Complex neurodevelopmental disorder

Summary

Complex neurodevelopmental disorder (MONDO:0100038) is a disease (an umbrella term covering 15 Mondo subtypes) caused by variants in BRSK2, CC2D1A, CNOT3, and 60 other genes, with 150 cohort genes and 2 clinical trials. The dominant Reactome pathway is Folding of actin by CCT/TriC (5 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: BRSK2 (GenCC Definitive), CC2D1A (GenCC Definitive), CNOT3 (GenCC Definitive), CUL3 (GenCC Definitive) (+59 more)
• Umbrella term: 15 Mondo subtypes
• Cohort genes: 150
• ClinVar variants: 289
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	complex neurodevelopmental disorder
Mondo ID	MONDO:0100038
Orphanet	528084
UMLS	C5568766
MedGen	1800189
GARD	0017965
Is cancer (heuristic)	no

Also known as: complex neurodevelopmental disorder

Data availability: 289 ClinVar variants · 35 ClinGen variant curations · 255 GenCC gene-disease records.

Disease family

An umbrella term covering 15 Mondo subtypes.

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

Related subtypes (20): intellectual disability, microcephaly, Williams syndrome, Aicardi syndrome, Hao-Fountain syndrome, toluene embryopathy, alternating hemiplegia, atypical Rett syndrome, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, 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 (15): pervasive developmental disorder, Prader-Willi syndrome, intellectual disability, autosomal dominant 29, neurodevelopmental disorder with language impairment and behavioral abnormalities, neurodevelopmental disorder with severe motor impairment and absent language, X-linked complex neurodevelopmental disorder, neonatal encephalopathy with non-epileptic myoclonus, complex neurodevelopmental disorder with or without congenital anomalies, complex neurodevelopmental disorder with motor features, AFG2B-related complex neurodevelopmental disorder with motor features and hearing loss, developmental and epileptic encephalopathy, syndromic complex neurodevelopmental disorder, DEAF1-associated neurodevelopmental disorder, NACC1-related neurodevelopmental disorder with epilepsy, cataracts and episodic irritability, GRIN-related complex neurodevelopmental disorder

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

289 retrieved; paginated sample, class counts are floors:

89 pathogenic, 62 likely pathogenic, 56 uncertain significance, 33 pathogenic/likely pathogenic, 32 conflicting classifications of pathogenicity, 8 benign, 6 likely benign, 2 not provided, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
218395	NM_001271.4(CHD2):c.4173dup (p.Gln1392fs)	CHD2	Pathogenic	criteria provided, multiple submitters, no conflicts
560973	NM_001271.4(CHD2):c.2699G>A (p.Arg900Gln)	CHD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
984879	NM_001271.4(CHD2):c.2963C>G (p.Ser988Ter)	CHD2	Pathogenic	no assertion criteria provided
4075809	NM_016284.5(CNOT1):c.4800+1G>A	CNOT1	Pathogenic	criteria provided, single submitter
984751	GRCh37/hg19 2q24.3(chr2:166060478-166349787)x1	CSRNP3	Pathogenic	no assertion criteria provided
1699112	NM_003590.5(CUL3):c.578T>G (p.Leu193Ter)	CUL3	Pathogenic	criteria provided, single submitter
162158	NM_001347721.2(DYRK1A):c.1282C>T (p.Arg428Ter)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
204006	NM_001347721.2(DYRK1A):c.434del (p.Lys145fs)	DYRK1A	Pathogenic	criteria provided, single submitter
209150	NM_001347721.2(DYRK1A):c.1373G>A (p.Arg458Gln)	DYRK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
265592	NM_001347721.2(DYRK1A):c.630C>A (p.Tyr210Ter)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
373087	NM_001347721.2(DYRK1A):c.322C>T (p.Arg108Ter)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
419635	NM_001347721.2(DYRK1A):c.1221del (p.Lys407fs)	DYRK1A	Pathogenic	criteria provided, single submitter
423335	NM_001347721.2(DYRK1A):c.545_548del (p.Lys182fs)	DYRK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
423502	NM_001347721.2(DYRK1A):c.664C>T (p.Arg222Ter)	DYRK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430402	NM_001347721.2(DYRK1A):c.678_680delinsAC (p.Cys226_Leu227delinsTer)	DYRK1A	Pathogenic	criteria provided, single submitter
435011	NM_001347721.2(DYRK1A):c.924+4_924+7del	DYRK1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
441126	NM_001347721.2(DYRK1A):c.1373dup (p.Ile459fs)	DYRK1A	Pathogenic	no assertion criteria provided
520853	NM_001347721.2(DYRK1A):c.658_659del (p.Met220fs)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
522162	NM_001347721.2(DYRK1A):c.1008G>A (p.Trp336Ter)	DYRK1A	Pathogenic	criteria provided, multiple submitters, no conflicts
524106	NM_001347721.2(DYRK1A):c.220dup (p.Gln74fs)	DYRK1A	Pathogenic	criteria provided, single submitter
984686	NCBI36/hg18 21q22.13-22.2(chr21:37662974-39195976)x1	DYRK1A	Pathogenic	no assertion criteria provided
984687	NCBI36/hg18 21q22.13-22.2(chr21:37662974-39236719)x1	DYRK1A	Pathogenic	no assertion criteria provided
984756	NM_001347721.2(DYRK1A):c.301-2A>G	DYRK1A	Pathogenic	criteria provided, single submitter
984757	GRCh37/hg19 21q22.13(chr21:38744158-38830251)x1	DYRK1A	Pathogenic	no assertion criteria provided
984805	NM_001347721.2(DYRK1A):c.424_439del (p.Asn142fs)	DYRK1A	Pathogenic	no assertion criteria provided
100782	NM_001958.5(EEF1A2):c.208G>A (p.Gly70Ser)	EEF1A2	Pathogenic	criteria provided, multiple submitters, no conflicts
205730	NM_000834.5(GRIN2B):c.1832G>T (p.Gly611Val)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208643	NM_000834.5(GRIN2B):c.2459G>C (p.Gly820Ala)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224818	NM_000834.5(GRIN2B):c.2065G>A (p.Gly689Ser)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234500	NM_000834.5(GRIN2B):c.2252T>C (p.Ile751Thr)	GRIN2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 524 · Orphanet: 121 · 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
BRSK2	Definitive	Autosomal dominant	complex neurodevelopmental disorder	5
CELF4	Definitive	Autosomal dominant	neurodevelopmental disorder	2
CNOT3	Definitive	Autosomal dominant	complex neurodevelopmental disorder	4
CUL3	Definitive	Autosomal dominant	complex neurodevelopmental disorder	6
EEF1A2	Definitive	Autosomal dominant	complex neurodevelopmental disorder	7
GRIN2A	Definitive	Autosomal dominant	complex neurodevelopmental disorder	12
GRIN2B	Definitive	Autosomal dominant	complex neurodevelopmental disorder	9
KMT5B	Definitive	Autosomal dominant	complex neurodevelopmental disorder	5
MSL2	Definitive	Autosomal dominant	Karayol-Borroto-Haghshenas neurodevelopmental syndrome	3
NAV3	Definitive	Autosomal recessive	complex neurodevelopmental disorder	3
NR4A2	Definitive	Autosomal dominant	complex neurodevelopmental disorder	4
SATB1	Definitive	Autosomal dominant	complex neurodevelopmental disorder	5
SCN2A	Definitive	Autosomal dominant	complex neurodevelopmental disorder	16
SCN8A	Definitive	Autosomal dominant	complex neurodevelopmental disorder	13
VCP	Definitive	Autosomal dominant	complex neurodevelopmental disorder	13
ZNF292	Definitive	Autosomal dominant	complex neurodevelopmental disorder	5
ANK2	Strong	Autosomal dominant	complex neurodevelopmental disorder	11
ANO4	Strong	Autosomal dominant	neurodevelopmental disorder	2
ATG4D	Strong	Autosomal recessive	neurodevelopmental disorder	3
ATXN7L3	Strong	Autosomal dominant	complex neurodevelopmental disorder	2
CACNA1I	Strong	Autosomal dominant	neurodevelopmental disorder with speech impairment and with or without seizures	2
CDC42BPB	Strong	Autosomal dominant	Chilton-Okur-Chung neurodevelopmental syndrome	3
CLCN3	Strong	Autosomal dominant	complex neurodevelopmental disorder	8
CRELD1	Strong	Autosomal recessive	complex neurodevelopmental disorder	5
CTNND2	Strong	Autosomal dominant	complex neurodevelopmental disorder	3
DEAF1	Strong	Semidominant	complex neurodevelopmental disorder	11
FAM177A1	Strong	Autosomal recessive	Mendelian neurodevelopmental disorder	3
FEM1C	Strong	Autosomal dominant	neurodevelopmental disorder	2
FEZF2	Strong	Autosomal dominant	neurodevelopmental disorder	2
FOXP4	Strong	Autosomal dominant	complex neurodevelopmental disorder	3

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
SCN8A	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SCN8A	Orphanet:306	Self-limited infantile epilepsy
SCN8A	Orphanet:352582	Familial infantile myoclonic epilepsy
SCN8A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
BRSK2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ZNF292	Orphanet:528084	Non-specific syndromic intellectual disability
CHD1	Orphanet:529965	Intellectual disability-autism-speech apraxia-craniofacial dysmorphism syndrome
SCAF4	Orphanet:528084	Non-specific syndromic intellectual disability
CLCN3	Orphanet:528084	Non-specific syndromic intellectual disability
MBD5	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
MBD5	Orphanet:228402	2q23.1 microdeletion syndrome
CTNND2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
CTNND2	Orphanet:281	Monosomy 5p syndrome
CTNND2	Orphanet:86814	Familial adult myoclonic epilepsy
CUL3	Orphanet:300530	Pseudohypoaldosteronism type 2E
CUL3	Orphanet:528084	Non-specific syndromic intellectual disability
EEF1A2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
EEF1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
GRIN2A	Orphanet:163721	Rolandic epilepsy-speech dyspraxia syndrome
GRIN2A	Orphanet:1945	Self-limited epilepsy with centrotemporal spikes
GRIN2A	Orphanet:289266	Early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation
GRIN2A	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
GRIN2A	Orphanet:98818	Landau-Kleffner syndrome
GRIN2B	Orphanet:589547	GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B	Orphanet:697160	Infantile epileptic spasms syndrome
ANK2	Orphanet:101016	Romano-Ward syndrome
KCNQ2	Orphanet:140927	Self-limited neonatal-infantile epilepsy
KCNQ2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
KCNQ2	Orphanet:1949	Self-limited neonatal epilepsy
KCNQ2	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
KCNQ2	Orphanet:306	Self-limited infantile epilepsy
KCNQ2	Orphanet:439218	KCNQ2-related developmental and epileptic encephalopathy
CNOT3	Orphanet:528084	Non-specific syndromic intellectual disability
CNOT3	Orphanet:99861	Precursor T-cell acute lymphoblastic leukemia
NR4A2	Orphanet:1617	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to 2q24 microdeletion
NR4A2	Orphanet:660012	Developmental delay-language impairment-dopa responsive dystonia-parkinsonism syndrome due to a NR4A2 point mutation
NR4A2	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
RREB1	Orphanet:567	22q11.2 deletion syndrome
SATB1	Orphanet:684232	Intellectual disability-epilepsy-dental anomalies-facial dysmorphism syndrome
SEMA3E	Orphanet:138	CHARGE syndrome
SF3B1	Orphanet:39044	Uveal melanoma
SF3B1	Orphanet:75564	Acquired idiopathic sideroblastic anemia

Cohort genes → proteins

150 cohort genes, 150 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	150

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gencc,clinvar
SCN8A	HGNC:10596	ENSG00000196876	Q9UQD0	Sodium channel protein type 8 subunit alpha	gencc,clinvar
BRSK2	HGNC:11405	ENSG00000174672	Q8IWQ3	Serine/threonine-protein kinase BRSK2	gencc,clinvar
TAF1C	HGNC:11534	ENSG00000103168	Q15572	TATA box-binding protein-associated factor RNA polymerase I subunit C	gencc,clinvar
ZNF292	HGNC:18410	ENSG00000188994	O60281	Zinc finger protein 292	gencc,clinvar
CHD1	HGNC:1915	ENSG00000153922	O14646	ATP-dependent chromatin remodeler CHD1	gencc,clinvar
SCAF4	HGNC:19304	ENSG00000156304	O95104	SR-related and CTD-associated factor 4	gencc,clinvar
CLCN3	HGNC:2021	ENSG00000109572	P51790	H(+)/Cl(-) exchange transporter 3	gencc,clinvar
MBD5	HGNC:20444	ENSG00000204406	Q9P267	Methyl-CpG-binding domain protein 5	gencc,clinvar
CTNND2	HGNC:2516	ENSG00000169862	Q9UQB3	Catenin delta-2	gencc,clinvar
CUL3	HGNC:2553	ENSG00000036257	Q13618	Cullin-3	gencc,clinvar
WDR47	HGNC:29141	ENSG00000085433	O94967	WD repeat-containing protein 47	gencc,clinvar
EEF1A2	HGNC:3192	ENSG00000101210	Q05639	Elongation factor 1-alpha 2	gencc,clinvar
ALDH1B1	HGNC:407	ENSG00000137124	P30837	Aldehyde dehydrogenase X, mitochondrial	gencc,clinvar
GRIN2A	HGNC:4585	ENSG00000183454	Q12879	Glutamate receptor ionotropic, NMDA 2A	gencc,clinvar
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	gencc,clinvar
ANK2	HGNC:493	ENSG00000145362	Q01484	Ankyrin-2	gencc,clinvar
KCNQ2	HGNC:6296	ENSG00000075043	O43526	Potassium voltage-gated channel subfamily KQT member 2	gencc,clinvar
CNOT3	HGNC:7879	ENSG00000088038	O75175	CCR4-NOT transcription complex subunit 3	gencc,clinvar
NR4A2	HGNC:7981	ENSG00000153234	P43354	Nuclear receptor subfamily 4 group A member 2	gencc,clinvar
RHEB	HGNC:10011	ENSG00000106615	Q15382	GTP-binding protein Rheb	gencc
RING1	HGNC:10018	ENSG00000204227	Q06587	E3 ubiquitin-protein ligase RING1	gencc
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	gencc
RREB1	HGNC:10449	ENSG00000124782	Q92766	Ras-responsive element-binding protein 1	gencc
RYBP	HGNC:10480	ENSG00000163602	Q8N488	RING1 and YY1-binding protein	gencc
SATB1	HGNC:10541	ENSG00000182568	Q01826	DNA-binding protein SATB1	gencc
SEMA3E	HGNC:10727	ENSG00000170381	O15041	Semaphorin-3E	gencc
SF3B1	HGNC:10768	ENSG00000115524	O75533	Splicing factor 3B subunit 1	gencc
SF3B2	HGNC:10769	ENSG00000087365	Q13435	Splicing factor 3B subunit 2	gencc
TRA2B	HGNC:10781	ENSG00000136527	P62995	Transformer-2 protein homolog beta	gencc
SHMT2	HGNC:10852	ENSG00000182199	P34897	Serine hydroxymethyltransferase, mitochondrial	gencc
SIAH1	HGNC:10857	ENSG00000196470	Q8IUQ4	E3 ubiquitin-protein ligase SIAH1	gencc
ST3GAL3	HGNC:10866	ENSG00000126091	Q11203	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	gencc
SIM1	HGNC:10882	ENSG00000112246	P81133	Single-minded homolog 1	gencc
SLC1A4	HGNC:10942	ENSG00000115902	P43007	Neutral amino acid transporter A	gencc
SLC7A5	HGNC:11063	ENSG00000103257	Q01650	Large neutral amino acids transporter small subunit 1	gencc
SMARCA5	HGNC:11101	ENSG00000153147	O60264	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	gencc
SMARCB1	HGNC:11103	ENSG00000099956	Q12824	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	gencc
SNRPA	HGNC:11151	ENSG00000077312	P09012	U1 small nuclear ribonucleoprotein A	gencc
SRPRA	HGNC:11307	ENSG00000182934	P08240	Signal recognition particle receptor subunit alpha	gencc
STX1A	HGNC:11433	ENSG00000106089	Q16623	Syntaxin-1A	gencc
SUPT16H	HGNC:11465	ENSG00000092201	Q9Y5B9	FACT complex subunit SPT16	gencc
MED22	HGNC:11477	ENSG00000148297	Q15528	Mediator of RNA polymerase II transcription subunit 22	gencc
CEP55	HGNC:1161	ENSG00000138180	Q53EZ4	Centrosomal protein of 55 kDa	gencc
TFE3	HGNC:11752	ENSG00000068323	P19532	Transcription factor E3	gencc
DNAJA3	HGNC:11808	ENSG00000103423	Q96EY1	DnaJ homolog subfamily A member 3, mitochondrial	gencc
JMJD1C	HGNC:12313	ENSG00000171988	Q15652	Jumonji domain-containing protein 1C	gencc
USP14	HGNC:12612	ENSG00000101557	P54578	Ubiquitin carboxyl-terminal hydrolase 14	gencc
USP2	HGNC:12618	ENSG00000036672	O75604	Ubiquitin carboxyl-terminal hydrolase 2	gencc
USP8	HGNC:12631	ENSG00000138592	P40818	Ubiquitin carboxyl-terminal hydrolase 8	gencc

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.
SCN8A	Sodium channel protein type 8 subunit alpha	Pore-forming subunit of a voltage-gated sodium channel complex assuming opened or closed conformations in response to the voltage difference across membranes and through which sodium ions selectively pass along their electrochemical gradie…
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.
TAF1C	TATA box-binding protein-associated factor RNA polymerase I subunit C	Component of the transcription factor SL1/TIF-IB complex, which is involved in the assembly of the PIC (pre-initiation complex) during RNA polymerase I-dependent transcription.
ZNF292	Zinc finger protein 292	May be involved in transcriptional regulation.
CHD1	ATP-dependent chromatin remodeler CHD1	ATP-dependent chromatin-remodeling factor which functions as substrate recognition component of the transcription regulatory histone acetylation (HAT) complex SAGA.
SCAF4	SR-related and CTD-associated factor 4	Anti-terminator protein required to prevent early mRNA termination during transcription.
CLCN3	H(+)/Cl(-) exchange transporter 3	Strongly outwardly rectifying, electrogenic H(+)/Cl(-)exchanger which mediates the exchange of chloride ions against protons.
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).
CTNND2	Catenin delta-2	Has a critical role in neuronal development, particularly in the formation and/or maintenance of dendritic spines and synapses.
CUL3	Cullin-3	Core component of multiple cullin-RING-based BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins.
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.
ALDH1B1	Aldehyde dehydrogenase X, mitochondrial	ALDHs play a major role in the detoxification of alcohol-derived acetaldehyde.
GRIN2A	Glutamate receptor ionotropic, NMDA 2A	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+).
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+).
ANK2	Ankyrin-2	Plays an essential role in the localization and membrane stabilization of ion transporters and ion channels in several cell types, including cardiomyocytes, as well as in striated muscle cells.
KCNQ2	Potassium voltage-gated channel subfamily KQT member 2	Pore-forming subunit of the voltage-gated potassium (Kv) M-channel which is responsible for the M-current, a key controller of neuronal excitability.
CNOT3	CCR4-NOT transcription complex subunit 3	Component of the CCR4-NOT complex which is one of the major cellular mRNA deadenylases and is linked to various cellular processes including bulk mRNA degradation, miRNA-mediated repression, translational repression during translational in…
NR4A2	Nuclear receptor subfamily 4 group A member 2	Transcriptional regulator which is important for the differentiation and maintenance of meso-diencephalic dopaminergic (mdDA) neurons during development.
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…
RING1	E3 ubiquitin-protein ligase RING1	Constitutes one of the E3 ubiquitin-protein ligases that mediate monoubiquitination of ‘Lys-119’ of histone H2A, thereby playing a central role in histone code and gene regulation.
RORB	Nuclear receptor ROR-beta	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
RREB1	Ras-responsive element-binding protein 1	Transcription factor that binds specifically to the RAS-responsive elements (RRE) of gene promoters.
RYBP	RING1 and YY1-binding protein	Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.
SATB1	DNA-binding protein SATB1	Crucial silencing factor contributing to the initiation of X inactivation mediated by Xist RNA that occurs during embryogenesis and in lymphoma.
SEMA3E	Semaphorin-3E	Plays an important role in signaling via the cell surface receptor PLXND1.
SF3B1	Splicing factor 3B subunit 1	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
SF3B2	Splicing factor 3B subunit 2	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
TRA2B	Transformer-2 protein homolog beta	Sequence-specific RNA-binding protein which participates in the control of pre-mRNA splicing.
SHMT2	Serine hydroxymethyltransferase, mitochondrial	Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis.
SIAH1	E3 ubiquitin-protein ligase SIAH1	E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of target proteins.
ST3GAL3	CMP-N-acetylneuraminate-beta-1,4-galactoside alpha-2,3-sialyltransferase	Catalyzes the formation of the NeuAc-alpha-2,3-Gal-beta-1,4-GlcNAc-, NeuAc-alpha-2,3-Gal-beta-1,3-GlcNAc- and NeuAc-alpha-2,3-Gal-beta-1,3-GalNAc- sequences found in terminal carbohydrate groups of glycoproteins and glycolipids.
SIM1	Single-minded homolog 1	Transcriptional factor that may have pleiotropic effects during embryogenesis and in the adult.
SLC1A4	Neutral amino acid transporter A	Sodium-coupled antiporter of neutral amino acids.
SLC7A5	Large neutral amino acids transporter small subunit 1	The heterodimer with SLC3A2 functions as a sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, leucine, histidine, methionine, tryptophan, valine, isoleucine and…
SMARCA5	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 5	ATPase that possesses intrinsic ATP-dependent nucleosome-remodeling activity.
SMARCB1	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1	Core component of the BAF (hSWI/SNF) complex.
SNRPA	U1 small nuclear ribonucleoprotein A	Component of the spliceosomal U1 snRNP, which is essential for recognition of the pre-mRNA 5’ splice-site and the subsequent assembly of the spliceosome.
SRPRA	Signal recognition particle receptor subunit alpha	Component of the signal recognition particle (SRP) complex receptor (SR).
STX1A	Syntaxin-1A	Plays an essential role in hormone and neurotransmitter calcium-dependent exocytosis and endocytosis.
SUPT16H	FACT complex subunit SPT16	Component of the FACT complex, a general chromatin factor that acts to reorganize nucleosomes.
MED22	Mediator of RNA polymerase II transcription subunit 22	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
CEP55	Centrosomal protein of 55 kDa	Plays a role in mitotic exit and cytokinesis.
TFE3	Transcription factor E3	Transcription factor that acts as a master regulator of lysosomal biogenesis and immune response.
DNAJA3	DnaJ homolog subfamily A member 3, mitochondrial	Modulates apoptotic signal transduction or effector structures within the mitochondrial matrix.
JMJD1C	Jumonji domain-containing protein 1C	Demethylates lysine in proteins, such as STAT3 or MDC1.
USP14	Ubiquitin carboxyl-terminal hydrolase 14	Proteasome-associated deubiquitinase which releases ubiquitin from the proteasome targeted ubiquitinated proteins.
USP2	Ubiquitin carboxyl-terminal hydrolase 2	Hydrolase that deubiquitinates polyubiquitinated target proteins such as MDM2, MDM4 and CCND1.
USP8	Ubiquitin carboxyl-terminal hydrolase 8	Hydrolase that can remove conjugated ubiquitin from proteins and therefore plays an important regulatory role at the level of protein turnover by preventing degradation.
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.

Protein-family classification

Druggable: 45 · Difficult: 40 · Unknown: 65 · Druggable fraction: 0.3

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
Nuclear receptor	2	5.2×	0.231
Ion channel	4	3.0×	0.231
Transcription factor	27	1.5×	0.231
Complement	2	3.6×	0.259
Scaffold/PPI	13	1.5×	0.259
Kinase	8	1.5×	0.317
Enzyme (other)	16	1.3×	0.317
Protease	5	1.2×	0.586
Transporter	2	1.0×	0.769
Antibody/Immunoglobulin	4	0.8×	0.912
Other/Unknown	65	0.8×	0.999
GPCR	2	0.3×	0.999

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
SCN8A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
BRSK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TAF1C	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf, TAF1C
ZNF292	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GH-ZnFinger_Regulators
CHD1	Other/Unknown	no		SNF2_N, Chromo/chromo_shadow_dom, Helicase_C-like
SCAF4	Other/Unknown	no		RRM_dom, CID_dom, ENTH_VHS
CLCN3	Other/Unknown	no		CBS_dom, ClC, ClC3
MBD5	Other/Unknown	no		PWWP_dom, Methyl_CpG_DNA-bd, DNA-bd_dom_sf
CTNND2	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
CUL3	Other/Unknown	no		Cullin_N, Cullin_CS, Cullin_homology
WDR47	Scaffold/PPI	no		WD40_rpt, LisH, CTLH_C
EEF1A2	Other/Unknown	no		T_Tr_GTP-bd_dom, EFTu-like_2, Transl_elong_EF1A_euk/arc
ALDH1B1	Enzyme (other)	yes	1.2.1.3	Aldehyde_DH_dom, Ald_DH_CS_CYS, Ald_DH/histidinol_DH
GRIN2A	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
ANK2	Scaffold/PPI	no		Death_dom, ZU5_dom, Ankyrin_rpt
KCNQ2	Ion channel	yes		K_chnl_volt-dep_KCNQ, K_chnl_volt-dep_KCNQ2, Ion_trans_dom
CNOT3	Other/Unknown	no		Not_N, NOT2/3/5_C, CCR4-NOT_su3/5
NR4A2	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RHEB	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTP-bd, Small_GTPase_Ras-type
RING1	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
RREB1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, RREB1
RYBP	Transcription factor	no		Znf_RanBP2, YAF2_RYBP, Znf_RanBP2_sf
SATB1	Transcription factor	no		HD, CUT_dom, Homeodomain-like_sf
SEMA3E	Antibody/Immunoglobulin	yes		Semap_dom, Ig-like_dom, Immunoglobulin_dom
SF3B1	Other/Unknown	no		ARM-like, SF3b_su1, ARM-type_fold
SF3B2	Other/Unknown	no		SAP_dom, PSP_pro-rich, DUF382
TRA2B	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
SHMT2	Enzyme (other)	yes	2.1.2.1	Ser_HO-MeTrfase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
SIAH1	Transcription factor	no		Znf_RING, SINA-like_animal, TRAF-like
ST3GAL3	Enzyme (other)	yes	2.4.99.2	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SIM1	Transcription factor	no		PAS, PAC, SIM_C
SLC1A4	Other/Unknown	no		Na-dicarboxylate_symporter, Na-dicarboxylate_symporter_CS, Na:dicarbo_symporter_sf
SLC7A5	Transporter	yes		AA/rel_permease1, L_AA_transporter, AminoAcid_Transporter
SMARCA5	Transcription factor	no		SNF2_N, SANT/Myb, Helicase_C-like
SMARCB1	Other/Unknown	no		SNF5, Sfh1/SNF5, INI1_DNA-bd
SNRPA	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, U1A_RRM1
SRPRA	Enzyme (other)	yes	3.6.5.4	SRP54_GTPase_dom, AAA+_ATPase, SRPRA_N
STX1A	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
SUPT16H	Protease	yes		Pept_M24, PH-like_dom_sf, RTT106/SPT16-like_middle_dom
MED22	Other/Unknown	no		Med22
CEP55	Other/Unknown	no		EABR, CEP55
TFE3	Transcription factor	no		bHLH_dom, MiT/TFE_C, bHLHzip_TFE3
DNAJA3	Other/Unknown	no		HSP_DnaJ_Cys-rich_dom, DnaJ_domain, DnaJ_C
JMJD1C	Enzyme (other)	yes	1.14.11.65	JmjC_dom, LSDs-like, KDM3A/B_DUF7030
USP14	Protease	yes		Ubiquitin-like_dom, Peptidase_C19_UCH, USP_CS
USP2	Protease	yes		Peptidase_C19_UCH, USP_CS, USP
USP8	Protease	yes	3.4.19.12	Peptidase_C19_UCH, Rhodanese-like_dom, USP8_dimer

Expression context

Cohort genes with no expression data: 0.

135 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)	150
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	24
ventricular zone	19
Brodmann (1909) area 23	15
middle temporal gyrus	14
calcaneal tendon	14
ganglionic eminence	14
secondary oocyte	14
right hemisphere of cerebellum	11
cerebellar hemisphere	10
primordial germ cell in gonad	9
adrenal tissue	8
buccal mucosa cell	8
left testis	8
granulocyte	8
oocyte	8
cerebellar cortex	7
endothelial cell	7
prefrontal cortex	7
sural nerve	6
stromal cell of endometrium	6

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
SCN8A	194	ubiquitous	marker	Brodmann (1909) area 23, middle temporal gyrus, postcentral gyrus
BRSK2	176	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TAF1C	242	ubiquitous	marker	left ovary, right ovary, body of uterus
ZNF292	293	ubiquitous	marker	caput epididymis, calcaneal tendon, cauda epididymis
CHD1	291	ubiquitous	marker	calcaneal tendon, cauda epididymis, adrenal tissue
SCAF4	267	ubiquitous	marker	tendon of biceps brachii, buccal mucosa cell, sperm
CLCN3	291	ubiquitous	marker	mucosa of sigmoid colon, endothelial cell, colonic mucosa
MBD5	243	ubiquitous	marker	calcaneal tendon, adrenal tissue, sural nerve
CTNND2	213	broad	marker	cortical plate, prefrontal cortex, amygdala
CUL3	296	ubiquitous	marker	sperm, male germ cell, left testis
WDR47	288	ubiquitous	marker	cortical plate, lateral nuclear group of thalamus, ganglionic eminence
EEF1A2	247	ubiquitous	marker	gastrocnemius, apex of heart, hindlimb stylopod muscle
ALDH1B1	211	ubiquitous	marker	buccal mucosa cell, right coronary artery, tendon of biceps brachii
GRIN2A	199	broad	marker	Brodmann (1909) area 23, endothelial cell, middle temporal gyrus
GRIN2B	138	broad	marker	buccal mucosa cell, cortical plate, Brodmann (1909) area 23
ANK2	281	ubiquitous	marker	substantia nigra pars compacta, lateral nuclear group of thalamus, substantia nigra pars reticulata
KCNQ2	183	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CNOT3	134	ubiquitous	marker	sural nerve, pituitary gland, granulocyte
NR4A2	278	ubiquitous	marker	mucosa of paranasal sinus, mucosa of stomach, trachea
RHEB	218	ubiquitous	marker	ventricular zone, embryo, ganglionic eminence
RING1	133	ubiquitous	marker	pituitary gland, adenohypophysis, right lobe of thyroid gland
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
RREB1	278	ubiquitous	marker	buccal mucosa cell, epithelium of nasopharynx, oral cavity
RYBP	292	tissue_specific	marker	lower lobe of lung, cartilage tissue, endothelial cell
SATB1	294	ubiquitous	marker	orbitofrontal cortex, frontal pole, thymus
SEMA3E	197	broad	marker	cortical plate, calcaneal tendon, blood vessel layer
SF3B1	295	ubiquitous	marker	tibia, ventricular zone, epithelium of nasopharynx
SF3B2	292	ubiquitous	marker	ventricular zone, left testis, right testis
TRA2B	305	ubiquitous	marker	germinal epithelium of ovary, parietal pleura, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 83.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
CUL3	9,954
ANK2	6,423
CCT5	6,388
CCT7	6,382
SMARCA5	6,214
CCT6A	6,034
CCT4	5,903
KATNAL2	5,866
SHMT2	5,293

Intra-cohort edges

A	B	Sources
ALDH1L2	SHMT2	string_interaction
ANKS1B	CPNE6	string_interaction
ANO4	CDC42BPB	string_interaction
ARHGAP33	ZNF292	string_interaction
BORCS5	YWHAE	intact
BORCS5	YWHAZ	intact
BRSK2	RHEB	string_interaction
BRSK2	YWHAE	intact
CACNA1I	GRIN2B	string_interaction
CACNA1I	SCN8A	string_interaction
CAMK2D	GRIN2A	string_interaction
CAPZA2	CNOT3	biogrid_interaction, intact
CCT4	CCT5	biogrid_interaction, string_interaction
CCT4	CCT6A	string_interaction
CCT4	CCT7	string_interaction
CCT4	CCT8	string_interaction
CCT5	CCT6A	string_interaction
CCT5	CCT7	string_interaction
CCT5	CCT8	string_interaction
CCT5	TAF1C	intact
CCT5	TUBAL3	intact
CCT6A	CCT7	string_interaction
CCT6A	CCT8	intact, string_interaction
CCT6A	TUBAL3	biogrid_interaction
CCT7	CCT8	string_interaction
CCT7	TAF1C	intact
CCT7	TUBA3E	biogrid_interaction
CCT7	TUBAL3	biogrid_interaction
CCT8	ZNF589	string_interaction
CELF2	CELF4	string_interaction
CHD1	SUPT16H	string_interaction
CLASP1	KIF1B	intact
CLASP1	YWHAE	intact
CLASP1	YWHAZ	intact
CRELD1	SLC38A12	intact
CSMD1	ZNF804A	string_interaction
CSMD3	NAV3	string_interaction
CUL3	FEM1C	string_interaction
CUL3	KLHL20	intact, string_interaction
CUL3	RHOBTB2	intact, string_interaction
EEF1A2	FAM177A1	biogrid_interaction
EEF1A2	NAV3	biogrid_interaction
EEF1A2	TRERF1	biogrid_interaction
FEM1C	KLHL20	string_interaction
FEZF2	RORB	string_interaction
GPHN	SLITRK3	string_interaction
GRIN2A	GRIN2B	biogrid_interaction, string_interaction
GRIN2A	RPH3A	string_interaction
GRIN2B	KATNAL2	string_interaction
GRIN2B	MBD5	string_interaction

Structural data

PDB: 92 · AlphaFold-only: 58 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VCP	P55072	144
SNRPA	P09012	95
MRPL42	Q9Y6G3	85
YWHAZ	P63104	77
SF3B1	O75533	74
CCT5	P48643	69
CCT4	P50991	66
CCT6A	P40227	65
CCT8	P50990	65
PHF5A	Q7RTV0	65
CCT7	Q99832	64
CHRNA7	P36544	51
SF3B2	Q13435	50
KCNQ2	O43526	39
GRIN2A	Q12879	37
GRIN2B	Q13224	36
CUL3	Q13618	30
SHMT2	P34897	27
USP14	P54578	23
SLC7A5	Q01650	21
CHD1	O14646	18
SMARCB1	Q12824	17
SUPT16H	Q9Y5B9	17
RHEB	Q15382	15
SMARCA5	O60264	15
INTS11	Q5TA45	15
FEM1C	Q96JP0	12
ANK2	Q01484	11
MED22	Q15528	11
YWHAE	P62258	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CAPZA2	P47755	93.11
ALDH1L2	Q3SY69	92.71
TUBA3E	Q6PEY2	91.38
TUBAL3	A6NHL2	90.88
ST3GAL3	Q11203	90.87
RARS2	Q5T160	89.18
CPNE6	O95741	86.85
CDK20	Q8IZL9	86.08
STX1A	Q16623	84.94
LMAN2L	Q9H0V9	84.90
WSB2	Q9NYS7	84.84
SEMA3E	O15041	84.62
GPN2	Q9H9Y4	84.60
ATP11A	P98196	83.48
ZFTRAF1	P0DTL6	82.71
SLC12A9	Q9BXP2	82.25
RHOBTB2	Q9BYZ6	81.89
CRELD1	Q96HD1	81.68
SLC38A12	Q8NE00	81.33
BORCS5	Q969J3	80.54
RORB	Q92753	79.48
ANO4	Q32M45	79.27
ATG4D	Q86TL0	78.22
OSBPL9	Q96SU4	77.10
LMBRD2	Q68DH5	76.95
SORCS3	Q9UPU3	75.70
DOCK8	Q8NF50	75.17
RING1	Q06587	72.69
KATNAL2	Q8IYT4	72.21
HNRNPUL2	Q1KMD3	70.36

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 761. Enrichment computed across 250 evidence-associated genes (175 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 175 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Folding of actin by CCT/TriC	5	32.6×	3e-05	CCT4, CCT5, CCT6A, CCT7, CCT8
Formation of tubulin folding intermediates by CCT/TriC	7	16.9×	3e-05	CCT4, CCT5, CCT6A, CCT7, CCT8, TUBA3E, TUBAL3
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	7	16.3×	3e-05	CCT4, CCT5, CCT6A, CCT7, CCT8, TUBA3E, TUBAL3
L1CAM interactions	11	7.6×	3e-05	SCN2A, SCN8A, ANK2, KCNQ2, SCN1A, TUBA3E, CNTN2, TUBAL3 (+3 more)
Neuronal System	18	4.5×	3e-05	KCNQ2, STX1A, CACNG2, SHANK2, CAMK2D, CAMK4, SHANK1, CHRNA7 (+10 more)
Chaperonin-mediated protein folding	7	12.0×	2e-04	CCT4, CCT5, CCT6A, CCT7, CCT8, TUBA3E, TUBAL3
Neurexins and neuroligins	8	9.0×	3e-04	GRIN2A, GRIN2B, STX1A, SHANK2, SHANK1, EPB41L1, GRIN1, NRXN1
Protein folding	7	10.4×	4e-04	CCT4, CCT5, CCT6A, CCT7, CCT8, TUBA3E, TUBAL3
Assembly and cell surface presentation of NMDA receptors	7	10.2×	4e-04	GRIN2A, GRIN2B, CAMK2D, TUBA3E, TUBAL3, GRIN1, NBEA
Interaction between L1 and Ankyrins	6	12.6×	4e-04	SCN2A, SCN8A, ANK2, KCNQ2, SCN1A, ANK3
Regulation of MECP2 expression and activity	6	12.6×	4e-04	CAMK2D, CAMK4, TBL1XR1, HDAC2, HDAC3, NCOR1
Axon guidance	15	3.9×	5e-04	SCN2A, SCN8A, ANK2, KCNQ2, SCN1A, SEMA3E, SIAH1, CACNA1I (+7 more)
Unblocking of NMDA receptors, glutamate binding and activation	5	15.5×	7e-04	GRIN2A, GRIN2B, CAMK2D, GRIA1, GRIN1
Negative regulation of NMDA receptor-mediated neuronal transmission	5	15.5×	7e-04	GRIN2A, GRIN2B, CAMK2D, CAMK4, GRIN1
Nervous system development	15	3.7×	7e-04	SCN2A, SCN8A, ANK2, KCNQ2, SCN1A, SEMA3E, SIAH1, CACNA1I (+7 more)
RHOBTB2 GTPase cycle	5	13.6×	0.001	CUL3, TRA2B, CCT6A, CCT7, RHOBTB2
Long-term potentiation	5	13.6×	0.001	GRIN2A, GRIN2B, CAMK2D, GRIA1, GRIN1
Association of TriC/CCT with target proteins during biosynthesis	6	10.0×	0.001	CCT4, CCT5, CCT6A, CCT7, CCT8, HDAC3
Developmental Biology	28	2.3×	0.001	SCN2A, SCN8A, ANK2, KCNQ2, SCN1A, SEMA3E, SIAH1, SMARCB1 (+20 more)
Prefoldin mediated transfer of substrate to CCT/TriC	5	11.2×	0.003	CCT4, CCT5, CCT6A, CCT7, CCT8
Organelle biogenesis and maintenance	11	4.2×	0.003	YWHAE, CAMK4, CCT4, CCT5, CCT8, TUBA3E, TUBAL3, TBL1XR1 (+3 more)
Voltage gated Potassium channels	6	8.3×	0.003	KCNQ2, KCNA2, KCNA6, KCNB1, KCNC1, KCND2
Loss of MECP2 binding ability to the NCoR/SMRT complex	3	28.0×	0.004	TBL1XR1, HDAC3, NCOR1
Loss of function of MECP2 in Rett syndrome	3	24.5×	0.005	CAMK4, TBL1XR1, NCOR1
Pervasive developmental disorders	3	24.5×	0.005	CAMK4, TBL1XR1, NCOR1
Disorders of Developmental Biology	3	24.5×	0.005	CAMK4, TBL1XR1, NCOR1
Disorders of Nervous System Development	3	24.5×	0.005	CAMK4, TBL1XR1, NCOR1
Other semaphorin interactions	4	13.7×	0.005	SEMA3E, SEMA6D, PLXNA1, PLXNA2
HCMV Infection	5	9.3×	0.005	SNF8, TUBA3E, TUBAL3, TBL1XR1, NCOR1
Signaling by Rho GTPases	15	2.9×	0.005	VCP, YWHAE, YWHAZ, CCT6A, CCT7, CDC42BPB, SPEN, TUBA3E (+7 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 238 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of excitatory postsynaptic potential	8	17.7×	2e-05	GRIN2A, GRIN2B, STX1A, SHANK1, CHRNA7, GRIA1, GRIN1, NRXN1
positive regulation of telomerase RNA localization to Cajal body	5	39.3×	5e-05	CCT4, CCT5, CCT6A, CCT7, CCT8
positive regulation of protein localization to Cajal body	5	35.4×	6e-05	CCT4, CCT5, CCT6A, CCT7, CCT8
positive regulation of telomere maintenance via telomerase	6	18.5×	2e-04	CCT4, CCT5, CCT6A, CCT7, CCT8, HNRNPD
neuronal action potential	7	14.2×	2e-04	SCN2A, SCN1A, CACNA1I, GRIA1, ANK3, KCNA2, KCND2
excitatory postsynaptic potential	7	13.0×	2e-04	GRIN2A, GRIN2B, CELF4, NPAS4, CHRNA7, GRIN1, MEF2C
positive regulation of synaptic transmission, glutamatergic	6	15.7×	4e-04	GRIN2A, GRIN2B, CACNG2, IQSEC2, GRIN1, NRXN1
action potential	7	10.6×	7e-04	SCN8A, KCNQ2, KCNA2, KCNA6, KCNB1, KCNC1, KCND2
neuron projection guidance	3	53.1×	0.002	EPHA4, ARHGAP35, PLXNA1
regulation of neuronal synaptic plasticity	5	14.2×	0.003	GRIN2A, GRIN2B, CAMK2D, CNTN2, GRIN1
synapse organization	7	8.3×	0.003	CTNND2, SEMA3E, SHANK2, SHANK1, CHRNA7, CNTN2, PPFIA3
positive regulation of calcium ion-dependent exocytosis	4	21.8×	0.003	STX1A, RPH3A, SCAMP5, KCNB1
AMPA selective glutamate receptor signaling pathway	3	42.5×	0.003	SHANK1, MEF2C, NRXN1
regulation of synaptic plasticity	7	7.6×	0.004	GRIN2A, GRIN2B, SYNGAP1, SORCS3, NPAS4, GRIN1, MEF2C
regulation of alternative mRNA splicing, via spliceosome	7	7.2×	0.005	TRA2B, CELF4, ZBTB7A, CELF2, DYRK1A, HNRNPL, HNRNPU
synapse assembly	7	6.8×	0.007	SHANK2, GPHN, KIRREL3, GRIA1, NRXN1, PLXNA1, PLXNA2
chromatin remodeling	12	3.7×	0.010	CHD1, RING1, RYBP, SATB1, SF3B1, SMARCA5, SMARCB1, ZBTB7A (+4 more)
positive regulation of DNA-templated transcription	21	2.5×	0.011	RORB, RREB1, RYBP, TFE3, CAMK4, DEAF1, MED16, PHF5A (+13 more)
regulation of monoatomic cation transmembrane transport	3	26.6×	0.012	GRIN2A, GRIN2B, GRIN1
long-term synaptic potentiation	6	7.1×	0.015	GRIN2A, GRIN2B, SHANK2, CAMK2D, CC2D1A, GRIA1
negative regulation of nuclear-transcribed mRNA catabolic process, deadenylation-dependent decay	3	23.6×	0.015	CSDE1, HNRNPD, HNRNPU
establishment of protein localization	5	9.1×	0.015	CEP55, VCP, GPHN, ANK3, NRXN1
social behavior	6	6.8×	0.015	SHANK2, SHANK1, NPAS4, CHD8, CC2D1A, NRXN1
axon guidance	10	3.8×	0.020	SEMA3E, SIAH1, CYFIP2, DSCAML1, SEMA6D, CNTN2, EPHA4, ARHGAP35 (+2 more)
calcium ion transmembrane import into cytosol	3	19.3×	0.025	GRIN2A, GRIN2B, GRIN1
positive regulation of norepinephrine secretion	2	47.2×	0.027	STX1A, KCNB1
negative regulation of microtubule polymerization or depolymerization	2	47.2×	0.027	CLASP1, FKBP4
positive regulation of catecholamine secretion	2	47.2×	0.027	STX1A, KCNB1
regulation of astrocyte differentiation	2	47.2×	0.027	CNTN2, EPHA4
glomerulus morphogenesis	2	47.2×	0.027	KIRREL3, MEF2C

Therapeutics

Drug target analysis

Approved (phase 4): 21 · Phase ≥3: 21 · Phased (≥1): 30 · Undrugged: 120

Druggability breadth: 128 of 250 evidence-associated genes (51%) 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
SCN8A	IMIPRAMINE
BRSK2	BRIGATINIB
GRIN2A	MEMANTINE HYDROCHLORIDE
GRIN2B	HALOPERIDOL
KCNQ2	FLUPIRTINE
NR4A2	BEXAROTENE
RORB	TRETINOIN
SHMT2	OXAPROZIN
SLC7A5	LEVODOPA
USP2	LEVODOPA
VCP	CLOTRIMAZOLE
CACNA1I	NIMODIPINE
CAMK2D	MOMELOTINIB
CAMK4	RUXOLITINIB
CDC42BPB	AXITINIB
LMTK3	ENTRECTINIB
CHRNA7	VARENICLINE
TUBA3E	COLCHICINE
CSNK1G1	RUXOLITINIB
EIF2AK1	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
USP2	124	4
SCN2A	99	4
CAMK2D	40	4
GRIN2A	37	4
GRIN2B	35	4
CHRNA7	30	4
SCN8A	25	4
CSNK1G1	22	4
TUBA3E	21	4
EIF2AK1	17	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A, SCN8A
DROPERIDOL	4	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	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A, SCN8A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A, SCN8A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 21.

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

Symbol	Assays	Type breakdown
TUBA3E	1,686	Binding:1645, Functional:35, ADMET:6
CHRNA7	562	Binding:474, Functional:84, ADMET:3, Toxicity:1
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1
CAMK4	342	Binding:342
CAMK2D	338	Binding:337, Functional:1
GRIN2A	324	Binding:296, Functional:23, ADMET:4, Toxicity:1
CSNK1G1	297	Binding:296, Functional:1
NR4A2	274	Binding:273, Functional:1
BRSK2	230	Binding:230
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
CDC42BPB	192	Binding:192
SCN8A	173	Binding:148, Functional:16, ADMET:7, Toxicity:2
KCNQ2	145	Binding:136, Functional:7, ADMET:1, Toxicity:1
EIF2AK1	124	Binding:124
VCP	120	Binding:120
RORB	90	Binding:87, Functional:3
SLC7A5	80	Binding:71, ADMET:9
KMT5B	72	Binding:72
TUBAL3	71	Binding:70, Functional:1
CACNA1I	56	Binding:44, Functional:9, ADMET:3
USP8	54	Binding:51, Functional:3
USP2	49	Binding:41, Functional:8
CDK20	40	Binding:40
PRMT9	40	Binding:40
USP14	27	Binding:24, Functional:3
YWHAZ	23	Binding:23
SF3B1	22	Binding:22
SF3B2	20	Binding:20
CLCN3	18	Binding:18
ALDH1B1	16	Binding:15, Functional:1
CLASP1	10	Binding:10
EEF1A2	8	Binding:8
SUPT16H	8	Binding:8
CUL3	7	Binding:7
TRA2B	7	Binding:7
SMARCB1	7	Binding:7
SNRPA	7	Binding:7
CCT4	7	Binding:7
CCT7	7	Binding:7
EXOSC4	7	Binding:7
LMTK3	7	Binding:7
SHMT2	6	Binding:6
MED16	6	Binding:6
SPEN	6	Binding:6
PHF5A	6	Binding:6
WAPL	6	Binding:6
WDR91	6	Binding:6
CHD1	5	Binding:5
RHEB	4	Binding:4
YWHAE	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALDH1B1	1.2.1.3	aldehyde dehydrogenase (NAD+)
RHEB	3.6.5.2	small monomeric GTPase
SHMT2	2.1.2.1	glycine hydroxymethyltransferase
ST3GAL3	2.4.99.2, 2.4.99.6	beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminide alpha-2,3-sialyltransferase, N-acetyllactosaminide alpha-2,3-sialyltransferase
SRPRA	3.6.5.4	signal-recognition-particle GTPase
JMJD1C	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase
USP8	3.4.19.12	ubiquitinyl hydrolase 1
VCP	3.6.4.6	vesicle-fusing ATPase
ATP11A	7.6.2.1	P-type phospholipid transporter
CAMK2D	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
CAMK4	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
POFUT1	2.4.1.221	peptide-O-fucosyltransferase
CCT4	3.6.4.B10
CCT5	3.6.4.B10
CCT6A	3.6.4.B10
CCT7	3.6.4.B10
CCT8	3.6.4.B10
TTL	6.3.2.25	tubulin-tyrosine ligase
CSNK1G1	2.7.11.1	non-specific serine/threonine protein kinase
PRMT9	2.1.1.320	type II protein arginine methyltransferase
ALDH1L2	1.5.1.6	formyltetrahydrofolate dehydrogenase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203
SCN8A	173
BRSK2	230
GRIN2A	324
GRIN2B	471
KCNQ2	145
NR4A2	274
VCP	120
CAMK2D	338
CAMK4	342
CDC42BPB	192
CHRNA7	562
TUBA3E	1,686
CSNK1G1	297
EIF2AK1	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 150; 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	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A, SCN8A
DROPERIDOL	4	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	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A, SCN8A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A, SCN8A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	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)	21	SCN2A, SCN8A, BRSK2, GRIN2A, GRIN2B, KCNQ2, NR4A2, RORB, SHMT2, SLC7A5 (+11 more)
B	Phased (≥1) drug, not yet approved	9	SF3B1, SF3B2, TRA2B, SRPRA, SUPT16H, MED16, SPEN, CDK20, WAPL
C	Druggable family + PDB, no drug	18	ALDH1B1, RHEB, JMJD1C, USP14, USP8, SLCO1C1, CSMD1, DSCAML1, POFUT1, CCT4 (+8 more)
D	Druggable family + AlphaFold only, no drug	7	SEMA3E, ST3GAL3, SORCS3, CSMD3, ATG4D, LMBRD2, ALDH1L2
E	Difficult family or no structure, no drug	95	TAF1C, ZNF292, CHD1, SCAF4, CLCN3, MBD5, CTNND2, CUL3, WDR47, EEF1A2 (+85 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC1A4	2	SLC7A5
PHF5A	6	SF3B2, SF3B1
PRMT9	40	SF3B2
KATNAL2	1	SCN2A
ALDH1L2	0	SHMT2
TAF1C	0	—
ZNF292	0	—
CHD1	5	—
SCAF4	0	—
CLCN3	18	—
MBD5	0	—
CTNND2	0	—
CUL3	7	—
WDR47	0	—
EEF1A2	8	—
ALDH1B1	16	—
ANK2	0	—
CNOT3	1	—
RHEB	4	—
RING1	1	—
RREB1	0	—
RYBP	1	—
SATB1	0	—
SEMA3E	0	—
SIAH1	0	—
ST3GAL3	2	—
SIM1	0	—
SMARCA5	1	—
SMARCB1	7	—
SNRPA	7	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability