encodes a serine/threonine protein kinase that plays a role in a variety of different signaling pathways including cytoskeleton regulation, cell motility, cell cycle progression, apoptosis or proliferation, and that acts as downstream effector of the small GTPases CDC42 and RAC1.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
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Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to PAK2 (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support 3q29 microdeletion syndrome: clinical and molecular characterization of a new syndrome Willatt L , et al. (2005) No -
2 Support Microdeletions of 3q29 confer high risk for schizophrenia Mulle JG , et al. (2010) No -
3 Support Autistic and psychiatric findings associated with the 3q29 microdeletion syndrome: case report and review Quintero-Rivera F , et al. (2010) No -
4 Primary PAK2 Haploinsufficiency Results in Synaptic Cytoskeleton Impairment and Autism-Related Behavior Wang Y , et al. (2018) Yes -
5 Support - Antonarakis SE et al. (2021) Yes DD, ID, epilepsy/seizures
6 Support - Ashraf Yahia et al. (2024) No -
Rare Variants   (5)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1435C>T p.Arg479Ter stop_gained De novo - Simplex 30134165 Wang Y , et al. (2018)
c.1051G>T p.Glu351Ter stop_gained De novo - Simplex 38300321 Ashraf Yahia et al. (2024)
c.931G>A p.Asp311Asn missense_variant Familial Paternal Simplex 30134165 Wang Y , et al. (2018)
c.1570C>T p.Arg524Cys missense_variant Familial Maternal Simplex 30134165 Wang Y , et al. (2018)
c.1303G>A p.Glu435Lys missense_variant De novo (germline mosaicism) - Multiplex 33693784 Antonarakis SE et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A rare de novo nonsense variant and inherited damaging missense variants in the PAK2 gene were identified in Han Chinese ASD probands. PAK2 resides within the 1.5-Mb region on chromosome 3q29 that defines the 3q29 microdeletion syndrome (OMIM 609425) and may contribute to the phenotypes observed in affected individuals, including autism/autistic features and schizophrenia in some individuals (Willatt et al., 2015; Mulle et al., 2010; Quintero-Rivera et al., 2010). Additionally, Pak2 +/- mice were found to exhibit reduced spine density, defective long-term potentiation, impaired actin polymerization, and autism-related behaviors, including increased stereotypic behavior and reduced social interactions (Wang et al., 2018).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

1/1/2021
2
icon
2

Score remained at 2

Description

A rare de novo nonsense variant and inherited damaging missense variants in the PAK2 gene were identified in Han Chinese ASD probands. PAK2 resides within the 1.5-Mb region on chromosome 3q29 that defines the 3q29 microdeletion syndrome (OMIM 609425) and may contribute to the phenotypes observed in affected individuals, including autism/autistic features and schizophrenia in some individuals (Willatt et al., 2015; Mulle et al., 2010; Quintero-Rivera et al., 2010). Additionally, Pak2 +/- mice were found to exhibit reduced spine density, defective long-term potentiation, impaired actin polymerization, and autism-related behaviors, including increased stereotypic behavior and reduced social interactions (Wang et al., 2018).

Reports Added
[Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 22021]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A rare de novo nonsense variant and inherited damaging missense variants in the PAK2 gene were identified in Han Chinese ASD probands. PAK2 resides within the 1.5-Mb region on chromosome 3q29 that defines the 3q29 microdeletion syndrome (OMIM 609425) and may contribute to the phenotypes observed in affected individuals, including autism/autistic features and schizophrenia in some individuals (Willatt et al., 2015; Mulle et al., 2010; Quintero-Rivera et al., 2010). Additionally, Pak2 +/- mice were found to exhibit reduced spine density, defective long-term potentiation, impaired actin polymerization, and autism-related behaviors, including increased stereotypic behavior and reduced social interactions (Wang et al., 2018).

Reports Added
[New Scoring Scheme]
10/1/2018
icon
3

Increased from to 3

Description

A rare de novo nonsense variant and inherited damaging missense variants in the PAK2 gene were identified in Han Chinese ASD probands. PAK2 resides within the 1.5-Mb region on chromosome 3q29 that defines the 3q29 microdeletion syndrome (OMIM 609425) and may contribute to the phenotypes observed in affected individuals, including autism/autistic features and schizophrenia in some individuals (Willatt et al., 2015; Mulle et al., 2010; Quintero-Rivera et al., 2010). Additionally, Pak2 +/- mice were found to exhibit reduced spine density, defective long-term potentiation, impaired actin polymerization, and autism-related behaviors, including increased stereotypic behavior and reduced social interactions (Wang et al., 2018).

Krishnan Probability Score

Score 0.49147650069409

Ranking 5515/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.93868856352437

Ranking 2847/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.92874376970195

Ranking 10991/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.36509549170434

Ranking 1839/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
CNVs associated with PAK2(1 CNVs)
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3q29 70 Deletion-Duplication 105  /  496
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