Intellectual disability

Summary

Intellectual disability (MONDO:0001071) is a disease (an umbrella term covering 10 Mondo subtypes) caused by variants in SCN2A, TUSC3, CHD8, and 3 other genes, with 42 cohort genes and 197 clinical trials. The dominant Reactome pathway is Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF) (10 cohort genes). Top therapeutic interventions include metformin, amisulpride, and clozapine.

At a glance

• Causal genes: SCN2A (GenCC Definitive), TUSC3 (GenCC Definitive), CHD8 (GenCC Strong), ERBB4 (GenCC Strong) (+2 more)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 42
• ClinVar variants: 3,831
• Clinical trials: 197

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	intellectual disability
Mondo ID	MONDO:0001071
MeSH	D008607
Orphanet	319658
DOID	DOID:1059
ICD-10-CM	F70-F79
ICD-11	605267007
NCIT	C97250
SNOMED CT	91138005
UMLS	C3714756
MedGen	811461
Is cancer (heuristic)	no

Also known as: intellectual disabilities · intellectual disability

Data availability: 3,831 ClinVar variants · 66 GenCC gene-disease records · 72 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › neurodevelopmental disorder › intellectual disability

Related subtypes (20): microcephaly, Williams syndrome, Aicardi syndrome, Hao-Fountain syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, complex neurodevelopmental disorder, Mendelian neurodevelopmental disorder, TCF7L2-related neurodevelopmental disorder, neurodevelopmental disorder with seizures and brain abnormalities, Yoon-Bellen neurodevelopmental syndrome, neurodevelopmental disorder with microcephaly, hypotonia, and absent language, neurodevelopmental disorder with poor growth, spastic tetraplegia, and hearing loss, neurodevelopmental disorder with poor growth, absent speech, progressive ataxia, and dysmorphic facies, neurodevelopmental disorder with parkinsonism or other movement abnormalities, neurodevelopmental disorder with seizures and impaired intellectual and language development, Ebstein-Bezieau neurodevelopmental syndrome, Luo-Agrawal neurodevelopmental syndrome

Subtypes (10): syndromic intellectual disability, non-syndromic intellectual disability, intellectual developmental disorder and retinitis pigmentosa; IDDRP, PPP2R1A-related intellectual disability, intellectual disability, autosomal dominant, X-linked intellectual disability, intellectual disability, autosomal recessive, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, SETD2-related neurodevelopmental disorder without or with macrocephaly/overgrowth, intellectual developmental disorder with polymicrogyria and seizures

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

600 retrieved; paginated sample, class counts are floors:

116 pathogenic, 112 conflicting classifications of pathogenicity, 100 uncertain significance, 98 likely benign, 67 likely pathogenic, 48 pathogenic/likely pathogenic, 29 benign/likely benign, 22 benign, 5 pathogenic, low penetrance, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012367	der(6)t(6;7)(p25.3;q32.3)		Pathogenic	no assertion criteria provided
1177532	NM_032360.4(ACBD6):c.360dup (p.Leu121fs)	ACBD6	Pathogenic	no assertion criteria provided
1700599	NM_014921.5(ADGRL1):c.2998T>C (p.Trp1000Arg)	ADGRL1	Pathogenic	criteria provided, single submitter
1700606	NM_014921.5(ADGRL1):c.3517C>T (p.Arg1173Ter)	ADGRL1	Pathogenic	criteria provided, single submitter
1700602	NM_014921.5(ADGRL1):c.819G>A (p.Trp273Ter)	ADGRL1-AS1	Pathogenic	criteria provided, single submitter
139631	NM_001282531.3(ADNP):c.2491_2494del (p.Leu831fs)	ADNP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1251924	NM_012199.5(AGO1):c.1123GAG[1] (p.Glu376del)	AGO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1299762	NM_012199.5(AGO1):c.569T>G (p.Leu190Arg)	AGO1	Pathogenic/Likely pathogenic	no assertion criteria provided
1299763	NM_012199.5(AGO1):c.595G>A (p.Gly199Ser)	AGO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
133326	NM_001371928.1(AHDC1):c.2373_2374del (p.Cys791fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
133327	NM_001371928.1(AHDC1):c.2898del (p.Tyr967fs)	AHDC1	Pathogenic	criteria provided, single submitter
133328	NM_001371928.1(AHDC1):c.2547del (p.Ser850fs)	AHDC1	Pathogenic	criteria provided, multiple submitters, no conflicts
156414	NM_001253852.3(AP4B1):c.1160_1161del (p.Thr387fs)	AP4B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697209	NM_001659.3(ARF3):c.95C>A (p.Thr32Asn)	ARF3	Pathogenic	criteria provided, single submitter
1697211	NM_001659.3(ARF3):c.200A>T (p.Asp67Val)	ARF3	Pathogenic	criteria provided, single submitter
1697212	NM_001659.3(ARF3):c.277G>A (p.Asp93Asn)	ARF3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1697213	NM_001659.3(ARF3):c.379A>G (p.Lys127Glu)	ARF3	Pathogenic	criteria provided, single submitter
180227	NC_000006.11:g.(116681080_116735056)_(119687719_119775014)del	ASF1A	Pathogenic	no assertion criteria provided
1013587	GRCh37/hg19 Xq28(chrX:153263517-155260560)x2	ATP6AP1	Pathogenic	no assertion criteria provided
11742	NM_000489.6(ATRX):c.109C>T (p.Arg37Ter)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804039	NM_003571.4(BFSP2):c.449G>A (p.Trp150Ter)	BFSP2	Pathogenic	criteria provided, single submitter
1708222	NM_001379291.1(BRD4):c.3693_3709dup (p.Arg1237fs)	BRD4	Pathogenic	criteria provided, single submitter
11530	NM_001367721.1(CASK):c.1915C>T (p.Arg639Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
120	NM_000071.3(CBS):c.833T>C (p.Ile278Thr)	CBS	Pathogenic	criteria provided, multiple submitters, no conflicts
143823	NM_001323289.2(CDKL5):c.532C>T (p.Arg178Trp)	CDKL5	Pathogenic	criteria provided, multiple submitters, no conflicts
1337	NM_025114.4(CEP290):c.2991+1655A>G	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1065604	NM_001271.4(CHD2):c.4349del (p.Gly1450fs)	CHD2	Pathogenic	no assertion criteria provided
1071676	NM_001271.4(CHD2):c.2536C>T (p.Arg846Ter)	CHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
1048638	NM_001170629.2(CHD8):c.3331_3332del (p.Glu1111fs)	CHD8	Pathogenic	criteria provided, single submitter
1183968	NM_152515.5(CKAP2L):c.1463_1467del (p.Thr488fs)	CKAP2L	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 170 · Orphanet: 51 · 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
SCN2A	Definitive	Autosomal dominant	intellectual disability	16
TUSC3	Definitive	Autosomal recessive	intellectual disability	5
VPS4A	Definitive	Autosomal dominant	cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome	5
ANK3	Strong	Autosomal recessive	intellectual disability-hypotonia-spasticity-sleep disorder syndrome	7
CHD8	Strong	Autosomal dominant	intellectual disability	4
ERBB4	Strong	Autosomal dominant	intellectual disability	5
JMJD1C	Strong	Autosomal dominant	intellectual disability	4
SEMA6B	Strong	Autosomal dominant	intellectual disability	5
SRPK3	Strong	X-linked	intellectual developmental disorder, X-linked 114	3
ZMYM3	Strong	X-linked	intellectual developmental disorder, X-linked 112	4
TCF7L2	Moderate	Autosomal dominant	intellectual disability	4
CDH15	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	5
CLIP1	Supportive	Autosomal recessive	autosomal recessive non-syndromic intellectual disability	2
STXBP1	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	12
TCF4	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	11
TRPM3	Supportive	Autosomal dominant	autosomal dominant non-syndromic intellectual disability	11
ACBD6	Limited	Autosomal recessive	intellectual disability	3
ADGRG6	Limited	Autosomal recessive	intellectual disability	5
AQP4	Limited	Autosomal dominant	intellectual disability	4
ARHGAP4	Limited	X-linked	intellectual disability
AURKA	Limited	Autosomal dominant	intellectual disability	2
CACNA1C	Limited	Autosomal dominant	intellectual disability	13
CACNA1G	Limited	Autosomal recessive	intellectual disability	11
CADPS2	Limited	Autosomal recessive	intellectual disability
CHAF1B	Limited	Autosomal recessive	intellectual disability
DHX34	Limited	Autosomal recessive	intellectual disability	3
LRP2	Limited	Autosomal dominant	intellectual disability	7
MYT1	Limited	Autosomal dominant	intellectual disability	3
SLC25A5	Limited	X-linked	intellectual disability
UBQLN1	Limited	Autosomal dominant	intellectual disability

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SEMA6B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related 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
TCF7L2	Orphanet:528084	Non-specific syndromic intellectual disability
JMJD1C	Orphanet:567	22q11.2 deletion syndrome
JMJD1C	Orphanet:91352	Germinoma of the central nervous system
CACNA1C	Orphanet:101016	Romano-Ward syndrome
CACNA1C	Orphanet:130	Brugada syndrome
CACNA1C	Orphanet:528084	Non-specific syndromic intellectual disability
CACNA1C	Orphanet:595098	Timothy syndrome type 1
CACNA1C	Orphanet:595105	Timothy syndrome type 2
CACNA1C	Orphanet:595109	Atypical Timothy syndrome
CACNA1G	Orphanet:458803	Spinocerebellar ataxia type 42
CDH15	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
TRPM3	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CHD8	Orphanet:261229	14q11.2 microduplication syndrome
CHD8	Orphanet:642675	CHD8 overgrowth syndrome
TUSC3	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
ANK3	Orphanet:356996	ANK3-related intellectual disability-sleep disturbance syndrome
LRP2	Orphanet:2143	Donnai-Barrow syndrome
CLIP1	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
VPS35	Orphanet:411602	Hereditary late-onset Parkinson disease
VPS4A	Orphanet:603448	Cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome
BCS1L	Orphanet:123	Björnstad syndrome
BCS1L	Orphanet:1460	Isolated complex III deficiency
BCS1L	Orphanet:254902	Renal tubulopathy-encephalopathy-liver failure syndrome
BCS1L	Orphanet:53693	GRACILE syndrome
ROBO1	Orphanet:95496	Pituitary stalk interruption syndrome
ROR2	Orphanet:1507	Autosomal recessive Robinow syndrome
ROR2	Orphanet:572385	Brachydactyly type B1
RPL10	Orphanet:435938	X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome
RPL10	Orphanet:459070	X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
RPL15	Orphanet:124	Diamond-Blackfan anemia
BFSP2	Orphanet:441452	Early-onset lamellar cataract
BFSP2	Orphanet:98984	Pulverulent cataract

Cohort genes → proteins

42 cohort genes, 42 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	42

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gencc,clinvar
SEMA6B	HGNC:10739	ENSG00000167680	Q9H3T3	Semaphorin-6B	gencc,clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	gencc,clinvar
TCF4	HGNC:11634	ENSG00000196628	P15884	Transcription factor 4	gencc,clinvar
TCF7L2	HGNC:11641	ENSG00000148737	Q9NQB0	Transcription factor 7-like 2	gencc,clinvar
JMJD1C	HGNC:12313	ENSG00000171988	Q15652	Jumonji domain-containing protein 1C	gencc,clinvar
ZMYM3	HGNC:13054	ENSG00000147130	Q14202	Zinc finger MYM-type protein 3	gencc,clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	gencc,clinvar
CACNA1G	HGNC:1394	ENSG00000006283	O43497	Voltage-dependent T-type calcium channel subunit alpha-1G	gencc,clinvar
DHX34	HGNC:16719	ENSG00000134815	Q14147	Probable ATP-dependent RNA helicase DHX34	gencc,clinvar
CDH15	HGNC:1754	ENSG00000129910	P55291	Cadherin-15	gencc,clinvar
TRPM3	HGNC:17992	ENSG00000083067	Q9HCF6	Transient receptor potential cation channel subfamily M member 3	gencc,clinvar
CHAF1B	HGNC:1911	ENSG00000159259	Q13112	Chromatin assembly factor 1 subunit B	gencc,clinvar
CHD8	HGNC:20153	ENSG00000100888	Q9HCK8	ATP-dependent chromatin remodeler CHD8	gencc,clinvar
ACBD6	HGNC:23339	ENSG00000230124	Q9BR61	Acyl-CoA-binding domain-containing protein 6	gencc,clinvar
TUSC3	HGNC:30242	ENSG00000104723	Q13454	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit TUSC3	gencc,clinvar
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	gencc,clinvar
ANK3	HGNC:494	ENSG00000151150	Q12955	Ankyrin-3	gencc,clinvar
AQP4	HGNC:637	ENSG00000171885	P55087	Aquaporin-4	gencc,clinvar
LRP2	HGNC:6694	ENSG00000081479	P98164	Low-density lipoprotein receptor-related protein 2	gencc,clinvar
ARHGAP4	HGNC:674	ENSG00000089820	P98171	Rho GTPase-activating protein 4	gencc,clinvar
MYT1	HGNC:7622	ENSG00000196132	Q01538	Myelin transcription factor 1	gencc,clinvar
CLIP1	HGNC:10461	ENSG00000130779	P30622	CAP-Gly domain-containing linker protein 1	gencc
SLC25A5	HGNC:10991	ENSG00000005022	P05141	ADP/ATP translocase 2	gencc
AURKA	HGNC:11393	ENSG00000087586	O14965	Aurora kinase A	gencc
SRPK3	HGNC:11402	ENSG00000184343	Q9UPE1	SRSF protein kinase 3	gencc
UBQLN1	HGNC:12508	ENSG00000135018	Q9UMX0	Ubiquilin-1	gencc
ZMYM6	HGNC:13050	ENSG00000163867	O95789	Zinc finger MYM-type protein 6	gencc
CAPN12	HGNC:13249	ENSG00000182472	Q6ZSI9	Calpain-12	gencc
VPS35	HGNC:13487	ENSG00000069329	Q96QK1	Vacuolar protein sorting-associated protein 35	gencc
VPS4A	HGNC:13488	ENSG00000132612	Q9UN37	Vacuolar protein sorting-associated protein 4A	gencc
ADGRG6	HGNC:13841	ENSG00000112414	Q86SQ4	Adhesion G-protein coupled receptor G6	gencc
WDR13	HGNC:14352	ENSG00000101940	Q9H1Z4	WD repeat-containing protein 13	gencc
CADPS2	HGNC:16018	ENSG00000081803	Q86UW7	Calcium-dependent secretion activator 2	gencc
RHEB	HGNC:10011	ENSG00000106615	Q15382	GTP-binding protein Rheb	clinvar
BCS1L	HGNC:1020	ENSG00000074582	Q9Y276	Mitochondrial chaperone BCS1	clinvar
ROBO1	HGNC:10249	ENSG00000169855	Q9Y6N7	Roundabout homolog 1	clinvar
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	clinvar
RPL10	HGNC:10298	ENSG00000147403	P27635	Large ribosomal subunit protein uL16	clinvar
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	clinvar
RPL15	HGNC:10306	ENSG00000174748	P61313	Large ribosomal subunit protein eL15	clinvar
BFSP2	HGNC:1041	ENSG00000170819	Q13515	Phakinin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SEMA6B	Semaphorin-6B	Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
TCF4	Transcription factor 4	Transcription factor that binds to the immunoglobulin enhancer Mu-E5/KE5-motif.
TCF7L2	Transcription factor 7-like 2	Participates in the Wnt signaling pathway and modulates MYC expression by binding to its promoter in a sequence-specific manner.
JMJD1C	Jumonji domain-containing protein 1C	Demethylates lysine in proteins, such as STAT3 or MDC1.
ZMYM3	Zinc finger MYM-type protein 3	Plays a role in the regulation of cell morphology and cytoskeletal organization.
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
CACNA1G	Voltage-dependent T-type calcium channel subunit alpha-1G	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
DHX34	Probable ATP-dependent RNA helicase DHX34	Probable ATP-binding RNA helicase required for nonsense-mediated decay (NMD) degradation of mRNA transcripts containing premature stop codons.
CDH15	Cadherin-15	Cadherins are calcium-dependent cell adhesion proteins.
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+).
CHAF1B	Chromatin assembly factor 1 subunit B	Acts as a component of the histone chaperone complex chromatin assembly factor 1 (CAF-1), which assembles histone octamers onto DNA during replication and repair.
CHD8	ATP-dependent chromatin remodeler CHD8	ATP-dependent chromatin-remodeling factor, it slides nucleosomes along DNA; nucleosome sliding requires ATP.
ACBD6	Acyl-CoA-binding domain-containing protein 6	Binds long-chain acyl-coenzyme A molecules with a strong preference for unsaturated C18:1-CoA, lower affinity for unsaturated C20:4-CoA, and very weak affinity for saturated C16:0-CoA.
TUSC3	Dolichyl-diphosphooligosaccharide–protein glycosyltransferase subunit TUSC3	Acts as accessory component of the N-oligosaccharyl transferase (OST) complex which catalyzes the transfer of a high mannose oligosaccharide from a lipid-linked oligosaccharide donor to an asparagine residue within an Asn-X-Ser/Thr consens…
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
ANK3	Ankyrin-3	Membrane-cytoskeleton linker.
AQP4	Aquaporin-4	Forms a water-specific channel.
LRP2	Low-density lipoprotein receptor-related protein 2	Multiligand endocytic receptor.
ARHGAP4	Rho GTPase-activating protein 4	Inhibitory effect on stress fiber organization.
MYT1	Myelin transcription factor 1	Binds to the promoter region of genes encoding proteolipid proteins of the central nervous system.
CLIP1	CAP-Gly domain-containing linker protein 1	Binds to the plus end of microtubules and regulates the dynamics of the microtubule cytoskeleton.
SLC25A5	ADP/ATP translocase 2	ADP:ATP antiporter that mediates import of ADP into the mitochondrial matrix for ATP synthesis, and export of ATP out to fuel the cell.
AURKA	Aurora kinase A	Mitotic serine/threonine kinase that contributes to the regulation of cell cycle progression.
SRPK3	SRSF protein kinase 3	Serine/arginine-rich protein-specific kinase which specifically phosphorylates its substrates at serine residues located in regions rich in arginine/serine dipeptides, known as RS domains.
UBQLN1	Ubiquilin-1	Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and endoplasmic reticulum-associated protein degradation (ERAD) pathway.
ZMYM6	Zinc finger MYM-type protein 6	Plays a role in the regulation of cell morphology and cytoskeletal organization.
CAPN12	Calpain-12	Calcium-regulated non-lysosomal thiol-protease.
VPS35	Vacuolar protein sorting-associated protein 35	Acts as a component of the retromer cargo-selective complex (CSC).
VPS4A	Vacuolar protein sorting-associated protein 4A	Involved in late steps of the endosomal multivesicular bodies (MVB) pathway.
ADGRG6	Adhesion G-protein coupled receptor G6	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as progesterone and 17alpha-hydroxyprogesterone (17OHP).
CADPS2	Calcium-dependent secretion activator 2	Calcium-binding protein involved in exocytosis of vesicles filled with neurotransmitters and neuropeptides.
RHEB	GTP-binding protein Rheb	Small GTPase that acts as an allosteric activator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule biosynthesis to promote cellular biomass generation…
BCS1L	Mitochondrial chaperone BCS1	Chaperone necessary for the incorporation of Rieske iron-sulfur protein UQCRFS1 into the mitochondrial respiratory chain complex III.
ROBO1	Roundabout homolog 1	Receptor for SLIT1 and SLIT2 that mediates cellular responses to molecular guidance cues in cellular migration, including axonal navigation at the ventral midline of the neural tube and projection of axons to different regions during neuro…
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
RPL10	Large ribosomal subunit protein uL16	Component of the large ribosomal subunit.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
RPL15	Large ribosomal subunit protein eL15	Component of the large ribosomal subunit.
BFSP2	Phakinin	Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.

Protein-family classification

Druggable: 13 · Difficult: 13 · Unknown: 16 · Druggable fraction: 0.31

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
Ion channel	4	10.6×	0.005
Scaffold/PPI	7	2.9×	0.044
Kinase	4	2.6×	0.192
Transcription factor	6	1.2×	0.900
Protease	1	0.9×	0.985
Antibody/Immunoglobulin	1	0.7×	0.985
Enzyme (other)	2	0.6×	0.985
GPCR	1	0.6×	0.985
Other/Unknown	16	0.7×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SEMA6B	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
TCF4	Transcription factor	no	7.6.2.3	bHLH_dom, HLH_DNA-bd_sf, NeuroDiff_E-box_TFs
TCF7L2	Other/Unknown	no		HMG_box_dom, CTNNB1-bd_N, TCF/LEF
JMJD1C	Enzyme (other)	yes	1.14.11.65	JmjC_dom, LSDs-like, KDM3A/B_DUF7030
ZMYM3	Transcription factor	no		Znf_MYM, TRASH_dom, ZMYM2-like_C
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
CACNA1G	Ion channel	yes		VDCCAlpha1, VDCC_T_a1, Ion_trans_dom
DHX34	Transcription factor	no	3.6.4.13	Helicase_C-like, Helicase-assoc_dom, DEAD/DEAH_box_helicase_dom
CDH15	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
TRPM3	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf
CHAF1B	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
CHD8	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
ACBD6	Scaffold/PPI	no		Acyl-CoA-binding_protein, Ankyrin_rpt, FERM/acyl-CoA-bd_prot_sf
TUSC3	Other/Unknown	no		MAGT1/OST3/OST6, Thioredoxin-like_sf
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ANK3	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
AQP4	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
LRP2	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
ARHGAP4	Scaffold/PPI	no		RhoGAP_dom, FCH_dom, SH3_domain
MYT1	Transcription factor	no		Znf_C2H2C, Myelin_TF, Znf_C2H2C_sf
CLIP1	Transcription factor	no		CAP-Gly_domain, CLIP1_ZNF, CAP-Gly_dom_sf
SLC25A5	Other/Unknown	no		MCP, ADT_euk_type, MCP_transmembrane
AURKA	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SRPK3	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
UBQLN1	Other/Unknown	no		Ubiquitin-like_dom, STI1_HS-bd, UBA-like_sf
ZMYM6	Transcription factor	no		Znf_MYM, TRASH_dom, RNaseH-like_sf
CAPN12	Protease	yes		Pept_cys_AS, Peptidase_C2_calpain_cat, EF_hand_dom
VPS35	Other/Unknown	no		Vps35, ARM-type_fold, Vps35_C
VPS4A	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
ADGRG6	GPCR	yes		GPS, GPCR_2_secretin-like, CUB_dom
WDR13	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf
CADPS2	Scaffold/PPI	no		C2_dom, PH_domain, MUN_dom
RHEB	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
BCS1L	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
ROBO1	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
RPL10	Other/Unknown	no		Ribosomal_uL16_euk_arch, Ribosomal_uL16_dom, Ribosomal_uL16_CS_euk_arc
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
RPL15	Other/Unknown	no		Ribosomal_eL15, Ribosomal_uL23/eL15/eS24_sf, Ribosomal_eL15_CS
BFSP2	Other/Unknown	no		Keratin_I, IF_rod_dom

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)	42
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endothelial cell	5
ventricular zone	5
secondary oocyte	4
cortical plate	4
ganglionic eminence	4
Brodmann (1909) area 23	3
cerebellar vermis	3
lateral nuclear group of thalamus	3
cerebellar hemisphere	3
right hemisphere of cerebellum	3
apex of heart	3
cerebellar cortex	3
gastrocnemius	3
oocyte	3
middle temporal gyrus	2
right frontal lobe	2
pancreatic ductal cell	2
right adrenal gland	2
muscle layer of sigmoid colon	2
left testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SEMA6B	177	ubiquitous	marker	right frontal lobe, anterior cingulate cortex, cingulate cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
TCF4	292	ubiquitous	marker	endothelial cell, skin of hip, pericardium
TCF7L2	291	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, pancreatic ductal cell
JMJD1C	291	ubiquitous	marker	calcaneal tendon, right hemisphere of cerebellum, cerebellar hemisphere
ZMYM3	281	ubiquitous	marker	right adrenal gland, right adrenal gland cortex, endothelial cell
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
CACNA1G	194	broad	yes	lateral nuclear group of thalamus, right hemisphere of cerebellum, right frontal lobe
DHX34	217	ubiquitous	marker	right testis, blood, left testis
CDH15	139	broad	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
TRPM3	193	broad	marker	pigmented layer of retina, dorsal motor nucleus of vagus nerve, medial globus pallidus
CHAF1B	175	ubiquitous	marker	secondary oocyte, oocyte, gastrocnemius
CHD8	283	ubiquitous	marker	sural nerve, ventricular zone, cortical plate
ACBD6	231	ubiquitous	marker	cortical plate, ganglionic eminence, left testis
TUSC3	266	ubiquitous	marker	type B pancreatic cell, cortical plate, stromal cell of endometrium
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II
ANK3	298	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, dorsal motor nucleus of vagus nerve
AQP4	218	tissue_specific	marker	lateral globus pallidus, substantia nigra pars reticulata, substantia nigra pars compacta
LRP2	169	broad	marker	adult organism, adult mammalian kidney, corpus callosum
ARHGAP4	229	broad	marker	granulocyte, spleen, monocyte
MYT1	101	broad	yes	ganglionic eminence, cerebellum, cerebellar cortex
CLIP1	299	ubiquitous	marker	biceps brachii, buccal mucosa cell, skeletal muscle tissue of rectus abdominis
SLC25A5	288	ubiquitous	marker	renal medulla, jejunal mucosa, ileal mucosa
AURKA	236	ubiquitous	marker	oocyte, secondary oocyte, ventricular zone
SRPK3	202	broad	marker	hindlimb stylopod muscle, gluteal muscle, gastrocnemius
UBQLN1	261	ubiquitous	marker	ileal mucosa, cardiac muscle of right atrium, upper arm skin
ZMYM6	227	ubiquitous	yes	monocyte, adrenal tissue, leukocyte
CAPN12	187	broad	marker	pancreatic ductal cell, gall bladder, right lobe of liver
VPS35	149	ubiquitous	marker	ventricular zone, adrenal tissue, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 8.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBQLN1	6,751
AURKA	6,376
ANK3	6,145
RPL10	5,485
CHD8	4,791
ERBB4	4,325
SLC25A5	3,816
BCS1L	3,789
TCF7L2	3,775
RHEB	3,739

Intra-cohort edges

A	B	Sources
ANK3	SCN2A	string_interaction
ARHGAP4	ROBO1	intact
CACNA1C	SCN2A	intact
CHD8	SCN2A	string_interaction
RHEB	UBQLN1	intact
RHEB	VPS4A	biogrid_interaction
SCN2A	STXBP1	string_interaction
STXBP1	TUSC3	biogrid_interaction, intact

Structural data

PDB: 30 · AlphaFold-only: 12 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AURKA	O14965	193
RPL15	P61313	192
RPL10	P27635	43
CACNA1C	Q13936	33
RHEB	Q15382	15
ERBB4	Q15303	14
VPS35	Q96QK1	13
ROBO1	Q9Y6N7	12
CHAF1B	Q13112	11
CLIP1	P30622	11
CNNM2	Q9H8M5	7
ROR2	Q01974	6
SCN2A	Q99250	5
TCF4	P15884	5
TUSC3	Q13454	4
AQP4	P55087	4
LRP2	P98164	4
TCF7L2	Q9NQB0	3
JMJD1C	Q15652	3
UBQLN1	Q9UMX0	3
VPS4A	Q9UN37	3
CACNA1G	O43497	2
CHD8	Q9HCK8	2
STXBP1	P61764	1
TRPM3	Q9HCF6	1
ACBD6	Q9BR61	1
ANK3	Q12955	1
ARHGAP4	P98171	1
MYT1	Q01538	1
ADGRG6	Q86SQ4	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC25A5	P05141	91.76
BCS1L	Q9Y276	87.10
CAPN12	Q6ZSI9	86.63
DHX34	Q14147	80.85
SRPK3	Q9UPE1	80.61
CADPS2	Q86UW7	79.91
WDR13	Q9H1Z4	79.85
CDH15	P55291	78.70
BFSP2	Q13515	78.15
SEMA6B	Q9H3T3	74.81
ZMYM6	O95789	69.69
ZMYM3	Q14202	63.19

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1,068. Enrichment computed across 250 evidence-associated genes (198 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 198 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	10	23.1×	5e-09	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, BCL11A (+2 more)
Formation of the embryonic stem cell BAF (esBAF) complex	8	24.3×	2e-07	SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, BCL11A, BCL11B
Sensory processing of sound	10	15.6×	2e-07	SNAP25, SPTAN1, SPTBN1, STX1A, SYN1, ACTB, CDH23, CACNA1D (+2 more)
Interaction between L1 and Ankyrins	9	16.7×	5e-07	SCN2A, ANK3, SCN1A, SCN8A, SPTAN1, SPTBN1, SPTBN2, ACTB (+1 more)
Developmental Biology	38	2.8×	1e-06	SCN2A, TCF4, TCF7L2, CACNA1C, CACNA1G, CDH15, ANK3, ROBO1 (+30 more)
Gene expression (Transcription)	33	3.0×	3e-06	TCF7L2, SRSF1, SEM1, SKI, SMARCA2, SMARCA4, SMARCA5, SMARCB1 (+25 more)
Sensory processing of sound by inner hair cells of the cochlea	11	9.1×	4e-06	SNAP25, SPTAN1, SPTBN1, STX1A, SYN1, ACTB, CDH23, CACNA1D (+3 more)
MAPK1/MAPK3 signaling	12	8.0×	4e-06	SEM1, BRAF, SOS1, SPTAN1, SPTBN1, SPTBN2, SYNGAP1, ACTB (+4 more)
Nervous system development	20	4.3×	4e-06	SCN2A, CACNA1C, CACNA1G, ANK3, ROBO1, RPS6KA3, SCN1A, SCN8A (+12 more)
RNA Polymerase II Transcription	28	3.2×	5e-06	TCF7L2, SRSF1, SEM1, SKI, SMARCA2, SMARCA4, SMARCB1, SMARCC2 (+20 more)
Transcriptional regulation by RUNX1	11	8.1×	9e-06	SEM1, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, KMT2C (+3 more)
MITF-M-regulated melanocyte development	12	6.9×	1e-05	TCF7L2, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, SOX9 (+4 more)
Sensory Perception	13	6.2×	1e-05	SCN2A, LRP2, SNAP25, SPTAN1, SPTBN1, STX1A, SYN1, ACTB (+5 more)
Chromatin organization	14	5.8×	1e-05	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, KDM5C, KDM6A (+6 more)
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	8	12.1×	2e-05	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, AUTS2, ACTL6B
Formation of the canonical BAF (cBAF) complex	6	19.2×	2e-05	SMARCA2, SMARCA4, SMARCB1, SMARCE1, ARID1A, ACTB
Formation of the polybromo-BAF (pBAF) complex	6	19.2×	2e-05	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ACTB
Axon guidance	18	4.1×	2e-05	SCN2A, CACNA1C, CACNA1G, ANK3, ROBO1, RPS6KA3, SCN1A, SCN8A (+10 more)
MAPK family signaling cascades	12	6.2×	3e-05	SEM1, BRAF, SOS1, SPTAN1, SPTBN1, SPTBN2, SYNGAP1, ACTB (+4 more)
NCAM signaling for neurite out-growth	8	11.0×	3e-05	CACNA1C, CACNA1G, SOS1, SPTAN1, SPTBN1, SPTBN2, CACNA1D, CACNA1S
Chromatin modifying enzymes	14	5.1×	3e-05	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, KDM5C, KDM6A (+6 more)
Regulation of endogenous retroelements	7	13.0×	4e-05	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB
Phase 0 - rapid depolarisation	7	12.2×	6e-05	SCN2A, CACNA1C, SCN1A, SCN8A, CACNG7, CAMK2A, CAMK2B
MITF-M-dependent gene expression	9	8.2×	6e-05	TCF7L2, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, TERT (+1 more)
Regulation of insulin secretion	8	8.9×	1e-04	STXBP1, CACNA1C, SLC2A1, SNAP25, STX1A, CACNA1A, CACNA1D, CACNA1E
L1CAM interactions	10	6.1×	2e-04	SCN2A, ANK3, RPS6KA3, SCN1A, SCN8A, SPTAN1, SPTBN1, SPTBN2 (+2 more)
Regulation of MITF-M-dependent genes involved in pigmentation	7	9.4×	3e-04	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB
GABA synthesis, release, reuptake and degradation	5	16.0×	4e-04	STXBP1, SLC32A1, SLC6A1, SNAP25, STX1A
Deactivation of the beta-catenin transactivating complex	7	8.2×	7e-04	TCF7L2, CHD8, SOX3, SOX4, SOX9, UBC, KMT2B
Epigenetic regulation of gene expression	12	4.3×	8e-04	SMARCA2, SMARCA4, SMARCA5, SMARCB1, SMARCC2, SMARCE1, ARID1A, MED12 (+4 more)

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 245 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nervous system development	26	4.9×	5e-08	SCN2A, TCF4, ERBB4, ARHGAP4, MYT1, ROBO1, SDHA, SEMA5A (+18 more)
chromatin remodeling	20	6.0×	2e-07	CHD8, SMARCA2, SMARCA4, SMARCA5, SMARCB1, SMARCC2, SMARCE1, ARID1A (+12 more)
regulation of G0 to G1 transition	8	22.0×	1e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, ACTL6B
regulation of nucleotide-excision repair	8	19.6×	2e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, ACTL6B
vocalization behavior	7	25.3×	2e-06	CNTNAP2, FOXP2, NLGN4X, NLGN3, SHANK3, SHANK2, SHANK1
positive regulation of myoblast differentiation	9	13.5×	5e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, SOX4, ACTB (+1 more)
regulation of mitotic metaphase/anaphase transition	8	16.2×	6e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, ACTL6B
positive regulation of double-strand break repair	9	12.6×	7e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, FMN2 (+1 more)
cardiac muscle cell action potential involved in contraction	7	20.1×	7e-06	SCN2A, CACNA1C, CACNA1G, SCN1A, SCN8A, CACNA1D, CACNA2D1
positive regulation of T cell differentiation	8	14.9×	9e-06	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, ACTL6B
positive regulation of DNA-templated transcription	28	3.2×	1e-05	TCF4, CHD8, ERBB4, BMP4, BRCA2, SMARCA2, SMARCA4, SMARCC2 (+20 more)
synapse organization	9	10.3×	3e-05	SLC6A1, SYN1, TSC1, GET1, NLGN4X, NLGN3, SHANK3, SHANK2 (+1 more)
calcium ion import across plasma membrane	7	15.5×	4e-05	CACNA1C, CACNA1G, CACNA1A, CACNA1D, CACNA1E, CACNA1S, CACNA2D1
positive regulation of cell differentiation	9	9.8×	4e-05	RPS6KA3, SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB (+1 more)
nucleosome disassembly	6	19.6×	5e-05	SET, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A
associative learning	7	13.8×	7e-05	SLC6A1, SNAP25, TACR1, TSC1, SHANK3, SHANK2, SHANK1
adult behavior	7	13.4×	8e-05	SPTBN2, CNTNAP2, NLGN4X, NLGN3, SHANK3, SHANK2, SHANK1
positive regulation of transcription by RNA polymerase II	38	2.3×	1e-04	TCF4, TCF7L2, CHD8, RPS6KA3, BMP4, SKI, SMARCA2, SMARCA4 (+30 more)
regulation of G1/S transition of mitotic cell cycle	8	10.0×	1e-04	SMARCA2, SMARCA4, SMARCB1, SMARCC2, SMARCE1, ARID1A, ACTB, ACTL6B
learning	8	9.2×	2e-04	TH, SLC12A5, CNTNAP2, CIC, NLGN4X, NLGN3, SHANK3, SHANK2
social behavior	8	8.9×	3e-04	CHD8, CNTNAP2, CIC, NLGN4X, NLGN3, SHANK3, SHANK2, SHANK1
positive regulation of stem cell population maintenance	7	9.8×	5e-04	SMARCA2, SMARCA4, SMARCB1, SMARCE1, ARID1A, ACTB, ACTL6B
neural tube closure	9	6.9×	5e-04	LRP2, BMP4, STIL, SKI, MED12, TSC1, TSC2, DEAF1 (+1 more)
dendrite extension	4	27.5×	6e-04	SLC9A6, WASF1, CYFIP2, AUTS2
axon extension	6	12.1×	6e-04	SEMA5A, SLC9A6, SPG11, USP9X, AUTS2, NLGN3
calcium ion transport	9	6.7×	6e-04	TRPM3, RYR1, TRPC5, CACNG7, CDH23, CACNA1D, CACNA1S, CACNA2D1 (+1 more)
calcium ion transmembrane transport	8	6.9×	0.001	CACNA1C, CACNA1G, TRPM3, TRPC5, MCOLN1, CACNA1A, CACNA1D, CACNA1S
axonogenesis	9	5.9×	0.001	ANK3, SPG11, BRSK2, SYNGAP1, TOP2B, ACTB, SLITRK2, ACTG1 (+1 more)
regulation of protein localization to plasma membrane	5	13.2×	0.002	SPTBN1, ACTB, VPS4A, CAMK2A, CAMK2B
establishment of mitotic sister chromatid cohesion	3	29.5×	0.006	SMC1A, STAG1, STAG2

Therapeutics

Drugs indicated for this disease

0 approved, 3 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Clozapine	Phase 3 (in late-stage trials)
Olanzapine	Phase 3 (in late-stage trials)
Risperidone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bromocriptine, Cannabidiol, Metformin.

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 10 · Phased (≥1): 14 · Undrugged: 28

Druggability breadth: 137 of 250 evidence-associated genes (55%) 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
SCN2A	BEPRIDIL
CACNA1C	REMIFENTANIL
CACNA1G	NIMODIPINE
ERBB4	MOBOCERTINIB
MYT1	DASATINIB ANHYDROUS
SLC25A5	GILTERITINIB
AURKA	INAMRINONE
SRPK3	FEDRATINIB
RPL10	GENTAMICIN SULFATE
RPL15	GENTAMICIN SULFATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
CACNA1C	85	4
AURKA	65	4
ERBB4	47	4
SRPK3	18	4
CACNA1G	8	4
MYT1	4	4
SLC25A5	2	4
TCF4	1	2
CHAF1B	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	CACNA1C, SCN2A
DIBUCAINE	4	CACNA1C, SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	CACNA1C, SCN2A
DROPERIDOL	4	CACNA1C, SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	CACNA1C, SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	CACNA1C, SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	CACNA1C, SCN2A
NIFEDIPINE	4	CACNA1C, SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	CACNA1C, SCN2A
PRENYLAMINE	4	CACNA1C, SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	CACNA1C, SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 8.

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

Symbol	Assays	Type breakdown
AURKA	1,500	Binding:1483, Functional:10, ADMET:7
ERBB4	591	Binding:579, ADMET:8, Functional:4
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
SRPK3	229	Binding:229
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
CACNA1G	105	Binding:91, Functional:11, ADMET:2, Toxicity:1
RPL10	90	Binding:90
RPL15	90	Binding:90
TCF4	31	Binding:31
TCF7L2	22	Binding:22
SLC25A5	12	Binding:12
VPS35	11	Binding:11
MYT1	9	Binding:9
AQP4	8	Binding:8
CHD8	7	Binding:7
CHAF1B	6	Binding:6
RHEB	4	Binding:4
ROR2	4	Binding:4
JMJD1C	2	Binding:2
TRPM3	2	Binding:2
ADGRG6	2	Binding:2
STXBP1	1	Binding:1
LRP2	1	Binding:1
UBQLN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
JMJD1C	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase
DHX34	3.6.4.13	RNA helicase
ERBB4	2.7.10.1	receptor protein-tyrosine kinase
AURKA	2.7.11.1	non-specific serine/threonine protein kinase
SRPK3	2.7.11.1	non-specific serine/threonine protein kinase
RHEB	3.6.5.2	small monomeric GTPase
ROR2	2.7.10.1	receptor protein-tyrosine kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
CACNA1C	575
CACNA1G	105
ERBB4	591
AURKA	1,500
SRPK3	229

Pharmacogenomics

Cohort genes with a PharmGKB record: 42; 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)
BEPRIDIL	4	CACNA1C, SCN2A
DIBUCAINE	4	CACNA1C, SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	CACNA1C, SCN2A
DROPERIDOL	4	CACNA1C, SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	CACNA1C, SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	CACNA1C, SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	CACNA1C, SCN2A
NIFEDIPINE	4	CACNA1C, SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	CACNA1C, SCN2A
PRENYLAMINE	4	CACNA1C, SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	CACNA1C, SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	SCN2A, CACNA1C, CACNA1G, ERBB4, MYT1, SLC25A5, AURKA, SRPK3, RPL10, RPL15
B	Phased (≥1) drug, not yet approved	4	TCF4, CHAF1B, CHD8, VPS35
C	Druggable family + PDB, no drug	6	JMJD1C, TRPM3, ADGRG6, RHEB, ROBO1, ROR2
D	Druggable family + AlphaFold only, no drug	1	CAPN12
E	Difficult family or no structure, no drug	21	SEMA6B, STXBP1, TCF7L2, ZMYM3, DHX34, CDH15, ACBD6, TUSC3, ANK3, AQP4 (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SEMA6B	0	—
STXBP1	1	—
TCF7L2	22	—
JMJD1C	2	—
ZMYM3	0	—
DHX34	0	—
CDH15	0	—
TRPM3	2	—
ACBD6	0	—
TUSC3	0	—
ANK3	0	—
AQP4	8	—
LRP2	1	—
ARHGAP4	0	—
CLIP1	0	—
UBQLN1	1	—
ZMYM6	0	—
CAPN12	0	—
VPS4A	0	—
ADGRG6	2	—
WDR13	0	—
CADPS2	0	—
RHEB	4	—
BCS1L	0	—
ROBO1	0	—
ROR2	4	—
CNNM2	0	—
BFSP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 197.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	180
PHASE1	5
PHASE4	4
PHASE2	4
PHASE3	1
PHASE2/PHASE3	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
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
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
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
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental 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
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02914951	Not specified	ENROLLING_BY_INVITATION	Cognitive-Behavioral Therapy for Irritability in Children With Autism Spectrum Disorder and Intellectual Disability
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
NCT04025398	Not specified	RECRUITING	A Computer-based Cognitive Remediation Program for Adults With Intellectual Disability
NCT04199299	Not specified	RECRUITING	Sensors for Communication for Persons Who Cannot Communicate Unequivocally
NCT04573530	Not specified	ACTIVE_NOT_RECRUITING	We Walk Plus Study for Older Adults With Intellectual Disabilities
NCT04781452	Not specified	RECRUITING	Evaluating the Treatment in the MZEB Aachen
NCT05131425	Not specified	ACTIVE_NOT_RECRUITING	Facing Your Fears: Adolescents With ASD and Intellectual Disability
NCT05290051	Not specified	RECRUITING	Prospective Study to Assess Medical Performance of Optical Mapping and Long Read Sequencing in Detecting Numerical and Structural Chromosome Abnormalities
NCT05432349	Not specified	RECRUITING	Rett Syndrome Registry
NCT05471232	Not specified	RECRUITING	Mental Health Crises in Youth With IDDs
NCT05473429	Not specified	RECRUITING	Characterization of Nociception Phenotype in Individuals With Intellectual Disability
NCT05709405	Not specified	ACTIVE_NOT_RECRUITING	Reading Intervention for Children With Intellectual Disabilities Who Require Augmentative and Alternative Communication
NCT05738278	Not specified	RECRUITING	Heart Rate Informed Changes in Care for Non-Communicating Patients
NCT05751525	Not specified	RECRUITING	Impact of Sulphonylureas on Neurodevelopmental Outcomes in KCNJ11-related Intermediate Developmental Delay, Epilepsy and Neonatal Diabetes (iDEND) Syndrome
NCT05767203	Not specified	RECRUITING	Genetic Markers and Biomarkers in Patients With Intellectual Disabilities of Genetic Origin
NCT05867940	Not specified	RECRUITING	Effects of Physical Activity on Prescription (PAP) as a Health-enhancing Intervention in People With Disabilities
NCT05872737	Not specified	RECRUITING	FAB Programme for Parents of Children With NDD
NCT05935722	Not specified	RECRUITING	Evaluation of a Home-based Parenting Support Program: Parenting Young Children
NCT05986305	Not specified	ACTIVE_NOT_RECRUITING	Improving the Health of Parents and Their Adolescent and Transition-age Youth With Intellectual and Developmental Disabilities
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
METFORMIN	4	3
AMISULPRIDE	4	1
CLOZAPINE	4	1
DEUTETRABENAZINE	4	1
HALOPERIDOL	4	1
NABILONE	4	1
PIMOZIDE	4	1
VALBENAZINE	4	1
CLOPIMOZIDE	2	1