Autosomal dominant non-syndromic intellectual disability

Summary

Autosomal dominant non-syndromic intellectual disability (MONDO:0015802) is a disease (an umbrella term covering 26 Mondo subtypes) with 40 cohort genes. The dominant Reactome pathway is Ras activation upon Ca2+ influx through NMDA receptor (4 cohort genes).

At a glance

• Umbrella term: 26 Mondo subtypes
• Cohort genes: 40
• ClinVar variants: 14

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant non-syndromic intellectual disability
Mondo ID	MONDO:0015802
Orphanet	178469
DOID	DOID:0060307
UMLS	C5680502
MedGen	1826082
GARD	0012107
Is cancer (heuristic)	no

Also known as: autosomal dominant mental retardation · autosomal dominant non-syndromic intellectual disability · non-syndromic intellectual disability, autosomal dominant

Data availability: 14 ClinVar variants · 34 GenCC gene-disease records · 24 cell lines.

Disease family

An umbrella term covering 26 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability › non-syndromic intellectual disability › autosomal dominant non-syndromic intellectual disability

Related subtypes (2): non-syndromic X-linked intellectual disability, autosomal recessive non-syndromic intellectual disability

Subtypes (26): intellectual disability, autosomal dominant 22, neurodevelopmental disorder with hypotonia, stereotypic hand movements, and impaired language, intellectual disability, autosomal dominant 33, intellectual disability, autosomal dominant 34, intellectual disability, autosomal dominant 41, intellectual disability, autosomal dominant 43, intellectual disability, autosomal dominant 58, intellectual disability, autosomal dominant 45, intellectual disability, autosomal dominant 46, intellectual disability, autosomal dominant 47, Clark-Baraitser syndrome, intellectual disability, autosomal dominant 50, intellectual disability, autosomal dominant 51, intellectual disability, autosomal dominant 52, intellectual disability, autosomal dominant 53, intellectual disability, autosomal dominant 54, intellectual disability, autosomal dominant 55, with seizures, intellectual disability, autosomal dominant 56, intellectual developmental disorder 61, intellectual developmental disorder 59, intellectual developmental disorder 60 with seizures, intellectual developmental disorder 62, intellectual developmental disorder, autosomal dominant 63, with macrocephaly, Coffin-Siris syndrome 6, intellectual disability, autosomal dominant 57, intellectual developmental disorder, autosomal dominant 73

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

14 retrieved; paginated sample, class counts are floors:

5 likely pathogenic, 4 pathogenic/likely pathogenic, 3 pathogenic, 2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1708217	NM_001386298.1(CIC):c.3059dup (p.His1021fs)	CIC	Pathogenic	criteria provided, single submitter
1283912	NM_004859.4(CLTC):c.2646_2649del (p.Ile882_Tyr883insTer)	CLTC	Pathogenic	criteria provided, single submitter
984851	NM_000834.5(GRIN2B):c.1177C>T (p.Arg393Ter)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
449043	NM_001244008.2(KIF1A):c.595G>A (p.Gly199Arg)	KIF1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13501	NM_002693.3(POLG):c.3151G>C (p.Gly1051Arg)	POLG	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3248542	NM_003620.4(PPM1D):c.1305_1308dup (p.Pro437fs)	PPM1D	Pathogenic	criteria provided, single submitter
585073	NM_001366145.2(TRPM3):c.3004G>A (p.Val1002Met)	TRPM3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1526270	NM_001320.7(CSNK2B):c.72+2T>G	CSNK2B	Likely pathogenic	criteria provided, single submitter
2444491	NM_021008.4(DEAF1):c.782G>C (p.Arg261Pro)	DEAF1	Likely pathogenic	criteria provided, single submitter
2442801	NM_002074.5(GNB1):c.498-2A>G	GNB1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339774	NM_004973.4(JARID2):c.12_13del (p.Arg5fs)	JARID2	Likely pathogenic	criteria provided, single submitter
3242240	NM_015021.3(ZNF292):c.4196_4197insAA (p.Tyr1399Ter)	ZNF292	Likely pathogenic	criteria provided, single submitter
3384194	NM_019842.4(KCNQ5):c.496G>A (p.Val166Met)	KCNQ5	Uncertain significance	criteria provided, single submitter
2573038	NM_198859.4(PRICKLE2):c.600G>C (p.Glu200Asp)	PRICKLE2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 226 · Orphanet: 80 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CAMK2B	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 40	4
CHAMP1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 40	4
CIC	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 45	5
CUX1	Definitive	Autosomal dominant	global developmental delay with or without impaired intellectual development	4
DEAF1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 24	11
DYNC1H1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 13	9
GRIN2B	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 6	9
HIVEP2	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 43	5
KIF1A	Definitive	Autosomal dominant	syndromic intellectual disability	19
SET	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 58	5
SYNGAP1	Definitive	Autosomal dominant	intellectual disability, autosomal dominant 5	6
TAOK1	Definitive	Autosomal dominant	syndromic intellectual disability	6
ASH1L	Strong	Autosomal dominant	intellectual disability, autosomal dominant 52	5
CAMK2A	Strong	Autosomal dominant	intellectual disability, autosomal dominant 53	6
CLTC	Strong	Autosomal dominant	intellectual disability, autosomal dominant 56	7
KCNQ5	Strong	Autosomal dominant	intellectual disability, autosomal dominant 46	4
MBD5	Strong	Autosomal dominant	intellectual disability, autosomal dominant 1	4
PPP3CA	Strong	Autosomal dominant	arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development	9
ZMYND11	Strong	Autosomal dominant	intellectual disability, autosomal dominant 30	5
BRSK2	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	5
CACNG2	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	3
CDH15	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	5
CSNK2B	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	5
DLL1	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	6
DOCK8	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	7
EEF1A2	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	7
EPB41L1	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	3
GRIN1	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	10
KIRREL3	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	4
MED12L	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CIC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DEAF1	Orphanet:468620	Intellectual disability-epilepsy-extrapyramidal syndrome
DEAF1	Orphanet:714385	Global developmental delay-high pain tolerance-intellectual disability syndrome
TRPM3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CLTC	Orphanet:178342	Inflammatory myofibroblastic tumor
CLTC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CLTC	Orphanet:319308	MiT family translocation renal cell carcinoma
CLTC	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CSNK2B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CSNK2B	Orphanet:689397	Poirier-Bienvenu neurodevelopmental syndrome
GRIN2B	Orphanet:589547	GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B	Orphanet:697160	Infantile epileptic spasms syndrome
KCNQ5	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KIF1A	Orphanet:101010	Autosomal spastic paraplegia type 30
KIF1A	Orphanet:662367	NESCAV syndrome
KIF1A	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SET	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SET	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
BRSK2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
SYNGAP1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SYNGAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SYNGAP1	Orphanet:544254	SYNGAP1-related developmental and epileptic encephalopathy
TCF4	Orphanet:171	Primary sclerosing cholangitis
TCF4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TCF4	Orphanet:2896	Pitt-Hopkins syndrome
TCF4	Orphanet:98974	Fuchs endothelial corneal dystrophy
CACNG2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CAMK2A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CAMK2B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
MED12L	Orphanet:528084	Non-specific syndromic intellectual disability
ZMYND11	Orphanet:687424	ZMYND11-related developmental delay-speech delay-seizures-behavioral abnormalities-craniofacial dysmorphism syndrome due to 10p15.3 microdeletion
ZMYND11	Orphanet:694308	ZMYND11-related developmental delay-speech delay-seizures-behavioral abnormalities-craniofacial dysmorphism syndrome due to a point mutation
CDH15	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ASH1L	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DOCK8	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DOCK8	Orphanet:217390	Combined immunodeficiency due to DOCK8 deficiency
CHAMP1	Orphanet:692193	CHAMP1-related intellectual disability-facial dysmorphism-behavioral abnormalities syndrome
MBD5	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
MBD5	Orphanet:228402	2q23.1 microdeletion syndrome
KIRREL3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CUX1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DLL1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DLL1	Orphanet:220386	Semilobar holoprosencephaly
DLL1	Orphanet:280195	Septopreoptic holoprosencephaly
DLL1	Orphanet:280200	Microform holoprosencephaly
DLL1	Orphanet:93924	Lobar holoprosencephaly
DLL1	Orphanet:93925	Alobar holoprosencephaly
DLL1	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly

Cohort genes → proteins

40 cohort genes, 40 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	40

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	gencc,clinvar
DEAF1	HGNC:14677	ENSG00000177030	O75398	Deformed epidermal autoregulatory factor 1 homolog	gencc,clinvar
TRPM3	HGNC:17992	ENSG00000083067	Q9HCF6	Transient receptor potential cation channel subfamily M member 3	gencc,clinvar
CLTC	HGNC:2092	ENSG00000141367	Q00610	Clathrin heavy chain 1	gencc,clinvar
CSNK2B	HGNC:2460	ENSG00000204435	P67870	Casein kinase II subunit beta	gencc,clinvar
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	gencc,clinvar
KCNQ5	HGNC:6299	ENSG00000185760	Q9NR82	Potassium voltage-gated channel subfamily KQT member 5	gencc,clinvar
KIF1A	HGNC:888	ENSG00000130294	Q12756	Kinesin-like protein KIF1A	gencc,clinvar
SET	HGNC:10760	ENSG00000119335	Q01105	Protein SET	gencc
BRSK2	HGNC:11405	ENSG00000174672	Q8IWQ3	Serine/threonine-protein kinase BRSK2	gencc
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	gencc
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	gencc
CACNG2	HGNC:1406	ENSG00000166862	Q9Y698	Voltage-dependent calcium channel gamma-2 subunit	gencc
CAMK2A	HGNC:1460	ENSG00000070808	Q9UQM7	Calcium/calmodulin-dependent protein kinase type II subunit alpha	gencc
CAMK2B	HGNC:1461	ENSG00000058404	Q13554	Calcium/calmodulin-dependent protein kinase type II subunit beta	gencc
MED12L	HGNC:16050	ENSG00000144893	Q86YW9	Mediator of RNA polymerase II transcription subunit 12-like protein	gencc
ZMYND11	HGNC:16966	ENSG00000015171	Q15326	Zinc finger MYND domain-containing protein 11	gencc
CDH15	HGNC:1754	ENSG00000129910	P55291	Cadherin-15	gencc
ASH1L	HGNC:19088	ENSG00000116539	Q9NR48	Histone-lysine N-methyltransferase ASH1L	gencc
DOCK8	HGNC:19191	ENSG00000107099	Q8NF50	Dedicator of cytokinesis protein 8	gencc
CHAMP1	HGNC:20311	ENSG00000198824	Q96JM3	Chromosome alignment-maintaining phosphoprotein 1	gencc
MBD5	HGNC:20444	ENSG00000204406	Q9P267	Methyl-CpG-binding domain protein 5	gencc
KIRREL3	HGNC:23204	ENSG00000149571	Q8IZU9	Kin of IRRE-like protein 3	gencc
CUX1	HGNC:2557	ENSG00000257923	P39880	Homeobox protein cut-like 1	gencc
DLL1	HGNC:2908	ENSG00000198719	O00548	Delta-like protein 1	gencc
TAOK1	HGNC:29259	ENSG00000160551	Q7L7X3	Serine/threonine-protein kinase TAO1	gencc
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	gencc
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	gencc
EPB41L1	HGNC:3378	ENSG00000088367	Q9H4G0	Band 4.1-like protein 1	gencc
GRIN1	HGNC:4584	ENSG00000176884	Q05586	Glutamate receptor ionotropic, NMDA 1	gencc
HIVEP2	HGNC:4921	ENSG00000010818	P31629	Transcription factor HIVEP2	gencc
PPP3CA	HGNC:9314	ENSG00000138814	Q08209	Protein phosphatase 3 catalytic subunit alpha	gencc
RAB11A	HGNC:9760	ENSG00000103769	P62491	Ras-related protein Rab-11A	gencc
ZNF292	HGNC:18410	ENSG00000188994	O60281	Zinc finger protein 292	clinvar
PRICKLE2	HGNC:20340	ENSG00000163637	Q7Z3G6	Prickle-like protein 2	clinvar
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	clinvar
JARID2	HGNC:6196	ENSG00000008083	Q92833	Protein Jumonji	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar
PPM1D	HGNC:9277	ENSG00000170836	O15297	Protein phosphatase 1D	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
DEAF1	Deformed epidermal autoregulatory factor 1 homolog	Transcription factor that binds to sequence with multiple copies of 5’-TTC[CG]G-3’ present in its own promoter and that of the HNRPA2B1 gene.
TRPM3	Transient receptor potential cation channel subfamily M member 3	Constitutively active, non-selective divalent cation-conducting channel that is permeable to Ca(2+), Mn(2+), and Mg(2+), with a high permeability for Ca(2+).
CLTC	Clathrin heavy chain 1	Clathrin is the major protein of the polyhedral coat of coated pits and vesicles.
CSNK2B	Casein kinase II subunit beta	Regulatory subunit of casein kinase II/CK2.
GRIN2B	Glutamate receptor ionotropic, NMDA 2B	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
KCNQ5	Potassium voltage-gated channel subfamily KQT member 5	Pore-forming subunit of the voltage-gated potassium (Kv) channel broadly expressed in brain and involved in the regulation of neuronal excitability.
KIF1A	Kinesin-like protein KIF1A	Kinesin motor with a plus-end-directed microtubule motor activity.
SET	Protein SET	Multitasking protein, involved in apoptosis, transcription, nucleosome assembly and histone chaperoning.
BRSK2	Serine/threonine-protein kinase BRSK2	Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
CACNG2	Voltage-dependent calcium channel gamma-2 subunit	Regulates the trafficking and gating properties of AMPA-selective glutamate receptors (AMPARs).
CAMK2A	Calcium/calmodulin-dependent protein kinase type II subunit alpha	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in various processes, such as synaptic plasticity, neurotransmitter release and long-term pote…
CAMK2B	Calcium/calmodulin-dependent protein kinase type II subunit beta	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic r…
MED12L	Mediator of RNA polymerase II transcription subunit 12-like protein	May be a component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
ZMYND11	Zinc finger MYND domain-containing protein 11	Chromatin reader that specifically recognizes and binds histone H3.3 trimethylated at ‘Lys-36’ (H3.3K36me3) and regulates RNA polymerase II elongation.
CDH15	Cadherin-15	Cadherins are calcium-dependent cell adhesion proteins.
ASH1L	Histone-lysine N-methyltransferase ASH1L	Histone methyltransferase specifically trimethylating ‘Lys-36’ of histone H3 forming H3K36me3.
DOCK8	Dedicator of cytokinesis protein 8	Guanine nucleotide exchange factor (GEF) which specifically activates small GTPase CDC42 by exchanging bound GDP for free GTP.
CHAMP1	Chromosome alignment-maintaining phosphoprotein 1	Required for proper alignment of chromosomes at metaphase and their accurate segregation during mitosis.
MBD5	Methyl-CpG-binding domain protein 5	Non-catalytic component of the polycomb repressive deubiquitinase (PR-DUB) complex, a complex that specifically mediates deubiquitination of histone H2A monoubiquitinated at ‘Lys-120’ (H2AK119ub1).
KIRREL3	Kin of IRRE-like protein 3	Synaptic adhesion molecule required for the formation of target-specific synapses.
CUX1	Homeobox protein cut-like 1	Transcription factor involved in the control of neuronal differentiation in the brain.
DLL1	Delta-like protein 1	Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner.
TAOK1	Serine/threonine-protein kinase TAO1	Serine/threonine-protein kinase involved in various processes such as p38/MAPK14 stress-activated MAPK cascade, DNA damage response and regulation of cytoskeleton stability.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
EEF1A2	Elongation factor 1-alpha 2	Translation elongation factor that catalyzes the GTP-dependent binding of aminoacyl-tRNA (aa-tRNA) to the A-site of ribosomes during the elongation phase of protein synthesis.
EPB41L1	Band 4.1-like protein 1	May function to confer stability and plasticity to neuronal membrane via multiple interactions, including the spectrin-actin-based cytoskeleton, integral membrane channels and membrane-associated guanylate kinases.
GRIN1	Glutamate receptor ionotropic, NMDA 1	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
HIVEP2	Transcription factor HIVEP2	This protein specifically binds to the DNA sequence 5’-GGGACTTTCC-3’ which is found in the enhancer elements of numerous viral promoters such as those of SV40, CMV, or HIV1.
PPP3CA	Protein phosphatase 3 catalytic subunit alpha	Calcium-dependent, calmodulin-stimulated protein phosphatase which plays an essential role in the transduction of intracellular Ca(2+)-mediated signals.
RAB11A	Ras-related protein Rab-11A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
ZNF292	Zinc finger protein 292	May be involved in transcriptional regulation.
PRICKLE2	Prickle-like protein 2	Is involved in the organization and maintenance of axon initial segment (AIS) architecture, likely cooperating with IGSF9B to regulate ANK3/ANKG localization to AIS.
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
JARID2	Protein Jumonji	Regulator of histone methyltransferase complexes that plays an essential role in embryonic development, including heart and liver development, neural tube fusion process and hematopoiesis.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).
PPM1D	Protein phosphatase 1D	Involved in the negative regulation of p53 expression.

Protein-family classification

Druggable: 10 · Difficult: 13 · Unknown: 17 · Druggable fraction: 0.25

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	5	3.5×	0.065
Transcription factor	10	2.1×	0.065
Ion channel	2	5.6×	0.116
Phosphatase	2	4.2×	0.144
Scaffold/PPI	3	1.3×	0.574
Antibody/Immunoglobulin	1	0.7×	0.878
Other/Unknown	17	0.8×	0.968

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
DEAF1	Transcription factor	no		SAND_dom, Znf_MYND, SAND-like_dom_sf
TRPM3	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf
CLTC	Other/Unknown	no		Clathrin_H-chain/VPS_repeat, TPR-like_helical_dom_sf, Clathrin_H-chain_linker_core
CSNK2B	Kinase	yes		Casein_kinase_II_reg-sub, Casein_kin_II_reg-sub_N, Casein_kinase_II_beta-like
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
KCNQ5	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C
KIF1A	Scaffold/PPI	no	5.6.1.3	FHA_dom, Kinesin_motor_dom, PH_domain
SET	Other/Unknown	no		NAP, NAP-like_sf
BRSK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
CACNG2	Other/Unknown	no		PMP22/EMP/MP20/Claudin, VDCC_g2su, VDCC_gsu
CAMK2A	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
CAMK2B	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
MED12L	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
ZMYND11	Transcription factor	no		PWWP_dom, Bromodomain, Znf_PHD
CDH15	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
ASH1L	Transcription factor	no	2.1.1.357	BAH_dom, SET_dom, Bromodomain
DOCK8	Other/Unknown	no		ARM-type_fold, DOCK_C/D_N, DOCK
CHAMP1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, CAMP
MBD5	Other/Unknown	no		PWWP_dom, Methyl_CpG_DNA-bd, DNA-bd_dom_sf
KIRREL3	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
CUX1	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
DLL1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, DSL
TAOK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
EPB41L1	Other/Unknown	no		FERM_domain, Ez/rad/moesin-like, SAB_dom
GRIN1	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
HIVEP2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf,
PPP3CA	Phosphatase	yes	3.1.3.16	Calcineurin-like_PHP, Ser/Thr-sp_prot-phosphatase, Metallo-depent_PP-like
RAB11A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
ZNF292	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GH-ZnFinger_Regulators
PRICKLE2	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
JARID2	Transcription factor	no		ARID_dom, JmjC_dom, JmjN
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf
PPM1D	Phosphatase	yes		PP2C_BS, PPM-type_phosphatase-like_dom, PP2C

Expression context

Cohort genes with no expression data: 0.

38 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	40
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	6
right hemisphere of cerebellum	6
Brodmann (1909) area 23	6
cerebellar cortex	5
secondary oocyte	5
cortical plate	4
lateral nuclear group of thalamus	3
buccal mucosa cell	3
endothelial cell	3
right frontal lobe	3
calcaneal tendon	3
ganglionic eminence	3
middle temporal gyrus	3
adrenal tissue	3
cauda epididymis	3
amygdala	2
medial globus pallidus	2
pons	2
endometrium epithelium	2
leukocyte	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CIC	274	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
DEAF1	134	ubiquitous	marker	amygdala, temporal lobe, Ammon’s horn
TRPM3	193	broad	marker	pigmented layer of retina, dorsal motor nucleus of vagus nerve, medial globus pallidus
CLTC	305	ubiquitous	marker	pons, lateral nuclear group of thalamus, Brodmann (1909) area 46
CSNK2B	134	ubiquitous	marker	left testis, right testis, skin of leg
GRIN2B	138	broad	marker	buccal mucosa cell, cortical plate, Brodmann (1909) area 23
KCNQ5	177	ubiquitous	marker	endothelial cell, pons, Brodmann (1909) area 23
KIF1A	198	broad	marker	right frontal lobe, postcentral gyrus, parietal lobe
SET	295	ubiquitous	marker	ganglionic eminence, endometrium epithelium, calcaneal tendon
BRSK2	176	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
TCF4	292	ubiquitous	marker	endothelial cell, skin of hip, pericardium
CACNG2	70	tissue_specific	yes	right hemisphere of cerebellum, cerebellar cortex, cerebellar hemisphere
CAMK2A	184	broad	marker	amygdala, prefrontal cortex, right frontal lobe
CAMK2B	233	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
MED12L	160	broad	marker	monocyte, leukocyte, adrenal tissue
ZMYND11	301	ubiquitous	marker	cranial nerve II, caput epididymis, cauda epididymis
CDH15	139	broad	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
ASH1L	267	ubiquitous	marker	Brodmann (1909) area 23, pylorus, cardia of stomach
DOCK8	236	ubiquitous	marker	bone marrow cell, leukocyte, monocyte
CHAMP1	244	ubiquitous	yes	ileal mucosa, cortical plate, secondary oocyte
MBD5	243	ubiquitous	marker	calcaneal tendon, adrenal tissue, sural nerve
KIRREL3	179	broad	marker	middle temporal gyrus, nucleus accumbens, Brodmann (1909) area 23
CUX1	297	ubiquitous	marker	secondary oocyte, buccal mucosa cell, oocyte
DLL1	132	broad	marker	spleen, ventricular zone, skin of abdomen
TAOK1	274	ubiquitous	marker	corpus callosum, globus pallidus, medial globus pallidus
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle
EPB41L1	278	ubiquitous	marker	superior vestibular nucleus, substantia nigra pars compacta, adrenal tissue

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLTC	5,550
PPP3CA	4,486
DYNC1H1	4,215
CAMK2A	3,914
JARID2	3,794
GRIN2B	3,611
POLG	3,400
TCF4	3,342
DLL1	3,147
STXBP1	3,003

Intra-cohort edges

A	B	Sources
CACNG2	GRIN1	biogrid_interaction
CACNG2	SYNGAP1	string_interaction
CAMK2A	CAMK2B	biogrid_interaction, intact, string_interaction
CAMK2A	GRIN2B	biogrid_interaction, intact, string_interaction
CAMK2B	GRIN2B	string_interaction
CAMK2B	SYNGAP1	string_interaction
CDH15	KIRREL3	string_interaction
CIC	CSNK2B	intact
DEAF1	ZMYND11	string_interaction
EPB41L1	PRICKLE2	intact
GRIN1	GRIN2B	biogrid_interaction
GRIN2B	MBD5	string_interaction
GRIN2B	SYNGAP1	string_interaction
HIVEP2	TCF4	string_interaction
PRICKLE2	SYNGAP1	intact

Structural data

PDB: 30 · AlphaFold-only: 10 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
DYNC1H1	Q14204	97
GRIN1	Q05586	85
GRIN2B	Q13224	36
POLG	P54098	36
RAB11A	P62491	30
CAMK2A	Q9UQM7	22
KIF1A	Q12756	21
PPP3CA	Q08209	21
ASH1L	Q9NR48	16
JARID2	Q92833	16
CLTC	Q00610	10
CSNK2B	P67870	10
ZMYND11	Q15326	8
CIC	Q96RK0	7
KCNQ5	Q9NR82	5
TCF4	P15884	5
CACNG2	Q9Y698	5
CAMK2B	Q13554	4
CHAMP1	Q96JM3	4
DEAF1	O75398	3
SET	Q01105	3
CUX1	P39880	3
EEF1A2	Q05639	2
ZNF292	O60281	2
TRPM3	Q9HCF6	1
STXBP1	P61764	1
KIRREL3	Q8IZU9	1
DLL1	O00548	1
PPM1D	O15297	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CDH15	P55291	78.70
TAOK1	Q7L7X3	77.36
DOCK8	Q8NF50	75.17
BRSK2	Q8IWQ3	68.46
MED12L	Q86YW9	66.04
EPB41L1	Q9H4G0	62.40
SYNGAP1	Q96PV0	60.43
PRICKLE2	Q7Z3G6	56.41
MBD5	Q9P267	43.20
HIVEP2	P31629	36.43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 246. Enrichment computed across 40 evidence-associated genes (31 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ras activation upon Ca2+ influx through NMDA receptor	4	73.7×	2e-05	GRIN2B, CAMK2A, CAMK2B, GRIN1
Trafficking of AMPA receptors	4	70.2×	2e-05	CACNG2, CAMK2A, CAMK2B, EPB41L1
Unblocking of NMDA receptors, glutamate binding and activation	4	70.2×	2e-05	GRIN2B, CAMK2A, CAMK2B, GRIN1
Negative regulation of NMDA receptor-mediated neuronal transmission	4	70.2×	2e-05	GRIN2B, CAMK2A, CAMK2B, GRIN1
Long-term potentiation	4	61.4×	2e-05	GRIN2B, CAMK2A, CAMK2B, GRIN1
Assembly and cell surface presentation of NMDA receptors	4	32.8×	3e-04	GRIN2B, CAMK2A, CAMK2B, GRIN1
Glutamate binding, activation of AMPA receptors and synaptic plasticity	3	73.7×	3e-04	CACNG2, CAMK2A, CAMK2B
Neurexins and neuroligins	4	25.4×	5e-04	GRIN2B, STXBP1, EPB41L1, GRIN1
RAF/MAP kinase cascade	5	9.8×	0.004	GRIN2B, SYNGAP1, CAMK2A, CAMK2B, GRIN1
CaMK IV-mediated phosphorylation of CREB	2	73.7×	0.008	CAMK2A, CAMK2B
CREB1 phosphorylation through NMDA receptor-mediated activation of RAS signaling	2	56.7×	0.012	CAMK2A, CAMK2B
Neuronal System	5	7.1×	0.012	KCNQ5, STXBP1, CACNG2, CAMK2A, CAMK2B
Ca2+ pathway	3	17.3×	0.013	CAMK2A, GNB1, PPP3CA
Synaptic adhesion-like molecules	2	35.1×	0.025	GRIN2B, GRIN1
MAPK1/MAPK3 signaling	3	12.7×	0.027	SYNGAP1, CAMK2A, CAMK2B
Signaling by RAS mutants	2	27.3×	0.035	CAMK2A, CAMK2B
Cellular response to heat stress	2	25.4×	0.035	CAMK2A, CAMK2B
Calmodulin induced events	2	24.6×	0.035	CAMK2A, CAMK2B
CaM pathway	2	24.6×	0.035	CAMK2A, CAMK2B
Myogenesis	2	24.6×	0.035	TCF4, CDH15
Ca-dependent events	2	23.8×	0.035	CAMK2A, CAMK2B
Regulation of MECP2 expression and activity	2	23.8×	0.035	CAMK2A, CAMK2B
Phase 0 - rapid depolarisation	2	22.3×	0.035	CAMK2A, CAMK2B
RAF activation	2	21.7×	0.035	CAMK2A, CAMK2B
G-protein mediated events	2	21.1×	0.035	CAMK2A, CAMK2B
DAG and IP3 signaling	2	20.5×	0.035	CAMK2A, CAMK2B
HSF1-dependent transactivation	2	20.5×	0.035	CAMK2A, CAMK2B
Transcriptional Regulation by MECP2	2	20.5×	0.035	CAMK2A, CAMK2B
MAPK family signaling cascades	3	10.0×	0.035	SYNGAP1, CAMK2A, CAMK2B
Neurotransmitter receptors and postsynaptic signal transmission	3	9.7×	0.035	CACNG2, CAMK2A, CAMK2B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of neuronal synaptic plasticity	4	67.4×	1e-04	GRIN2B, CAMK2A, CAMK2B, GRIN1
regulation of long-term neuronal synaptic plasticity	3	74.3×	0.002	SYNGAP1, CAMK2B, RAB11A
positive regulation of synaptic transmission, glutamatergic	3	46.8×	0.004	GRIN2B, CACNG2, GRIN1
monoatomic cation transmembrane transport	3	46.8×	0.004	TRPM3, GRIN2B, GRIN1
amyloid-beta clearance by transcytosis	2	120.4×	0.008	CLTC, RAB11A
excitatory postsynaptic potential	3	33.3×	0.008	GRIN2B, GRIN1, PPP3CA
regulation of monoatomic cation transmembrane transport	2	105.3×	0.009	GRIN2B, GRIN1
regulation of dendritic spine development	2	84.3×	0.013	KIF1A, CAMK2B
calcium ion transmembrane import into cytosol	2	76.6×	0.013	GRIN2B, GRIN1
visual learning	3	23.0×	0.013	DEAF1, SYNGAP1, GRIN1
ionotropic glutamate receptor signaling pathway	2	64.8×	0.014	GRIN2B, GRIN1
excitatory chemical synaptic transmission	2	64.8×	0.014	GRIN2B, GRIN1
long-term synaptic potentiation	3	21.1×	0.014	GRIN2B, CAMK2A, CAMK2B
regulation of synaptic plasticity	3	19.4×	0.015	GRIN2B, SYNGAP1, GRIN1
protein heterotetramerization	2	52.7×	0.019	GRIN2B, GRIN1
propylene metabolic process	1	421.3×	0.024	GRIN1
cerebellar molecular layer formation	1	421.3×	0.024	DLL1
regulation of skeletal muscle tissue growth	1	421.3×	0.024	DLL1
eye blink reflex	1	421.3×	0.024	CACNG2
Notch signaling pathway involved in arterial endothelial cell fate commitment	1	421.3×	0.024	DLL1
regulation of cell proliferation involved in kidney morphogenesis	1	421.3×	0.024	PPP3CA
memory T cell proliferation	1	421.3×	0.024	DOCK8
positive regulation of lipid kinase activity	1	421.3×	0.024	EEF1A2
synaptic vesicle endosomal processing	1	421.3×	0.024	RAB11A
obsolete positive regulation of vesicle docking	1	421.3×	0.024	STXBP1
negative regulation of angiotensin-activated signaling pathway	1	421.3×	0.024	PPP3CA
protein localization to pericentric heterochromatin	1	421.3×	0.024	JARID2
tarsal gland development	1	421.3×	0.024	ASH1L
uterine gland development	1	421.3×	0.024	ASH1L
regulation of retrograde protein transport, ER to cytosol	1	421.3×	0.024	BRSK2

Therapeutics

Drug target analysis

Approved (phase 4): 11 · Phase ≥3: 11 · Phased (≥1): 16 · Undrugged: 24

Druggability breadth: 26 of 40 evidence-associated genes (65%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
CSNK2B	PALBOCICLIB
GRIN2B	HALOPERIDOL
KCNQ5	EZOGABINE
BRSK2	BRIGATINIB
CACNG2	NIMODIPINE
CAMK2A	FEDRATINIB
CAMK2B	FEDRATINIB
TAOK1	FEDRATINIB
GRIN1	DEXTROMETHORPHAN
PPP3CA	ZINC CHLORIDE
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TAOK1	58	4
GRIN1	39	4
GRIN2B	35	4
CAMK2A	25	4
CAMK2B	25	4
CSNK2B	14	4
BRSK2	10	4
PPP3CA	4	4
KCNQ5	2	4
CACNG2	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PALBOCICLIB	4	CAMK2B, CSNK2B, TAOK1
MITOXANTRONE	4	CSNK2B
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN1, GRIN2B
KETAMINE	4	GRIN1, GRIN2B
CYCLOSERINE	4	GRIN1, GRIN2B
MEMANTINE	4	GRIN1, GRIN2B
TACRINE	4	CACNG2, GRIN1, GRIN2B
LEVORPHANOL	4	GRIN1, GRIN2B
AMANTADINE	4	GRIN1, GRIN2B
CHLORPROMAZINE	4	GRIN1, GRIN2B
PROCYCLIDINE	4	GRIN1, GRIN2B
ORPHENADRINE	4	GRIN1, GRIN2B
EZOGABINE	4	KCNQ5
BRIGATINIB	4	BRSK2, TAOK1
SUNITINIB	4	BRSK2, CAMK2A, CAMK2B, TAOK1
MIDOSTAURIN	4	BRSK2, CAMK2A, CAMK2B
NIMODIPINE	4	CACNG2
FEDRATINIB	4	CAMK2A, CAMK2B, TAOK1
OXYBATE	4	CAMK2A
RUXOLITINIB	4	CAMK2A, CAMK2B, TAOK1
TOFACITINIB CITRATE	4	CAMK2A
TOFACITINIB	4	CAMK2A
BOSUTINIB	4	CAMK2A, TAOK1
NINTEDANIB	4	CAMK2A
SORAFENIB	4	CAMK2B, TAOK1
ABEMACICLIB	4	CAMK2B, TAOK1
ENTRECTINIB	4	TAOK1
PACRITINIB	4	TAOK1
NILOTINIB	4	TAOK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GRIN1	481	Binding:435, Functional:40, ADMET:5, Toxicity:1
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1
CSNK2B	421	Binding:419, Functional:2
CAMK2A	341	Binding:340, Functional:1
CAMK2B	314	Binding:313, Functional:1
TAOK1	231	Binding:230, Functional:1
BRSK2	230	Binding:230
ASH1L	65	Binding:63, ADMET:1, Functional:1
KCNQ5	40	Binding:35, Functional:2, ADMET:2, Toxicity:1
POLG	33	Binding:30, ADMET:2, Functional:1
TCF4	31	Binding:31
PPP3CA	24	Binding:24
PPM1D	22	Binding:22
CACNG2	17	Binding:15, ADMET:2
GNB1	12	Binding:12
CLTC	8	Binding:8
SET	8	Binding:8
EEF1A2	8	Binding:8
DYNC1H1	7	Binding:7
CHAMP1	6	Binding:6
TRPM3	2	Binding:2
KIF1A	2	Binding:2
RAB11A	2	Binding:2
STXBP1	1	Binding:1
ZMYND11	1	Binding:1
HIVEP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KIF1A	5.6.1.3	plus-end-directed kinesin ATPase
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
CAMK2A	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
CAMK2B	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
ASH1L	2.1.1.357	[histone H3]-lysine36 N-dimethyltransferase
PPP3CA	3.1.3.16	protein-serine/threonine phosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
CSNK2B	421
GRIN2B	471
BRSK2	230
CAMK2A	341
CAMK2B	314
TAOK1	231
GRIN1	481

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PALBOCICLIB	4	CAMK2B, CSNK2B, TAOK1
MITOXANTRONE	4	CSNK2B
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN1, GRIN2B
KETAMINE	4	GRIN1, GRIN2B
CYCLOSERINE	4	GRIN1, GRIN2B
MEMANTINE	4	GRIN1, GRIN2B
TACRINE	4	CACNG2, GRIN1, GRIN2B
LEVORPHANOL	4	GRIN1, GRIN2B
AMANTADINE	4	GRIN1, GRIN2B
CHLORPROMAZINE	4	GRIN1, GRIN2B
PROCYCLIDINE	4	GRIN1, GRIN2B
ORPHENADRINE	4	GRIN1, GRIN2B
EZOGABINE	4	KCNQ5
BRIGATINIB	4	BRSK2, TAOK1
SUNITINIB	4	BRSK2, CAMK2A, CAMK2B, TAOK1
MIDOSTAURIN	4	BRSK2, CAMK2A, CAMK2B
NIMODIPINE	4	CACNG2
FEDRATINIB	4	CAMK2A, CAMK2B, TAOK1
OXYBATE	4	CAMK2A
RUXOLITINIB	4	CAMK2A, CAMK2B, TAOK1
TOFACITINIB CITRATE	4	CAMK2A
TOFACITINIB	4	CAMK2A
BOSUTINIB	4	CAMK2A, TAOK1
NINTEDANIB	4	CAMK2A
SORAFENIB	4	CAMK2B, TAOK1
ABEMACICLIB	4	CAMK2B, TAOK1
ENTRECTINIB	4	TAOK1
PACRITINIB	4	TAOK1
NILOTINIB	4	TAOK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	11	CSNK2B, GRIN2B, KCNQ5, BRSK2, CACNG2, CAMK2A, CAMK2B, TAOK1, GRIN1, PPP3CA (+1 more)
B	Phased (≥1) drug, not yet approved	5	SET, TCF4, CHAMP1, DYNC1H1, GNB1
C	Druggable family + PDB, no drug	3	TRPM3, KIRREL3, PPM1D
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	21	CIC, DEAF1, CLTC, KIF1A, STXBP1, SYNGAP1, MED12L, ZMYND11, CDH15, ASH1L (+11 more)

Undrugged target profiles

24 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SYNGAP1	0	GRIN2B
HIVEP2	1	TCF4
CIC	0	—
DEAF1	0	—
TRPM3	2	—
CLTC	8	—
KIF1A	2	—
STXBP1	1	—
MED12L	0	—
ZMYND11	1	—
CDH15	0	—
ASH1L	65	—
DOCK8	0	—
MBD5	0	—
KIRREL3	0	—
CUX1	0	—
DLL1	0	—
EEF1A2	8	—
EPB41L1	0	—
RAB11A	2	—
ZNF292	0	—
PRICKLE2	0	—
JARID2	0	—
PPM1D	22	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.