CASK

Summary

CASK (calcium/calmodulin dependent serine protein kinase, HGNC:1497) is a protein-coding gene on chromosome Xp11.4, encoding Peripheral plasma membrane protein CASK (O14936). Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.

This gene encodes a calcium/calmodulin-dependent serine protein kinase. The encoded protein is a MAGUK (membrane-associated guanylate kinase) protein family member. These proteins are scaffold proteins and the encoded protein is located at synapses in the brain. Mutations in this gene are associated with FG syndrome 4, intellectual disability and microcephaly with pontine and cerebellar hypoplasia, and a form of X-linked intellectual disability. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8573 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked syndromic intellectual disability (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 1,215 total — 138 pathogenic, 78 likely-pathogenic
• Phenotypes (HPO): 146
• Druggable target: yes — 9 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_001367721

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1497
Approved symbol	CASK
Name	calcium/calmodulin dependent serine protein kinase
Location	Xp11.4
Locus type	gene with protein product
Status	Approved
Aliases	LIN2, CAGH39, FGS4
Ensembl gene	ENSG00000147044
Ensembl biotype	protein_coding
OMIM	300172
Entrez	8573

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 30 protein_coding, 8 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000378154, ENST00000378158, ENST00000378163, ENST00000378166, ENST00000378168, ENST00000378179, ENST00000421587, ENST00000442742, ENST00000468986, ENST00000472704, ENST00000477823, ENST00000486402, ENST00000642361, ENST00000642499, ENST00000642584, ENST00000642641, ENST00000643043, ENST00000643733, ENST00000643831, ENST00000643853, ENST00000644219, ENST00000644347, ENST00000644770, ENST00000645566, ENST00000645937, ENST00000645986, ENST00000646087, ENST00000646120, ENST00000647118, ENST00000675354, ENST00000915519, ENST00000915520, ENST00000915521, ENST00000915522, ENST00000956252, ENST00000956253, ENST00000956254, ENST00000956255, ENST00000956256, ENST00000956257

RefSeq mRNA: 5 — MANE Select: NM_001367721 NM_001126054, NM_001126055, NM_001367721, NM_001410745, NM_003688

CCDS: CCDS14257, CCDS48094, CCDS48095, CCDS94597, CCDS94598

Canonical transcript exons

ENST00000378163 — 27 exons

Exon	Start	End
ENSE00000978463	41557032	41557100
ENSE00000978466	41542691	41542806
ENSE00000978468	41534706	41534786
ENSE00000978469	41531007	41531209
ENSE00000978470	41523951	41524034
ENSE00001035465	41589515	41589592
ENSE00001035476	41586907	41586987
ENSE00001035482	41578340	41578528
ENSE00001091529	41671428	41671530
ENSE00001091536	41626604	41626703
ENSE00001091537	41609904	41610025
ENSE00001238919	41534893	41534973
ENSE00001476466	41922930	41923554
ENSE00001640898	41787178	41787283
ENSE00001672698	41514934	41520596
ENSE00001755987	41739384	41739456
ENSE00001765981	41622617	41622634
ENSE00003463225	41555600	41555635
ENSE00003466150	41569668	41569746
ENSE00003476062	41559779	41559847
ENSE00003498994	41853115	41853227
ENSE00003551510	41660439	41660561
ENSE00003579195	41561559	41561644
ENSE00003640327	41553719	41553915
ENSE00003655853	41745524	41745601
ENSE00003666434	41665277	41665452
ENSE00003668811	41636578	41636661

Expression profiles

Bgee: expression breadth ubiquitous, 284 present calls, max score 95.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.4629 / max 114.4052, expressed in 1734 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198972	8.8098	1663
198973	2.5464	1128
198971	0.7835	482
198974	0.4489	264
198975	0.3577	177
198964	0.3298	140
198970	0.1767	76
198963	0.0100	5

Top tissues by expression

293 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	95.92	gold quality
hair follicle	UBERON:0002073	95.31	gold quality
cortical plate	UBERON:0005343	94.15	gold quality
duodenum	UBERON:0002114	93.47	gold quality
jejunal mucosa	UBERON:0000399	93.45	gold quality
pancreatic ductal cell	CL:0002079	93.32	silver quality
cranial nerve II	UBERON:0000941	92.81	gold quality
calcaneal tendon	UBERON:0003701	92.76	gold quality
ganglionic eminence	UBERON:0004023	92.69	gold quality
adrenal tissue	UBERON:0018303	92.58	gold quality
ventricular zone	UBERON:0003053	92.33	gold quality
superior vestibular nucleus	UBERON:0007227	92.21	gold quality
embryo	UBERON:0000922	92.15	gold quality
rectum	UBERON:0001052	91.94	gold quality
corpus callosum	UBERON:0002336	91.85	gold quality
colonic epithelium	UBERON:0000397	91.70	gold quality
stromal cell of endometrium	CL:0002255	91.66	gold quality
pylorus	UBERON:0001166	91.66	gold quality
blood vessel layer	UBERON:0004797	90.81	gold quality
epithelial cell of pancreas	CL:0000083	90.78	gold quality
tendon	UBERON:0000043	90.77	gold quality
islet of Langerhans	UBERON:0000006	90.73	gold quality
colonic mucosa	UBERON:0000317	90.65	gold quality
subthalamic nucleus	UBERON:0001906	90.57	gold quality
saphenous vein	UBERON:0007318	90.30	gold quality
oviduct epithelium	UBERON:0004804	90.11	gold quality
cervix squamous epithelium	UBERON:0006922	90.08	gold quality
medulla oblongata	UBERON:0001896	90.04	gold quality
mucosa of sigmoid colon	UBERON:0004993	89.94	gold quality
ventral tegmental area	UBERON:0002691	89.82	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.49
E-CURD-10	no	805.22
E-ENAD-20	no	80.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

225 targeting CASK, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817

Literature-anchored findings (GeneRIF, showing 40)

• Upregulation of CASK protein is associated with tumorigenesis of esophagus (PMID:11880184)
• coordinated folding and association of the LIN-2, -7 domain (PMID:12110687)
• plasma membrane Ca2+ pump 4b/CI binds to Ca2+/calmodulin-dependent membrane-associated kinase CASK (PMID:12511555)
• Thus, we speculate that the regulation of cell growth mediated by CASK may be involved in Id1. (PMID:15694377)
• CASK combines the scaffolding activity of MAGUKs with an unusual kinase activity that phosphorylates substrates recuited by the scaffolding activity. (PMID:18423203)
• Genetic deletion of CASK results in haploinsufficiency, which might cause X-linked dominant mental retardation. (PMID:18629876)
• CASK is targeted to nuclei of the basal epidermis and controls keratinocyte proliferation. (PMID:18664494)
• hCASK regulation of cell growth might involve p21 expression, and that the bHLH (basic helix-loop-helix) transcription factor E2A probably participates in hCASK regulation of p21 expression (PMID:19125693)
• Here we describe a previously unreported X-linked brain malformation syndrome caused by mutations of CASK (PMID:19165920)
• study reports that a p.R28L (c.83G–>T) missense mutation in CASK causes FG syndrome phenotype in an Italian family (PMID:19200522)
• Post-translational modifications to CASK are major regulatory steps leading to its proteasomal degradation. (PMID:19781660)
• The molecular functions of CASK may explain, at least partially in this review, the malformations of the brain and the mental retardation in human patients carrying mutations in the CASK gene. (PMID:19847910)
• syndecan’s interactions with both CASK and neurofibromin are dependent on syndecan homodimerization. (PMID:20006588)
• These findings reinforce the CASK gene as a relatively frequent cause of X-linked mental retardation in females and males. (PMID:20029458)
• CASK plays a role in axonogenesis, which may be related to brain anatomical characteristics in humans (PMID:20623620)
• Intragenic duplications and mutations of CASK is associated with mental retardation and microcephaly with pontine and cerebellar hypoplasia (PMID:21735175)
• Study shows that a short linear EEIWVLRK peptide motif from Caskin1 is necessary and sufficient for binding CASK. (PMID:21763699)
• The liprin-alpha2/CASK complex structure is solved here. (PMID:21855798)
• Heterozygous mutations in the CASK gene are described in 20 female patients that are associated with distinct brain malformations and phenotypes of remarkably varying degrees. (PMID:21954287)
• During wounding, CASK is mobilized to the plasma membrane where it colocalizes with Cx43 and CADM1 1 hour after skin explant wounding. (PMID:22389404)
• CASK related PCH is the second most frequent cause of PCH. The identification of a de novo mutation in these patients enables accurate and reassuring genetic counselling (PMID:22452838)
• case reports - mutations resulting in Ohtahara syndrome and cerebellar hypoplasia (PMID:22709267)
• An early diagnosis and be useful for medical care of females with ID and MICPCH associated with CASK mutations. (PMID:23165780)
• a model whereby CASK recruits FRMD7 to the plasma membrane to promote neurite outgrowth during development of the oculomotor neural network and that defects in this interaction result in nystagmus. (PMID:23406872)
• The findings suggest that CASK and the truncated prestin splice isoform contribute to confinement of prestin to the basolateral region of the plasma membrane. (PMID:23542924)
• CASK regulates CaMKII autophosphorylation in a pathway required for memory formation. (PMID:23543616)
• CASK represents an intracellular gateway to regulate purinergic nociceptive signaling. (PMID:23600800)
• our findings suggest a molecular mechanism by which CASK binding regulates SAP97 conformation and its subsequent sorting and synaptic targeting of AMPARs and NMDARs during trafficking to synapses. (PMID:23864692)
• Data indicate that patients with low calcium/calmodulin-dependent serine protein kinase (CASK) staining had a significantly better survival compared to patients with high CASK staining. (PMID:24927672)
• In clinical specimens, CASK was over-expressed in tumors and H. pylori positive tissues, and its mRNA levels were inversely correlated with miR-203 expression. (PMID:25373785)
• we report a patient presenting with a complex phenotype consisting of severe, adult-onset, dilated cardiomyopathy, hearing loss and developmental delay, in which exome sequencing revealed two genetic variants that are inherited from a healthy mother: a novel missense variant in the CASK gene, mutations in which cause a spectrum of neurocognitive manifestations (PMID:27173948)
• During atrial dilation/remodeling, CASK expression was reduced but its localization remained unchanged. (PMID:27364017)
• The CASK as a novel regulator of Cav1.2 via a modulation of the voltage-gated calcium channel Cav1.2 open probability. (PMID:27720444)
• we provide a further characterization of genotype-phenotype correlations in CASK mutations and the presentation of nystagmus and the FGS4 phenotype. (PMID:28139025)
• Authors have identified mutations in PAK3, CASK, and MECP2 that likely contribute to intellectual disability, and the findings extend the spectrum of mutations and phenotypes associated with X-linked intellectual disability. (PMID:28481730)
• findings demonstrate that microcephaly with pontine and cerebellar hypoplasia (MICPCH) is a genetically heterogeneous condition, in which CASK inactivating mutations appear to account for the majority of MICPCH cases and with severer phenotypes, while the non-CASK mutation cases tend to have milder microcephaly (PMID:28783747)
• Data suggest that children with heterozygous mutation in the gene CASK kinase (CASK) and mental retardation and microcephaly with pontine and cerebellar hypoplasia (MICPCH) are responsive to intensive therapy aimed at increasing functional skills/independence. (PMID:29258560)
• Our results suggest that disruption of the CASK-neurexin interaction, not the CASK-Tbr-1 interaction, produces microcephaly and cerebellar hypoplasia. (PMID:29426960)
• we utilized in vivo complementation studies to demonstrate that the three point mutations confer a loss-of-function effect. This work endorses zebrafish as a tractable model to rapidly assess the effect of novel CASK variants on brain development. (PMID:29691940)
• Our data suggest that the CASK interactions mediated by the CaMK domain may play a crucial role in retinal function, and thus, in addition to optic nerve hypoplasia , individuals with mutations in the CASK gene may exhibit other retinal disorders, depending on the nature of mutation. (PMID:30549415)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	caska	ENSDARG00000059809
danio_rerio	caskb	ENSDARG00000100119
mus_musculus	Cask	ENSMUSG00000031012
rattus_norvegicus	Cask	ENSRNOG00000060946

Paralogs (7): PALS1 (ENSG00000072415), MPP4 (ENSG00000082126), PALS2 (ENSG00000105926), MPP2 (ENSG00000108852), MPP1 (ENSG00000130830), MPP7 (ENSG00000150054), MPP3 (ENSG00000161647)

Protein

Protein identifiers

Peripheral plasma membrane protein CASK — O14936 (reviewed: O14936)

Alternative names: Calcium/calmodulin-dependent serine protein kinase, Protein lin-2 homolog

All UniProt accessions (17): O14936, A0A2R8Y3B3, A0A2R8Y472, A0A2R8Y4K4, A0A2R8Y6D8, A0A2R8Y6F8, A0A2R8Y7X6, A0A2R8YE77, A0A2R8YEJ7, A0A2R8YEK3, A0A2R8YFN5, A0A2R8YGH2, A0A2U3TZM1, A0A2U3TZM4, A0A2U3TZN6, A0A7I2RJN6, Q5JS79

UniProt curated annotations — full annotation on UniProt →

Function. Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking. Contributes to neural development and regulation of gene expression via interaction with the transcription factor TBR1. Binds to cell-surface proteins, including amyloid precursor protein, neurexins and syndecans. May mediate a link between the extracellular matrix and the actin cytoskeleton via its interaction with syndecan and with the actin/spectrin-binding protein 4.1. Component of the LIN-10-LIN-2-LIN-7 complex, which associates with the motor protein KIF17 to transport vesicles containing N-methyl-D-aspartate (NMDA) receptor subunit NR2B along microtubules.

Subunit / interactions. CASK and LIN7 form two mutually exclusive tripartite complexes with APBA1 or CASKIN1. Component of the brain-specific heterotrimeric complex (LIN-10-LIN-2-LIN-7 complex) composed of at least APBA1, CASK, and LIN7, which associates with the motor protein KIF17 to transport vesicles along microtubules. Forms a heterotrimeric complex with DLG1 and LIN7B via their L27 domains. Identified in a complex with ACTN4, IQGAP1, MAGI2, NPHS1, SPTAN1 and SPTBN1. Part of a complex containing CASK, TBR1 and TSPYL2. Interacts with WHRN. Interacts (via the PDZ, SH3 and guanylate kinase-like domains) with NRXN1 (via C-terminus). Interacts with CASKIN1, APBA1, LIN7(A/B/C) and L27 domain of DLG1 and isoform 2 of DLG4. Interacts with FCHSD2. Interacts with KIRREL3. Interacts with TBR1. Interacts with TSPYL2.

Subcellular location. Nucleus. Cytoplasm. Cell membrane.

Tissue specificity. Ubiquitous. Expression is significantly greater in brain relative to kidney, lung, and liver and in fetal brain and kidney relative to lung and liver.

Disease relevance. Intellectual developmental disorder with microcephaly and pontine and cerebellar hypoplasia (MICPCH) [MIM:300749] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Affected individuals can manifest a severe phenotype consisting of severe intellectual deficit, congenital or postnatal microcephaly, disproportionate brainstem and cerebellar hypoplasia. A milder phenotype consists of intellectual disability alone or associated with nystagmus. The disease is caused by variants affecting the gene represented in this entry. FG syndrome 4 (FGS4) [MIM:300422] FG syndrome (FGS) is an X-linked disorder characterized by intellectual disability, relative macrocephaly, hypotonia and constipation. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Differs from archetypal CaMK members in that the kinase domain exhibits a constitutively active conformation and the autoinhibitory region does not engage in direct contact with the ATP-binding cleft, although it still binds Ca(2+)/CAM.

Cofactor. Unlike other protein kinases, does not require a divalent cation such as magnesium for catalytic activity.

Domain organisation. The first L27 domain binds DLG1 and the second L27 domain probably binds LIN7. The protein kinase domain mediates the interaction with FCHSD2.

Similarity. In the N-terminal section; belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. CaMK subfamily. Belongs to the MAGUK family.

Isoforms (6)

UniProt ID	Names	Canonical?
O14936-1	1	yes
O14936-2	2
O14936-3	3
O14936-4	4
O14936-5	5
O14936-6	6

RefSeq proteins (5): NP_001119526, NP_001119527, NP_001354650, NP_001397674, NP_003679 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR004172	L27_dom	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR014775	L27_C	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035473	CASK_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036892	L27_dom_sf	Homologous_superfamily
IPR050716	MAGUK	Family

Pfam: PF00069, PF00595, PF00625, PF02828, PF07653

Enzyme classification (BRENDA):

• EC 2.7.11.1 — non-specific serine/threonine protein kinase (BRENDA: 71 organisms, 682 substrates, 228 inhibitors, 23 Km, 6 kcat entries)
• EC 2.7.4.8 — guanylate kinase (BRENDA: 22 organisms, 121 substrates, 63 inhibitors, 85 Km, 28 kcat entries)

Substrate kinetics (BRENDA)

26 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GMP	0.002–1.8	39
DGMP	0.01–0.4	15
ATP	0.0007–0.64	11
ATP	0.12–1	6
MGATP2-	0.2–0.45	5
KKRAARATSNVFA	0.013–0.045	3
8-AZAGUANOSINE 5’-MONOPHOSPHATE	0.013–0.091	3
PAH1 PHOSPHATIDATE PHOSPHATASE	0.0002	2
RRRLSSLRA	0.0036–0.0037	2
GTP	0.46	1
KKRAARASSNVFA	0.02	1
LYS-LYS-PHE-ASN-ARG-THR-LEU-SER-VAL-ALA	0.0093	1
MYELIN BASIC PROTEIN	0.145	1
(R)-GANCICLOVIR PHOSPHONATE	0.052	1
6-THIOGUANOSINE 5’-MONOPHOSPHATE	2.1	1

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (99 total): helix 33, strand 23, modified residue 8, domain 6, splice variant 6, sequence variant 6, turn 6, sequence conflict 4, region of interest 3, binding site 2, chain 1, active site 1

Structure

Experimental structures (PDB)

22 structures.

PDB	Method	Resolution (Å)
1KGD	X-RAY DIFFRACTION	1.31
9M6G	X-RAY DIFFRACTION	1.7
9KYS	X-RAY DIFFRACTION	1.76
9M5Y	X-RAY DIFFRACTION	1.8
3C0I	X-RAY DIFFRACTION	1.85
6NH9	X-RAY DIFFRACTION	1.85
6NID	X-RAY DIFFRACTION	1.86
1KWA	X-RAY DIFFRACTION	1.93
7OAJ	X-RAY DIFFRACTION	1.93
3MFR	X-RAY DIFFRACTION	2
3MFS	X-RAY DIFFRACTION	2.1
7OAL	X-RAY DIFFRACTION	2.17
3C0G	X-RAY DIFFRACTION	2.19
3MFT	X-RAY DIFFRACTION	2.2
3TAC	X-RAY DIFFRACTION	2.2
8Y68	X-RAY DIFFRACTION	2.2
7OAK	X-RAY DIFFRACTION	2.23
3C0H	X-RAY DIFFRACTION	2.3
3MFU	X-RAY DIFFRACTION	2.3
7OAI	X-RAY DIFFRACTION	2.3
6KMH	X-RAY DIFFRACTION	2.4
1ZL8	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14936-F1	79.45	0.46

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 141

Ligand- & substrate-binding residues (2): 18–26; 41

Post-translational modifications (8): 51, 151, 155, 182, 313, 571, 577, 192

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-212676	Dopamine Neurotransmitter Release Cycle
R-HSA-3000170	Syndecan interactions
R-HSA-373753	Nephrin family interactions
R-HSA-6794361	Neurexins and neuroligins
R-HSA-9609736	Assembly and cell surface presentation of NMDA receptors
R-HSA-9662360	Sensory processing of sound by inner hair cells of the cochlea
R-HSA-9662361	Sensory processing of sound by outer hair cells of the cochlea

MSigDB gene sets: 715 (showing top): GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_TRANSPORT, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, ACTACCT_MIR196A_MIR196B, GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, WANG_CLIM2_TARGETS_UP, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_KERATINOCYTE_PROLIFERATION, GCANCTGNY_MYOD_Q6, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_EXOCYTOSIS, AREB6_01, GOBP_NEUROTRANSMITTER_TRANSPORT, KEGG_TIGHT_JUNCTION

GO Biological Process (15): negative regulation of cell-matrix adhesion (GO:0001953), cell adhesion (GO:0007155), intracellular protein localization (GO:0008104), negative regulation of keratinocyte proliferation (GO:0010839), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neurotransmitter secretion (GO:0046928), establishment of localization in cell (GO:0051649), negative regulation of wound healing (GO:0061045), calcium ion import (GO:0070509), positive regulation of calcium ion import (GO:0090280), negative regulation of cellular response to growth factor stimulus (GO:0090288), regulation of synaptic vesicle exocytosis (GO:2000300), protein phosphorylation (GO:0006468), GMP metabolic process (GO:0046037), GDP metabolic process (GO:0046710)

GO Molecular Function (12): GMP kinase activity (GO:0004385), protein serine/threonine kinase activity (GO:0004674), signaling receptor binding (GO:0005102), calmodulin binding (GO:0005516), ATP binding (GO:0005524), neurexin family protein binding (GO:0042043), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (20): basement membrane (GO:0005604), nuclear lamina (GO:0005652), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), basolateral plasma membrane (GO:0016323), nuclear matrix (GO:0016363), vesicle (GO:0031982), presynaptic membrane (GO:0042734), ciliary membrane (GO:0060170), Schaffer collateral - CA1 synapse (GO:0098685), nucleus (GO:0005634), membrane (GO:0016020), cell junction (GO:0030054), synapse (GO:0045202), cell periphery (GO:0071944)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Sensory processing of sound	2
Neurotransmitter release cycle	1
Non-integrin membrane-ECM interactions	1
Cell-Cell communication	1
Protein-protein interactions at synapses	1
Activation of NMDA receptors and postsynaptic events	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
purine ribonucleotide metabolic process	2
protein kinase activity	2
protein binding	2
nuclear lumen	2
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
negative regulation of cell-substrate adhesion	1
cellular process	1
macromolecule localization	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
negative regulation of epithelial cell proliferation	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
neurotransmitter secretion	1
modulation of chemical synaptic transmission	1
regulation of neurotransmitter transport	1
regulation of secretion by cell	1
establishment of localization	1
cellular localization	1
negative regulation of response to external stimulus	1
wound healing	1
regulation of wound healing	1
negative regulation of response to wounding	1
calcium ion transport	1
positive regulation of calcium ion transport	1
calcium ion import	1
regulation of calcium ion import	1
negative regulation of response to stimulus	1
cellular response to growth factor stimulus	1
regulation of cellular response to growth factor stimulus	1
synaptic vesicle exocytosis	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
phosphorylation	1
protein modification process	1
purine ribonucleoside monophosphate metabolic process	1
purine ribonucleoside diphosphate metabolic process	1

Protein interactions and networks

STRING

3337 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CASK	LIN7A	O14910	999
CASK	APBA1	Q02410	982
CASK	FRMD7	Q6ZUT3	897
CASK	CASKIN1	Q8WXD9	871
CASK	KIF17	Q9P2E2	846
CASK	NRXN1	Q9ULB1	839
CASK	LIN7C	Q9NUP9	826
CASK	TBR1	Q16650	817
CASK	SDC2	P34741	789
CASK	NRXN2	Q9P2S2	788
CASK	EPB41	P11171	775
CASK	DLG1	Q12959	744
CASK	CD2BP2	O95400	720
CASK	GRIN2B	Q13224	713
CASK	EPS8	Q12929	708

IntAct

579 interactions, top by confidence:

A	B	Type	Score
LIN7A	CASK	psi-mi:“MI:0915”(physical association)	0.830
CASK	LIN7A	psi-mi:“MI:0915”(physical association)	0.830
CASK	CFTR	psi-mi:“MI:0407”(direct interaction)	0.710
CASK	APC	psi-mi:“MI:0407”(direct interaction)	0.710
APC	CASK	psi-mi:“MI:0407”(direct interaction)	0.710
CFTR	CASK	psi-mi:“MI:0407”(direct interaction)	0.710
ARHGEF26	CASK	psi-mi:“MI:0914”(association)	0.690
ARHGEF26	CASK	psi-mi:“MI:0407”(direct interaction)	0.690
CASK	SNTB2	psi-mi:“MI:0915”(physical association)	0.670
SNTB2	CASK	psi-mi:“MI:0915”(physical association)	0.670
SH2D4A	CASK	psi-mi:“MI:0915”(physical association)	0.670
CASK	SH2D4A	psi-mi:“MI:0915”(physical association)	0.670
CASK	SDC2	psi-mi:“MI:0915”(physical association)	0.670
CASK	SDC2	psi-mi:“MI:0407”(direct interaction)	0.670
SNTB2	CASK	psi-mi:“MI:0914”(association)	0.670
KCNJ2	KCNJ18	psi-mi:“MI:2364”(proximity)	0.660
E6	CASK	psi-mi:“MI:0407”(direct interaction)	0.660
E6	TAX1BP3	psi-mi:“MI:0914”(association)	0.650
CYSLTR2	CASK	psi-mi:“MI:0914”(association)	0.590
MAS1	CASK	psi-mi:“MI:0914”(association)	0.590
ADRA1D	LIN7A	psi-mi:“MI:0914”(association)	0.590
DUSP10	CASK	psi-mi:“MI:0914”(association)	0.590
DLGAP4	LIN7A	psi-mi:“MI:0914”(association)	0.590
APBA1	LIN7A	psi-mi:“MI:0914”(association)	0.590
SLC16A3	CASK	psi-mi:“MI:0914”(association)	0.590
DLGAP4	CASK	psi-mi:“MI:0407”(direct interaction)	0.590
KCNA4	CASK	psi-mi:“MI:0407”(direct interaction)	0.590

BioGRID (307): LIN7A (Two-hybrid), SH2D4A (Two-hybrid), CASK (Affinity Capture-MS), ABLIM1 (Affinity Capture-MS), DLG1 (Affinity Capture-MS), DTNB (Affinity Capture-MS), EEF2 (Affinity Capture-MS), LIN7C (Affinity Capture-MS), ARHGEF26 (Affinity Capture-MS), SNTB2 (Affinity Capture-MS), CASK (Affinity Capture-MS), CASK (Affinity Capture-MS), CASK (Affinity Capture-MS), CASK (Co-fractionation), CASK (Affinity Capture-MS)

ESM2 similar proteins: A0A4X1T4U3, A4IFD0, O00329, O14936, O35904, O61069, O65583, O70589, P07953, P16118, P25114, P49872, P70266, Q13057, Q16875, Q16877, Q24210, Q28901, Q298L5, Q2UM43, Q32M07, Q4R3W4, Q4R8B6, Q4V8A1, Q502L7, Q5B5L3, Q5M7G4, Q5R9C1, Q623S8, Q62915, Q68FP8, Q6DGQ8, Q6DTY7, Q6P618, Q80UN9, Q8IMX7, Q8MIR4, Q91309, Q91348, Q91YL3

Diamond homologs: A2ASS6, A2CG49, A4IFM7, A8C984, A8X6H4, E9PT87, F1M0Z1, O02827, O14936, O43293, O44997, O49717, O54784, O60229, O70589, O75962, O80673, O88764, O94768, P07313, P08414, P0C5E3, P11801, P13234, P20689, P25323, P53355, P53681, P53684, P70402, P93759, P97924, Q05623, Q06850, Q0KL02, Q0V7M1, Q10KY3, Q13203, Q14012, Q16566

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
ID1	unknown	CASK	binding
CASK	up-regulates	Exocytosis
KIRREL3	“up-regulates activity”	CASK	binding
CASK	“form complex”	“CASK-Mint1-Veli complex”	binding
CASK	up-regulates	Synaptic_vesicle_exocytosis
CDK5	“up-regulates activity”	CASK	phosphorylation
APBA1	“up-regulates activity”	CASK	binding
CASK	up-regulates	TBR1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 170 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Neurexins and neuroligins	11	17.8×	1e-08
Formation of paraxial mesoderm	5	16.7×	1e-03
Assembly and cell surface presentation of NMDA receptors	8	16.6×	8e-06
Activation of NMDA receptors and postsynaptic events	7	10.6×	8e-04
EPH-Ephrin signaling	7	9.5×	1e-03
Recycling pathway of L1	5	9.2×	9e-03
Transcriptional and post-translational regulation of MITF-M expression and activity	6	8.8×	4e-03
Neurotransmitter receptors and postsynaptic signal transmission	9	7.4×	8e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

1215 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	138
Likely pathogenic	78
Uncertain significance	373
Likely benign	279
Benign	87

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1047878	GRCh37/hg19 Xp11.4-11.3(chrX:41342834-43901936)	Pathogenic
1047884	GRCh37/hg19 Xp11.4(chrX:41553564-41696352)	Pathogenic
1076957	NM_001367721.1(CASK):c.938C>G (p.Ser313Ter)	Pathogenic
11530	NM_001367721.1(CASK):c.1915C>T (p.Arg639Ter)	Pathogenic
11531	NM_001367721.1(CASK):c.915G>A (p.Lys305=)	Pathogenic
11532	NM_001367721.1(CASK):c.83G>T (p.Arg28Leu)	Pathogenic
11535	NM_001367721.1(CASK):c.2755T>C (p.Trp919Arg)	Pathogenic
1180515	GRCh37/hg19 Xp11.4(chrX:41700325-41826061)x1	Pathogenic
1205490	NM_001367721.1(CASK):c.437G>A (p.Cys146Tyr)	Pathogenic
1299183	NM_001367721.1(CASK):c.588C>G (p.Tyr196Ter)	Pathogenic
1338270	NM_001367721.1(CASK):c.1683dup (p.Ser562fs)	Pathogenic
1377857	NM_001367721.1(CASK):c.29_30dup (p.Val11fs)	Pathogenic
1440705	NM_001367721.1(CASK):c.2138T>A (p.Leu713Ter)	Pathogenic
1453222	NM_001367721.1(CASK):c.1652_1655dup (p.Gln553fs)	Pathogenic
1460206	NM_001367721.1(CASK):c.2040-2A>G	Pathogenic
153161	GRCh38/hg38 Xp11.4-11.3(chrX:41827804-43285505)x1	Pathogenic
158066	NM_001367721.1(CASK):c.1644_1645del (p.Val549fs)	Pathogenic
158069	NM_001367721.1(CASK):c.2041C>T (p.Arg681Ter)	Pathogenic
158071	NM_001367721.1(CASK):c.20_27del (p.Leu7fs)	Pathogenic
158074	NM_001367721.1(CASK):c.2485C>T (p.Gln829Ter)	Pathogenic
158077	NM_001367721.1(CASK):c.430-2A>T	Pathogenic
158082	NM_001367721.1(CASK):c.708+1G>A	Pathogenic
158086	NM_001367721.1(CASK):c.82C>T (p.Arg28Ter)	Pathogenic
158087	NM_001367721.1(CASK):c.880C>T (p.Gln294Ter)	Pathogenic
1676383	NM_001367721.1(CASK):c.1972C>T (p.Gln658Ter)	Pathogenic
1692990	NM_001367721.1(CASK):c.825G>A (p.Trp275Ter)	Pathogenic
1699292	NM_001367721.1(CASK):c.2039+1G>A	Pathogenic
1701858	NM_001367721.1(CASK):c.2252_2253del (p.Gly751fs)	Pathogenic
1707714	NC_000023.10:g.(?41387096)(41396627_?)del	Pathogenic
1784171	NM_001367721.1(CASK):c.1A>G (p.Met1Val)	Pathogenic

SpliceAI

5121 predictions. Top by Δscore:

Variant	Effect	Δscore
X:41520630:A:C	acceptor_gain	1.0000
X:41523945:TCTTA:T	donor_loss	1.0000
X:41523946:CTTAC:C	donor_loss	1.0000
X:41523948:TACC:T	donor_loss	1.0000
X:41523949:A:AC	donor_gain	1.0000
X:41523950:C:CA	donor_loss	1.0000
X:41523950:C:CC	donor_gain	1.0000
X:41523950:CCT:C	donor_gain	1.0000
X:41524033:GCC:G	acceptor_loss	1.0000
X:41524034:CCTG:C	acceptor_gain	1.0000
X:41524035:C:A	acceptor_loss	1.0000
X:41524035:C:CC	acceptor_gain	1.0000
X:41524036:T:A	acceptor_loss	1.0000
X:41524037:G:GC	acceptor_gain	1.0000
X:41524040:T:TC	acceptor_gain	1.0000
X:41531001:CATTA:C	donor_loss	1.0000
X:41531002:ATTAC:A	donor_loss	1.0000
X:41531003:TTA:T	donor_loss	1.0000
X:41531004:TA:T	donor_loss	1.0000
X:41531006:C:CG	donor_loss	1.0000
X:41531207:TATCT:T	acceptor_loss	1.0000
X:41531209:TCTGC:T	acceptor_loss	1.0000
X:41531210:C:A	acceptor_loss	1.0000
X:41531210:C:CC	acceptor_gain	1.0000
X:41531219:CGCA:C	acceptor_gain	1.0000
X:41534700:GCTTA:G	donor_loss	1.0000
X:41534701:CT:C	donor_loss	1.0000
X:41534702:TTAC:T	donor_loss	1.0000
X:41534703:T:TG	donor_loss	1.0000
X:41534704:A:AC	donor_gain	1.0000

AlphaMissense

6137 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:41520431:A:G	W924R	1.000
X:41520431:A:T	W924R	1.000
X:41520446:A:G	W919R	1.000
X:41520446:A:T	W919R	1.000
X:41520484:A:G	L906P	1.000
X:41520513:G:C	N896K	1.000
X:41520513:G:T	N896K	1.000
X:41520565:G:A	S879F	1.000
X:41520566:A:G	S879P	1.000
X:41520577:A:G	L875P	1.000
X:41524021:A:G	L845P	1.000
X:41531021:C:G	D836H	1.000
X:41531023:A:G	L835P	1.000
X:41531026:A:C	I834R	1.000
X:41531026:A:T	I834K	1.000
X:41531077:C:A	G817V	1.000
X:41531077:C:T	G817E	1.000
X:41531078:C:A	G817W	1.000
X:41531078:C:G	G817R	1.000
X:41531078:C:T	G817R	1.000
X:41531081:A:G	Y816H	1.000
X:41531101:C:T	G809D	1.000
X:41531110:A:G	L806S	1.000
X:41531200:C:G	R776T	1.000
X:41534714:G:C	P770R	1.000
X:41534714:G:T	P770H	1.000
X:41534747:A:G	L759P	1.000
X:41534752:G:C	N757K	1.000
X:41534752:G:T	N757K	1.000
X:41534755:T:A	K756N	1.000

dbSNP variants (sampled 300 via entrez): RS1000014335 (X:41726803 T>C), RS1000023565 (X:41551761 T>A), RS1000050542 (X:41677465 T>C), RS1000056582 (X:41536490 C>T), RS1000057435 (X:41720813 C>T), RS1000059615 (X:41866857 C>T), RS1000075310 (X:41622979 C>T), RS1000078079 (X:41602770 A>G), RS1000112660 (X:41605705 G>A,T), RS1000149726 (X:41630615 G>T), RS1000151631 (X:41799901 T>C), RS1000184283 (X:41848748 C>G), RS1000219020 (X:41802084 T>A,C), RS1000225713 (X:41611001 C>T), RS1000226116 (X:41757402 A>G)

Disease associations

OMIM: gene MIM:300172 | disease phenotypes: MIM:300749, MIM:300422, MIM:300908, MIM:309510, MIM:213000, MIM:300486, MIM:617936, MIM:300958, MIM:305450, MIM:308350

GenCC curated gene-disease

Disease	Classification	Inheritance
FG syndrome 4	Definitive	X-linked
syndromic X-linked intellectual disability Najm type	Definitive	X-linked
genetic developmental and epileptic encephalopathy	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked syndromic intellectual disability	Definitive	XL

Mondo (17): syndromic X-linked intellectual disability Najm type (MONDO:0010417), microcephaly (MONDO:0001149), neurodevelopmental disorder (MONDO:0700092), intellectual disability (MONDO:0001071), FG syndrome 4 (MONDO:0010318), anemia, nonspherocytic hemolytic, due to G6PD deficiency (MONDO:0010480), prostate cancer (MONDO:0008315), X-linked syndromic intellectual disability (MONDO:0020119), isolated cerebellar hypoplasia/agenesis (MONDO:0008939), X-linked intellectual disability-cerebellar hypoplasia syndrome (MONDO:0010337), butyrylcholinesterase deficiency (MONDO:0015270), intellectual disability, X-linked 102 (MONDO:0010497), dystonic disorder (MONDO:0003441), pathologic nystagmus (MONDO:0004843), FG syndrome (MONDO:0002010)

Orphanet (11): X-linked intellectual disability, Najm type (Orphanet:163937), Class I glucose-6-phosphate dehydrogenase deficiency (Orphanet:466026), Familial prostate cancer (Orphanet:1331), X-linked intellectual disability-cerebellar hypoplasia syndrome (Orphanet:137831), Isolated cerebellar agenesis (Orphanet:1398), Cerebellar hypoplasia-tapetoretinal degeneration syndrome (Orphanet:2246), Hereditary butyrylcholinesterase deficiency (Orphanet:132), X-linked intellectual disability-hypotonia-movement disorder syndrome (Orphanet:457260), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658), OBSOLETE: X-linked syndromic intellectual disability (Orphanet:98464), NON RARE IN EUROPE: FG syndrome phenotypic spectrum (Orphanet:323)

HPO phenotypes

146 total (30 of 146 shown, HPO-id order):

HPO	Term
HP:0000054	Micropenis
HP:0000070	Ureterocele
HP:0000110	Renal dysplasia
HP:0000175	Cleft palate
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000300	Oval face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000337	Broad forehead
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000365	Hearing impairment
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000431	Wide nasal bridge
HP:0000455	Broad nasal tip
HP:0000463	Anteverted nares
HP:0000480	Retinal coloboma
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000505	Visual impairment
HP:0000543	Optic disc pallor
HP:0000545	Myopia
HP:0000609	Optic nerve hypoplasia

GWAS associations

0 associations (top):

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D065886	Neurodevelopmental Disorders	F03.625
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750
C567533	Anemia, Nonspherocytic Hemolytic, Due To G6pd Deficiency (supp.)
C537417	Butyrylcholinesterase deficiency (supp.)
C562568	Cerebellar Hypoplasia (supp.)
C567466	Mental Retardation And Microcephaly With Pontine And Cerebellar Hypoplasia (supp.)
C537456	Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1908381 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

9 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 46,929 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL288441	BOSUTINIB	4	12,255
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL603469	LESTAURTINIB	3
CHEMBL3655762	CYC-065	2	388
CHEMBL384304	RG-547	2	93
CHEMBL445813	AT-7519	2	2,614
CHEMBL296468	BMS-387032	1	2,075

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — CASK family

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 26 [PMID: 34543009]	Binding	7.66	pKd

ChEMBL bioactivities

44 potent at pChembl≥5 of 45 total, top 42 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.34	Kd	4.6	nM	CHEMBL2312304
8.29	Ki	5.1	nM	STAUROSPORINE
8.20	IC50	6.3	nM	STAUROSPORINE
8.09	IC50	8.1	nM	CHEMBL4850857
7.96	Ki	11	nM	CHEMBL4850857
7.88	IC50	13.2	nM	CHEMBL3969723
7.82	Ki	15	nM	CHEMBL2312304
7.82	Ki	15	nM	CHEMBL4876584
7.72	Kd	19	nM	STAUROSPORINE
7.66	Kd	22	nM	CHEMBL4850857
7.66	Kd	22	nM	CHEMBL4762515
7.62	Kd	24	nM	AT-7519
7.42	Kd	38	nM	CHEMBL4876584
7.22	Kd	60	nM	CHEMBL4846209
7.18	Kd	66	nM	RG-547
7.10	IC50	80	nM	CHEMBL4850857
7.10	IC50	80	nM	CHEMBL4762515
7.06	Kd	87	nM	CHEMBL2312304
6.97	IC50	106	nM	CHEMBL4876584
6.89	IC50	130	nM	CHEMBL2312304
6.85	Kd	140	nM	CHEMBL2312303
6.85	Kd	140	nM	CRIZOTINIB
6.66	Kd	220	nM	CHEMBL4847568
6.65	IC50	224.4	nM	BMS-387032
6.48	Kd	330	nM	LESTAURTINIB
6.40	Kd	400	nM	BMS-387032
6.36	IC50	439.7	nM	CHEMBL4587232
6.34	Kd	454	nM	CHEMBL4465866
6.26	Kd	550	nM	CHEMBL6108991
6.20	Kd	630	nM	CHEMBL4856516
6.08	Kd	830	nM	BOSUTINIB
6.04	Kd	920	nM	TAE-684
6.00	IC50	1000	nM	TP-030-1
6.00	IC50	1000	nM	TP-030-2
6.00	IC50	1000	nM	TP-030n
5.96	Kd	1088	nM	CHEMBL4576489
5.92	IC50	1200	nM	BISINDOLYLMALEIMIDE IX
5.82	Kd	1500	nM	RUXOLITINIB
5.80	Kd	1600	nM	CHEMBL1241674
5.77	Kd	1700	nM	PHA-665752
5.71	IC50	1930	nM	CHEMBL4847568
5.55	Kd	2800	nM	FEDRATINIB

PubChem BioAssay actives

29 with measured affinity, of 175 total; 21 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-(cyclopentylamino)-2-[(2,5-dichlorophenyl)methylamino]-N-[3-(2-oxo-1,3-oxazolidin-3-yl)propyl]pyrimidine-5-carboxamide	1771915: Binding affinity to human CASK by KINOMEscan scanMAX assay	kd	0.0046	uM
4-(cyclopentylamino)-2-[(2,5-dibromo-4-methylphenyl)methylamino]-N-[3-(2-oxo-1,3-oxazolidin-3-yl)propyl]pyrimidine-5-carboxamide	1771932: Inhibition of tracer K5 binding to NanoLuc-fused CASK (unknown origin) expressed in HEK293T cells measured after 2 hrs by NanoBRET assay	ki	0.0110	uM
4-(cyclohexylamino)-2-[(2,5-dibromo-4-methylphenyl)methylamino]-N-[3-(2-oxo-1,3-oxazolidin-3-yl)propyl]pyrimidine-5-carboxamide	1771932: Inhibition of tracer K5 binding to NanoLuc-fused CASK (unknown origin) expressed in HEK293T cells measured after 2 hrs by NanoBRET assay	ki	0.0150	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624749: Binding constant for CASK kinase domain	kd	0.0190	uM
4-[(2,6-dichlorobenzoyl)amino]-N-piperidin-4-yl-1H-pyrazole-5-carboxamide	624749: Binding constant for CASK kinase domain	kd	0.0240	uM
4-(cyclopentylamino)-2-[(2,5-dibromophenyl)methylamino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide	1771928: Binding affinity to recombinant N-terminal His-tagged CASK (1 to 337 residues) (unknown origin) expressed in Escherichia coli assessed as dissociation constant by isothermal titration calorimetry	kd	0.0600	uM
[4-amino-2-[(1-methylsulfonylpiperidin-4-yl)amino]pyrimidin-5-yl]-(2,3-difluoro-6-methoxyphenyl)methanone	624749: Binding constant for CASK kinase domain	kd	0.0660	uM
Crizotinib	624749: Binding constant for CASK kinase domain	kd	0.1400	uM
4-(cyclopentylamino)-2-[(2,5-dichlorophenyl)methylamino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide	1771928: Binding affinity to recombinant N-terminal His-tagged CASK (1 to 337 residues) (unknown origin) expressed in Escherichia coli assessed as dissociation constant by isothermal titration calorimetry	kd	0.1400	uM
4-(cyclopentylamino)-2-[(2,4-dichlorophenyl)methylamino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide	1771928: Binding affinity to recombinant N-terminal His-tagged CASK (1 to 337 residues) (unknown origin) expressed in Escherichia coli assessed as dissociation constant by isothermal titration calorimetry	kd	0.2200	uM
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	624749: Binding constant for CASK kinase domain	kd	0.3300	uM
N-[5-[(5-tert-butyl-1,3-oxazol-2-yl)methylsulfanyl]-1,3-thiazol-2-yl]piperidine-4-carboxamide	624749: Binding constant for CASK kinase domain	kd	0.4000	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]amino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526156: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged CASK (unknown origin) (1 to 570 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	0.4540	uM
4-(cyclopentylamino)-2-[(2,5-difluorophenyl)methylamino]-N-[3-(2-oxopyrrolidin-1-yl)propyl]pyrimidine-5-carboxamide	1771928: Binding affinity to recombinant N-terminal His-tagged CASK (1 to 337 residues) (unknown origin) expressed in Escherichia coli assessed as dissociation constant by isothermal titration calorimetry	kd	0.6300	uM
Bosutinib	624749: Binding constant for CASK kinase domain	kd	0.8300	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624749: Binding constant for CASK kinase domain	kd	0.9200	uM
3-(2,2-difluoro-10,12-dimethyl-1-aza-3-azonia-2-boranuidatricyclo[7.3.0.03,7]dodeca-3,5,7,9,11-pentaen-4-yl)-N-[2-[2-[2-[2-[[(2S,3R,4R,6R)-3-methoxy-2-methyl-16-oxo-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-4-yl]-methylamino]ethoxy]ethoxy]ethoxy]ethyl]propanamide	1526156: Binding affinity to recombinant N-terminal His-FLAG-GST-tagged CASK (unknown origin) (1 to 570 residues) expressed in baculovirus infected Sf9 insect cells incubated for 1 hr by TR-FRET assay	kd	1.0880	uM
Ruxolitinib	624749: Binding constant for CASK kinase domain	kd	1.5000	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624749: Binding constant for CASK kinase domain	kd	1.6000	uM
(3Z)-5-[(2,6-dichlorophenyl)methylsulfonyl]-3-[[3,5-dimethyl-4-[(2R)-2-(pyrrolidin-1-ylmethyl)pyrrolidine-1-carbonyl]-1H-pyrrol-2-yl]methylidene]-1H-indol-2-one	624749: Binding constant for CASK kinase domain	kd	1.7000	uM
Fedratinib	624749: Binding constant for CASK kinase domain	kd	2.8000	uM

CTD chemical–gene interactions

55 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	6
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	5
Aflatoxin B1	affects expression, decreases methylation, increases methylation	3
bisphenol A	increases expression, decreases methylation	2
bisphenol S	increases expression, increases methylation	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Lead	increases response to substance, decreases expression	2
Valproic Acid	increases methylation, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
butyraldehyde	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
benzo(e)pyrene	affects methylation	1
potassium chromate(VI)	decreases expression	1
4-hydroxy-2-nonenal	decreases expression	1
aflatoxin B2	increases methylation	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
deguelin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
torcetrapib	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

92 unique, capped per target: 92 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1174099	Binding	Inhibition of CASK at 10 uM	Broad spectrum alkynyl inhibitors of T315I Bcr-Abl. — Bioorg Med Chem Lett

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D7LR	Ubigene A-549 CASK KO	Cancer cell line	Male
CVCL_SG89	HAP1 CASK (-)	Cancer cell line	Male

Clinical trials (associated diseases)

310 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT06719141	PHASE3	RECRUITING	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathies (DEE)
NCT06908226	PHASE3	ENROLLING_BY_INVITATION	A Study to Investigate LP352 in Children and Adults With Developmental and Epileptic Encephalopathy (DEE)
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT05626634	PHASE2	COMPLETED	Open-label, Long-term Safety Study of LP352 in Subjects With Developmental and Epileptic Encephalopathy
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT06700811	PHASE1	RECRUITING	Ketogenic Diet for Prevention of Epileptic Spasms in Infantile Onset Genetic Epilepsies
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05364021	PHASE1/PHASE2	COMPLETED	Study to Investigate LP352 in Subjects With Developmental and Epileptic Encephalopathies
NCT06983158	PHASE1/PHASE2	SUSPENDED	A Clinical Trial of CAP-002 Gene Therapy in Pediatric Patients With Syntaxin-Binding Protein 1 (STXBP1) Encephalopathy
NCT04937062	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Phenylbutyrate for Monogenetic Developmental and Epileptic Encephalopathy
NCT06149663	Not specified	AVAILABLE	Intermediate-Size Expanded Access Protocol (EAP) for LP352
NCT06380192	Not specified	RECRUITING	Developmental and Epileptic Encephalopathy of Genetic Etiology: Natural History Through Reuse of Clinical Data
NCT07396883	Not specified	NOT_YET_RECRUITING	Developmental and Epileptic Encephalopathies Diagnosed Via Long-read Genome Sequencing
NCT07531511	Not specified	NOT_YET_RECRUITING	SLC6A1-NDD Prospective Longitudinal Natural History Study
NCT07585643	Not specified	NOT_YET_RECRUITING	IBIS - Investigating Reliability of BIS and SEDLINE Monitoring in Children With Developmental and Epileptic Encephalopathies (DEE).
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities