Congenital nervous system disorder

Summary

Congenital nervous system disorder (MONDO:0002320) is a disease (an umbrella term covering 217 Mondo subtypes) with 75 cohort genes (1 GWAS associations across 4 studies). The dominant Reactome pathway is Transcriptional Regulation by MECP2 (4 cohort genes).

At a glance

• Umbrella term: 217 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 1
• ClinVar variants: 139

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital nervous system disorder
Mondo ID	MONDO:0002320
DOID	DOID:2490
NCIT	C97172
UMLS	C0497552
MedGen	105425
Anatomy (UBERON)	UBERON:0001016
Is cancer (heuristic)	no

Also known as: congenital abnormality of the nervous system · congenital nervous system disorder

Data availability: 139 ClinVar variants · 1 GWAS association (4 studies) · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 217 Mondo subtypes.

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

Related subtypes (71): central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, peripheral nervous system disorder, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, restless legs syndrome, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, periodic paralysis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AL amyloidosis, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, central nervous system malformation, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Subtypes (217): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, multiple congenital anomalies-hypotonia-seizures syndrome 2, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Genetics & variants

GWAS landscape

1 GWAS associations across 4 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs188665160	6e-07	DROSHA	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90474254	UK Biobank Whole-Genome Sequencing Consortium	2025	709	457,731	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90482463	Verma A	2024	346	450,393	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90652175	Liu TY	2025	272	231,765	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90436767	Zhou W	2018	80	408,394	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	1

MAF distribution

Bucket	Variants
common (>=0.05)	0
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

Consequence	Count
intron_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs188665160	5	31448513	A>G		intron_variant	DROSHA	6e-07	Tier 4: intronic/intergenic

ClinVar germline variants

139 retrieved; paginated sample, class counts are floors:

43 pathogenic/likely pathogenic, 39 pathogenic, 37 likely pathogenic, 17 conflicting classifications of pathogenicity, 1 benign/likely benign, 1 uncertain significance, 1 conflicting classifications of pathogenicity; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
17999	NM_001182.5(ALDH7A1):c.1597del (p.Ala533fs)	ALDH7A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180624	NM_001368809.2(AMPD2):c.532-1G>T	AMPD2	Pathogenic	criteria provided, single submitter
812782	NM_013275.6(ANKRD11):c.3309dup (p.Asp1104fs)	ANKRD11	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
1180640	NM_007347.5(AP4E1):c.910C>T (p.Arg304Ter)	AP4E1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180679	NM_004722.4(AP4M1):c.53_54del (p.Lys18fs)	AP4M1	Pathogenic	criteria provided, single submitter
1180742	NM_018136.5(ASPM):c.1592_1595del (p.Val531fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1180743	NM_018136.5(ASPM):c.6047_6053del (p.His2015_Leu2016insTer)	ASPM	Pathogenic	criteria provided, single submitter
1180803	NM_018136.5(ASPM):c.1694del (p.Ser565fs)	ASPM	Pathogenic	criteria provided, single submitter
21560	NM_018136.5(ASPM):c.1959_1962del (p.Asn653fs)	ASPM	Pathogenic	criteria provided, multiple submitters, no conflicts
1180765	NM_000489.6(ATRX):c.6253C>T (p.Arg2085Cys)	ATRX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
554330	NM_152618.3(BBS12):c.265_266del (p.Leu89fs)	BBS12	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
254268	NM_001127222.2(CACNA1A):c.2134G>A (p.Ala712Thr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
430922	NM_001220.5(CAMK2B):c.416C>T (p.Pro139Leu)	CAMK2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
810578	NM_001367721.1(CASK):c.1466G>A (p.Arg489Gln)	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1333	NM_025114.4(CEP290):c.5668G>T (p.Gly1890Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217629	NM_025114.4(CEP290):c.3176del (p.Ile1059fs)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
1180629	NM_017882.3(CLN6):c.396dup (p.Val133fs)	CLN6	Pathogenic	criteria provided, multiple submitters, no conflicts
8958	NM_000098.3(CPT2):c.1148T>A (p.Phe383Tyr)	CPT2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9433	NM_004380.3(CREBBP):c.3832G>A (p.Glu1278Lys)	CREBBP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1180597	NM_001195553.2(DCX):c.240dup (p.Asp81Ter)	DCX	Pathogenic	criteria provided, single submitter
375881	NM_022552.5(DNMT3A):c.2645G>A (p.Arg882His)	DNMT3A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
40180	NM_014239.4(EIF2B2):c.254T>A (p.Val85Glu)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
522641	NM_014239.4(EIF2B2):c.922G>A (p.Val308Met)	EIF2B2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
31688	NM_016042.4(EXOSC3):c.395A>C (p.Asp132Ala)	EXOSC3	Pathogenic	criteria provided, multiple submitters, no conflicts
16340	NM_000142.5(FGFR3):c.749C>G (p.Pro250Arg)	FGFR3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189613	NM_005249.5(FOXG1):c.256dup (p.Gln86fs)	FOXG1	Pathogenic	criteria provided, multiple submitters, no conflicts
984720	NM_000147.5(FUCA1):c.768+1G>A	FUCA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188815	NM_000153.4(GALC):c.908+1G>A	GALC	Pathogenic	criteria provided, multiple submitters, no conflicts
566624	NM_000156.6(GAMT):c.316C>T (p.Gln106Ter)	GAMT	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 210 · 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
CRIPTO	Limited	Autosomal dominant	congenital heart disease	2
UNC13A	Limited	Unknown	congenital nervous system disorder	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRIPTO	Orphanet:220386	Semilobar holoprosencephaly
CRIPTO	Orphanet:280195	Septopreoptic holoprosencephaly
CRIPTO	Orphanet:280200	Microform holoprosencephaly
CRIPTO	Orphanet:93924	Lobar holoprosencephaly
CRIPTO	Orphanet:93925	Alobar holoprosencephaly
CRIPTO	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
UNC13A	Orphanet:803	Amyotrophic lateral sclerosis
SCN1A	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SCN1A	Orphanet:2382	Lennox-Gastaut syndrome
SCN1A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN1A	Orphanet:33069	Dravet syndrome
SCN1A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SCN1A	Orphanet:569	Familial or sporadic hemiplegic migraine
SLC22A5	Orphanet:158	Systemic primary carnitine deficiency
SMC1A	Orphanet:199	Cornelia de Lange syndrome
SMC1A	Orphanet:220386	Semilobar holoprosencephaly
SMC1A	Orphanet:3095	Atypical Rett syndrome
SMC1A	Orphanet:708203	Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome
ATL1	Orphanet:100984	Autosomal dominant spastic paraplegia type 3
ATL1	Orphanet:36386	Hereditary sensory and autonomic neuropathy type 1
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
TSC2	Orphanet:210159	Adult hepatocellular carcinoma
TSC2	Orphanet:269001	Isolated focal cortical dysplasia type IIa
TSC2	Orphanet:269008	Isolated focal cortical dysplasia type IIb
TSC2	Orphanet:538	Lymphangioleiomyomatosis
TSC2	Orphanet:805	Tuberous sclerosis complex
TSC2	Orphanet:88924	Autosomal dominant polycystic kidney disease type 1 with tuberous sclerosis
VLDLR	Orphanet:1766	Dysequilibrium syndrome
WWOX	Orphanet:251510	46,XY partial gonadal dysgenesis
WWOX	Orphanet:284282	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to WWOX deficiency
WWOX	Orphanet:708171	Facial dysmorphism-corpus callosum hypoplasia-infantile epileptic encephalopathy
WWOX	Orphanet:99977	Squamous cell carcinoma of the esophagus
ZIC2	Orphanet:220386	Semilobar holoprosencephaly
ZIC2	Orphanet:280195	Septopreoptic holoprosencephaly
ZIC2	Orphanet:280200	Microform holoprosencephaly
ZIC2	Orphanet:93924	Lobar holoprosencephaly
ZIC2	Orphanet:93925	Alobar holoprosencephaly
ZIC2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
MCOLN1	Orphanet:578	Mucolipidosis type IV
ERLIN2	Orphanet:209951	Autosomal spastic paraplegia type 18
ERLIN2	Orphanet:247604	Juvenile primary lateral sclerosis
ERLIN2	Orphanet:280384	Recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome
AAAS	Orphanet:869	Triple A syndrome
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	75

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CRIPTO	HGNC:11701	ENSG00000241186	P13385	Protein Cripto	gencc
UNC13A	HGNC:23150	ENSG00000130477	Q9UPW8	Protein unc-13 homolog A	gencc
SCN1A	HGNC:10585	ENSG00000144285	P35498	Sodium channel protein type 1 subunit alpha	clinvar
SLC22A5	HGNC:10969	ENSG00000197375	O76082	Organic cation/carnitine transporter 2	clinvar
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	clinvar
ATL1	HGNC:11231	ENSG00000198513	Q8WXF7	Atlastin-1	clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
TSC2	HGNC:12363	ENSG00000103197	P49815	Tuberin	clinvar
VLDLR	HGNC:12698	ENSG00000147852	P98155	Very low-density lipoprotein receptor	clinvar
WWOX	HGNC:12799	ENSG00000186153	Q9NZC7	WW domain-containing oxidoreductase	clinvar
ZIC2	HGNC:12873	ENSG00000043355	O95409	Zinc finger protein ZIC 2	clinvar
MCOLN1	HGNC:13356	ENSG00000090674	Q9GZU1	Mucolipin-1	clinvar
ERLIN2	HGNC:1356	ENSG00000147475	O94905	Erlin-2	clinvar
AAAS	HGNC:13666	ENSG00000094914	Q9NRG9	Aladin	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
NTNG2	HGNC:14288	ENSG00000196358	Q96CW9	Netrin-G2	clinvar
CAMK2B	HGNC:1461	ENSG00000058404	Q13554	Calcium/calmodulin-dependent protein kinase type II subunit beta	clinvar
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
MICU1	HGNC:1530	ENSG00000107745	Q9BPX6	Calcium uptake protein 1, mitochondrial	clinvar
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	clinvar
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	clinvar
MLC1	HGNC:17082	ENSG00000100427	Q15049	Membrane protein MLC1	clinvar
GJC2	HGNC:17494	ENSG00000198835	Q5T442	Gap junction gamma-2 protein	clinvar
EXOSC3	HGNC:17944	ENSG00000107371	Q9NQT5	Exosome complex component RRP40	clinvar
ASPM	HGNC:19048	ENSG00000066279	Q8IZT6	Abnormal spindle-like microcephaly-associated protein	clinvar
VPS13A	HGNC:1908	ENSG00000197969	Q96RL7	Intermembrane lipid transfer protein VPS13A	clinvar
NALCN	HGNC:19082	ENSG00000102452	Q8IZF0	Sodium leak channel NALCN	clinvar
POMGNT1	HGNC:19139	ENSG00000085998	Q8WZA1	Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1	clinvar
KCNV2	HGNC:19698	ENSG00000168263	Q8TDN2	Potassium voltage-gated channel subfamily V member 2	clinvar
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	clinvar
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
RMND1	HGNC:21176	ENSG00000155906	Q9NWS8	Required for meiotic nuclear division protein 1 homolog	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
VPS13B	HGNC:2183	ENSG00000132549	Q7Z7G8	Intermembrane lipid transfer protein VPS13B	clinvar
ETHE1	HGNC:23287	ENSG00000105755	O95571	Persulfide dioxygenase ETHE1, mitochondrial	clinvar
CPT2	HGNC:2330	ENSG00000157184	P23786	Carnitine O-palmitoyltransferase 2, mitochondrial	clinvar
CREBBP	HGNC:2348	ENSG00000005339	Q92793	CREB-binding protein	clinvar
RNASEH2C	HGNC:24116	ENSG00000172922	Q8TDP1	Ribonuclease H2 subunit C	clinvar
WDR62	HGNC:24502	ENSG00000075702	O43379	WD repeat-containing protein 62	clinvar
TMEM216	HGNC:25018	ENSG00000187049	Q9P0N5	Transmembrane protein 216	clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	clinvar
CTNNB1	HGNC:2514	ENSG00000168036	P35222	Catenin beta-1	clinvar
UFSP2	HGNC:25640	ENSG00000109775	Q9NUQ7	Ufm1-specific protease 2	clinvar
RNASEH2B	HGNC:25671	ENSG00000136104	Q5TBB1	Ribonuclease H2 subunit B	clinvar
SRD5A3	HGNC:25812	ENSG00000128039	Q9H8P0	Polyprenal reductase	clinvar
WDR73	HGNC:25928	ENSG00000177082	Q6P4I2	Integrator complex assembly factor WDR73	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRIPTO	Protein Cripto	GPI-anchored cell membrane protein involved in Nodal signaling.
UNC13A	Protein unc-13 homolog A	Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
SCN1A	Sodium channel protein type 1 subunit alpha	Pore-forming subunit of Nav1.1, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
SLC22A5	Organic cation/carnitine transporter 2	Sodium-ion dependent, high affinity carnitine transporter.
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
ATL1	Atlastin-1	Atlastin-1 (ATL1) is a membrane-anchored GTPase that mediates the GTP-dependent fusion of endoplasmic reticulum (ER) membranes, maintaining the continuous ER network.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
TSC2	Tuberin	Catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolecule…
VLDLR	Very low-density lipoprotein receptor	Multifunctional cell surface receptor that binds VLDL and transports it into cells by endocytosis and therefore plays an important role in energy metabolism.
WWOX	WW domain-containing oxidoreductase	Putative oxidoreductase.
ZIC2	Zinc finger protein ZIC 2	Acts as a transcriptional activator or repressor.
MCOLN1	Mucolipin-1	Nonselective cation channel probably playing a role in the regulation of membrane trafficking events and of metal homeostasis.
ERLIN2	Erlin-2	Component of the ERLIN1/ERLIN2 complex which mediates the endoplasmic reticulum-associated degradation (ERAD) of inositol 1,4,5-trisphosphate receptors (IP3Rs) such as ITPR1.
AAAS	Aladin	Plays a role in the normal development of the peripheral and central nervous system.
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	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…
NTNG2	Netrin-G2	Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels.
CAMK2B	Calcium/calmodulin-dependent protein kinase type II subunit beta	Calcium/calmodulin-dependent protein kinase that functions autonomously after Ca(2+)/calmodulin-binding and autophosphorylation, and is involved in dendritic spine and synapse formation, neuronal plasticity and regulation of sarcoplasmic r…
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
MICU1	Calcium uptake protein 1, mitochondrial	Calcium sensor of the mitochondrial calcium uniporter (MCU) channel, which senses calcium level via its EF-hand domains.
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
MLC1	Membrane protein MLC1	Transmembrane protein mainly expressed in brain astrocytes that may play a role in transport across the blood-brain and brain-cerebrospinal fluid barriers.
GJC2	Gap junction gamma-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
EXOSC3	Exosome complex component RRP40	Non-catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
ASPM	Abnormal spindle-like microcephaly-associated protein	Involved in mitotic spindle regulation and coordination of mitotic processes.
VPS13A	Intermembrane lipid transfer protein VPS13A	Mediates the transfer of lipids between membranes at organelle contact sites.
NALCN	Sodium leak channel NALCN	Voltage-gated ion channel responsible for the resting Na(+) permeability that controls neuronal excitability.
POMGNT1	Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1	Participates in O-mannosyl glycosylation by catalyzing the addition of N-acetylglucosamine to O-linked mannose on glycoproteins.
KCNV2	Potassium voltage-gated channel subfamily V member 2	Potassium channel subunit.
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.
TPP1	Tripeptidyl-peptidase 1	Lysosomal serine protease with tripeptidyl-peptidase I activity.
TUBA1A	Tubulin alpha-1A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
TUBB4A	Tubulin beta-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
RMND1	Required for meiotic nuclear division protein 1 homolog	Required for mitochondrial translation, possibly by coordinating the assembly or maintenance of the mitochondrial ribosome.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
VPS13B	Intermembrane lipid transfer protein VPS13B	Mediates the transfer of lipids between membranes at organelle contact sites.
ETHE1	Persulfide dioxygenase ETHE1, mitochondrial	Sulfur dioxygenase that plays an essential role in hydrogen sulfide catabolism in the mitochondrial matrix.
CPT2	Carnitine O-palmitoyltransferase 2, mitochondrial	Involved in the intramitochondrial synthesis of acylcarnitines from accumulated acyl-CoA metabolites.
CREBBP	CREB-binding protein	Acetylates histones, giving a specific tag for transcriptional activation.
RNASEH2C	Ribonuclease H2 subunit C	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
WDR62	WD repeat-containing protein 62	Required for cerebral cortical development.
TMEM216	Transmembrane protein 216	Essential for primary ciliogenesis and embryonic development, facilitating the activation of Hedgehog (Hh) signaling pathway.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
CTNNB1	Catenin beta-1	Key downstream component of the canonical Wnt signaling pathway.
UFSP2	Ufm1-specific protease 2	Thiol-dependent isopeptidase that specifically cleaves UFM1, a ubiquitin-like modifier protein, from conjugated proteins, such as CD274/PD-L1, CYB5R3, DDRGK1, MRE11, RPL26/uL24, TRIP4 and RPL26/uL24.
RNASEH2B	Ribonuclease H2 subunit B	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
SRD5A3	Polyprenal reductase	Plays a key role in early steps of protein N-linked glycosylation by being involved in the conversion of polyprenol into dolichol.
WDR73	Integrator complex assembly factor WDR73	Component of a multiprotein complex required for the assembly of the RNA endonuclease module of the integrator complex.
BBS12	Chaperonin-containing T-complex member BBS12	Component of the chaperonin-containing T-complex (TRiC), a molecular chaperone complex that assists the folding of proteins upon ATP hydrolysis.
DCX	Neuronal migration protein doublecortin	Microtubule-associated protein required for initial steps of neuronal dispersion and cortex lamination during cerebral cortex development.

Protein-family classification

Druggable: 26 · Difficult: 11 · Unknown: 38 · Druggable fraction: 0.35

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	6.0×	0.051
Kinase	6	2.2×	0.294
Enzyme (other)	10	1.6×	0.340
Scaffold/PPI	7	1.6×	0.391
Complement	1	3.6×	0.460
Transporter	2	2.1×	0.460
Phosphatase	1	1.1×	0.933
Other/Unknown	38	0.9×	0.985
Protease	1	0.5×	0.985
Transcription factor	4	0.4×	0.985
Antibody/Immunoglobulin	1	0.4×	0.985

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRIPTO	Other/Unknown	no		EGF, Cripto, Cryptic/Cripto_CFC-dom
UNC13A	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
SCN1A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a1su
SLC22A5	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
ATL1	Other/Unknown	no		Guanylate-bd_N, P-loop_NTPase, G_GB1_RHD3_dom
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
TSC2	Other/Unknown	no		Rap/Ran_GAP_dom, Tuberin, ARM-like
VLDLR	Other/Unknown	no		LDLR_classB_rpt, EGF-type_Asp/Asn_hydroxyl_site, EGF
WWOX	Scaffold/PPI	no		WW_dom, SDR_fam, WW_dom_sf
ZIC2	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf_ZIC
MCOLN1	Other/Unknown	no		PKD1_2_channel, Mucolipin, ML1_ELD
ERLIN2	Other/Unknown	no		Band_7, Erlin1/2, Band_7/SPFH_dom_sf
AAAS	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
NTNG2	Other/Unknown	no		EGF, LE_dom, Laminin_N
CAMK2B	Kinase	yes	2.7.11.17	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
MICU1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
MLC1	Other/Unknown	no		Membrane_MLC1
GJC2	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
EXOSC3	Other/Unknown	no		KH_dom_type_1, NA-bd_OB-fold, Exosome_RNA_bind1/RRP40/RRP4
ASPM	Antibody/Immunoglobulin	yes		IQ_motif_EF-hand-BS, CH_dom, ARM-like
VPS13A	Other/Unknown	no		VPS13_VAB, VPS13, VPS13_N
NALCN	Ion channel	yes		Ion_trans_dom, Volt_channel_dom_sf, NALCN
POMGNT1	Enzyme (other)	yes	2.4.1.312	Glyco_trans_13, Nucleotide-diphossugar_trans, POMGNT1_PANDER-like
KCNV2	Ion channel	yes		T1-type_BTB, K_chnl_volt-dep_Kv, K_chnl_volt-dep_Kv5/Kv9
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
TPP1	Protease	yes	3.4.14.9	Peptidase_S8/S53_dom, S53_propep, Sedolisin_dom
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
CLN6	Other/Unknown	no		CLN6
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
RMND1	Other/Unknown	no		DUF155, RMD1/Sad1-interacting
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
VPS13B	Other/Unknown	no		VPS13_VAB, VPS13_N, VPS13B
ETHE1	Other/Unknown	no		Metallo-B-lactamas, RibonucZ/Hydroxyglut_hydro, POD-like_MBL-fold
CPT2	Enzyme (other)	yes	2.3.1.21	Carn_acyl_trans, CAT-like_dom_sf, Cho/carn_acyl_trans_1_2
CREBBP	Transcription factor	no	2.3.1.48	Znf_TAZ, Znf_ZZ, Bromodomain
RNASEH2C	Enzyme (other)	yes	3.1.26.4	RNase_H2_suC, RNase_H2_subunit_C
WDR62	Scaffold/PPI	no		WD40_rpt, Quinoprotein_ADH-like_sf, WD40/YVTN_repeat-like_dom_sf
TMEM216	Other/Unknown	no		Uncharacterised_TM-17
ACD	Other/Unknown	no		TPP1/Est3, ACD
CTNNB1	Other/Unknown	no		Armadillo, ARM-like, Beta-catenin
UFSP2	Other/Unknown	no		UFSP1/2_DUB_cat, UFSP2-like_2nd
RNASEH2B	Enzyme (other)	yes	3.1.26.4	RNase_H2_suB_wHTH, RNase_H2_suB, Rnh202_N
SRD5A3	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, Dfg10/SRD5A3
WDR73	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

Expression context

Cohort genes with no expression data: 0.

71 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)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	10
ventricular zone	10
cerebellar cortex	9
calcaneal tendon	9
cortical plate	8
primordial germ cell in gonad	7
right hemisphere of cerebellum	7
Brodmann (1909) area 23	7
adrenal tissue	6
sural nerve	6
ganglionic eminence	6
right uterine tube	5
hindlimb stylopod muscle	5
gastrocnemius	4
mucosa of transverse colon	4
middle temporal gyrus	4
endothelial cell	3
right adrenal gland	3
monocyte	3
buccal mucosa cell	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRIPTO	124	tissue_specific	marker	adrenal tissue, primordial germ cell in gonad, metanephros cortex
UNC13A	193	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SCN1A	154	tissue_specific	marker	Brodmann (1909) area 23, lateral nuclear group of thalamus, primary visual cortex
SLC22A5	235	ubiquitous	marker	gastrocnemius, mucosa of transverse colon, muscle of leg
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
ATL1	241	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, endothelial cell
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
TSC2	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
VLDLR	273	ubiquitous	marker	heart right ventricle, left ovary, right ovary
WWOX	286	ubiquitous	marker	parotid gland, cervix squamous epithelium, cranial nerve II
ZIC2	139	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
MCOLN1	255	ubiquitous	marker	spleen, right adrenal gland cortex, right adrenal gland
ERLIN2	277	ubiquitous	marker	choroid plexus epithelium, renal medulla, calcaneal tendon
AAAS	254	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, right uterine tube
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
NTNG2	173	broad	marker	pancreatic ductal cell, monocyte, leukocyte
CAMK2B	233	broad	marker	cerebellar cortex, cerebellar hemisphere, right hemisphere of cerebellum
ZEB2	290	ubiquitous	marker	cortical plate, sural nerve, monocyte
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
MICU1	283	ubiquitous	marker	calcaneal tendon, cerebellar hemisphere, cerebellar cortex
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
COQ8A	134	ubiquitous	marker	gastrocnemius, skeletal muscle tissue, hindlimb stylopod muscle
MLC1	192	broad	marker	nucleus accumbens, ventricular zone, caudate nucleus
GJC2	181	tissue_specific	yes	C1 segment of cervical spinal cord, spinal cord, inferior vagus X ganglion
EXOSC3	246	ubiquitous	marker	oocyte, secondary oocyte, tendon of biceps brachii
ASPM	176	ubiquitous	marker	oocyte, ventricular zone, secondary oocyte
VPS13A	287	ubiquitous	marker	jejunal mucosa, biceps brachii, skeletal muscle tissue of biceps brachii
NALCN	201	ubiquitous	marker	middle temporal gyrus, Brodmann (1909) area 23, corpus callosum
POMGNT1	269	ubiquitous	marker	apex of heart, C1 segment of cervical spinal cord, adenohypophysis
KCNV2	61	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad

Protein interactions among cohort

Intra-cohort edges: 26.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CTNNB1	15,668
CREBBP	6,959
WWOX	5,892
SMC1A	5,246
TUBB4A	5,138
DNMT3A	4,771
FGFR3	4,510
CASK	4,223
DYNC1H1	4,215
TSC2	4,135

Intra-cohort edges

A	B	Sources
ANKRD11	SMC1A	string_interaction
ARV1	TMX2	intact
ASPM	WDR62	string_interaction
BBS12	CEP290	string_interaction
BBS12	TMEM67	string_interaction
BBS12	VPS13B	string_interaction
CDKL5	NTNG2	string_interaction
CDKL5	SCN1A	string_interaction
CEP290	TMEM216	string_interaction
CEP290	TMEM67	string_interaction
CLN6	MFSD8	string_interaction
CLN6	TPP1	string_interaction
COQ8A	CPT2	biogrid_interaction
CPT2	SLC22A5	string_interaction
CREBBP	CTNNB1	string_interaction
CTNNB1	ZEB2	string_interaction
CTNNB1	ZIC2	string_interaction
DYNC1H1	SCN1A	biogrid_interaction
ERLIN2	TMEM67	biogrid_interaction
EXOSC3	TSEN54	string_interaction
MFSD8	TPP1	string_interaction
RNASEH2B	RNASEH2C	biogrid_interaction, intact, string_interaction
SCN1A	TBC1D24	string_interaction
TBC1D24	TBCK	string_interaction
TMEM216	TMEM67	string_interaction
VPS13A	VPS13B	string_interaction

Structural data

PDB: 47 · AlphaFold-only: 28 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CREBBP	Q92793	144
DYNC1H1	Q14204	97
CTNNB1	P35222	50
DNMT3A	Q9Y6K1	43
VLDLR	P98155	27
EIF2B2	P49770	27
MCOLN1	Q9GZU1	25
CASK	O14936	22
ACD	Q96AP0	19
SMC1A	Q14683	18
ERCC8	Q13216	16
TUBA1A	Q71U36	15
FGFR3	P22607	15
ATL1	Q8WXF7	14
DCX	O43602	14
MICU1	Q9BPX6	12
POMGNT1	Q8WZA1	10
EXOSC3	Q9NQT5	8
TMEM94	Q12767	6
NALCN	Q8IZF0	5
TSEN54	Q7Z6J9	5
ERLIN2	O94905	4
CACNA1A	O00555	4
CAMK2B	Q13554	4
COQ8A	Q8NI60	4
RNASEH2B	Q5TBB1	4
TUSC3	Q13454	4
SLC22A5	O76082	3
CDKL5	O76039	3
NTNG2	Q96CW9	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GALC	P54803	94.56
CPT2	P23786	94.52
TUBB4A	P04350	92.25
UFSP2	Q9NUQ7	91.21
TMEM216	Q9P0N5	89.18
SRD5A3	Q9H8P0	89.07
CYP2U1	Q7Z449	88.45
TBCK	Q8TEA7	87.42
CLN6	Q9NWW5	85.86
TBC1D24	Q9ULP9	84.46
MFSD8	Q8NHS3	83.20
TRAPPC9	Q96Q05	82.98
ARV1	Q9H2C2	82.17
KCNV2	Q8TDN2	75.55
BBS12	Q6ZW61	73.92
UNC13A	Q9UPW8	73.58
MLC1	Q15049	71.29
RMND1	Q9NWS8	70.28
GJC2	Q5T442	68.50
CRIPTO	P13385	67.47
WDR62	O43379	61.19
CEP290	O15078	60.90
ZIC2	O95409	51.36
SETBP1	Q9Y6X0	43.30
ANKRD11	Q6UB99	39.44
ASPM	Q8IZT6
VPS13A	Q96RL7
VPS13B	Q7Z7G8

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 616. Enrichment computed across 105 evidence-associated genes (82 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 82 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Transcriptional Regulation by MECP2	4	15.5×	0.038	CAMK2B, GAMT, MECP2, PTEN
Anchoring of the basal body to the plasma membrane	6	8.3×	0.038	TUBA1A, TUBB4A, TMEM216, TMEM67, CEP290, DYNC1H1
DAG1 core M1 glycosylations	2	69.6×	0.047	POMGNT1, POMT1
Assembly and cell surface presentation of NMDA receptors	4	12.4×	0.047	CAMK2B, CASK, TUBA1A, TUBB4A
LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production	2	55.7×	0.052	CREBBP, CTNNB1
DAG1 core M2 glycosylations	2	55.7×	0.052	POMGNT1, POMT1
COPI-independent Golgi-to-ER retrograde traffic	4	10.1×	0.056	TUBA1A, TUBB4A, DYNC1H1, PLA2G6
Cellular response to heat stress	3	14.4×	0.063	AAAS, CAMK2B, CREBBP
Regulation of MECP2 expression and activity	3	13.5×	0.063	CAMK2B, FOXG1, MECP2
RHO GTPases activate IQGAPs	3	12.7×	0.063	TUBA1A, TUBB4A, CTNNB1
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	3	12.3×	0.063	CTNNB1, ANK3, POMT1
Lysosome Vesicle Biogenesis	3	11.9×	0.063	AP4B1, AP4E1, AP4M1
HCMV Infection	3	11.9×	0.063	AAAS, TUBA1A, TUBB4A
Loss of Nlp from mitotic centrosomes	4	7.7×	0.063	TUBA1A, TUBB4A, CEP290, DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	4	7.7×	0.063	TUBA1A, TUBB4A, CEP290, DYNC1H1
AURKA Activation by TPX2	4	7.4×	0.063	TUBA1A, TUBB4A, CEP290, DYNC1H1
Cilium Assembly	5	6.6×	0.063	TUBA1A, TUBB4A, BBS12, TMEM67, CEP290
Organelle biogenesis and maintenance	6	4.8×	0.063	TUBA1A, TUBB4A, CREBBP, BBS12, TMEM67, CEP290
M Phase	6	4.8×	0.063	SMC1A, AAAS, TUBA1A, TUBB4A, CEP290, MCPH1
Cell Cycle	8	3.5×	0.063	SMC1A, AAAS, TUBA1A, TUBB4A, ACD, CEP290, MCPH1, ATRX
Formation of the anterior neural plate	2	25.3×	0.072	ZIC2, ZEB2
Gap junction assembly	3	10.7×	0.072	GJC2, TUBA1A, TUBB4A
Glycosphingolipid catabolism	3	10.7×	0.072	GALC, ARSA, ASAH1
Activation of the TFAP2 (AP-2) family of transcription factors	2	23.2×	0.079	WWOX, CREBBP
Recruitment of mitotic centrosome proteins and complexes	4	6.6×	0.079	TUBA1A, TUBB4A, CEP290, DYNC1H1
Beta-oxidation of very long chain fatty acids	2	21.4×	0.085	HSD17B4, ABCD1
trans-Golgi Network Vesicle Budding	3	9.3×	0.085	AP4B1, AP4E1, AP4M1
Centrosome maturation	3	9.3×	0.085	TUBA1A, TUBB4A, CEP290
Cargo trafficking to the periciliary membrane	3	9.1×	0.085	TUBA1A, TUBB4A, BBS12
Aggrephagy	3	9.1×	0.085	TUBA1A, TUBB4A, DYNC1H1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 105 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
central nervous system development	8	8.8×	0.004	ZIC2, ZEB2, TPP1, VPS13B, DCX, EIF2B2, SERPINI1, PTEN
protein localization to chromosome, telomeric region	3	43.8×	0.010	TPP1, ACD, ATRX
dentate gyrus development	4	23.8×	0.010	POMGNT1, TUBA1A, VPS13B, PTEN
positive regulation of neuroblast proliferation	4	22.1×	0.010	ASPM, WDR62, CTNNB1, FOXG1
regulation of resting membrane potential	3	37.0×	0.012	NALCN, KCNJ10, PSEN1
intracellular protein localization	7	7.0×	0.012	TSC2, CASK, VPS13A, AP4B1, AP4E1, AP4M1, MECP2
Golgi to endosome transport	3	30.1×	0.016	VPS13A, AP4M1, ALDH7A1
lysosomal protein catabolic process	3	30.1×	0.016	VPS13A, TPP1, MFSD8
neuron migration	6	7.6×	0.016	CDKL5, ASPM, TUBA1A, CTNNB1, DCX, PSEN1
cerebral cortex development	5	9.8×	0.017	ASPM, TUBA1A, WDR62, TRAPPC9, MCPH1
gene expression	7	5.3×	0.034	VPS13A, POMGNT1, TUBA1A, RNASEH2B, MFSD8, HFE, MECP2
adult locomotory behavior	4	11.5×	0.036	VPS13A, TUBA1A, MECP2, PPT1
nervous system development	9	3.9×	0.039	VLDLR, CAMK2B, ZEB2, TPP1, VPS13B, DCX, OPHN1, PPT1 (+1 more)
social behavior	4	10.3×	0.045	VPS13A, VPS13B, MECP2, PTEN
positive regulation of homotypic cell-cell adhesion	2	45.9×	0.052	CTNNB1, ANK3
vesicle-mediated transport	6	5.5×	0.052	TSC2, MLC1, VPS13B, AP4B1, AP4E1, AP4M1
motor behavior	3	16.1×	0.053	VPS13A, TUBA1A, MFSD8
neuron fate determination	2	40.1×	0.056	CTNNB1, FOXG1
positive regulation of telomere maintenance	3	14.6×	0.056	ACD, ATRX, PNKP
regulation of synaptic transmission, glutamatergic	3	14.6×	0.056	UNC13A, OPHN1, PSEN1
multicellular organism growth	5	6.5×	0.056	AAAS, VPS13A, VPS13B, MFSD8, ATRX
G protein-coupled dopamine receptor signaling pathway	2	35.7×	0.057	GNAO1, GNB5
regulation of centrosome cycle	2	35.7×	0.057	WDR62, MCPH1
neuron projection arborization	2	35.7×	0.057	VPS13A, TUBA1A
skeletal system morphogenesis	3	14.2×	0.057	WWOX, ANKRD11, PSEN1
positive regulation of intracellular transport	2	32.1×	0.063	MLC1, DYNC1H1
regulation of protein localization to cell surface	2	32.1×	0.063	CTNNB1, HFE
RNA catabolic process	3	13.0×	0.063	EXOSC3, RNASEH2C, RNASEH2B
regulation of neuron projection development	3	12.3×	0.067	NTNG2, PSEN1, PTEN
microglia differentiation	2	29.2×	0.067	VPS13A, MFSD8

Therapeutics

Drug target analysis

Approved (phase 4): 14 · Phase ≥3: 14 · Phased (≥1): 16 · Undrugged: 59

Druggability breadth: 52 of 105 evidence-associated genes (50%) 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
SCN1A	MEXILETINE HYDROCHLORIDE
SMC1A	SELUMETINIB
CDKL5	FEDRATINIB
CACNA1A	NIMODIPINE
CAMK2B	FEDRATINIB
CASK	FEDRATINIB
COQ8A	FEDRATINIB
CYP2U1	PAZOPANIB
TUBA1A	COLCHICINE
TUBB4A	COLCHICINE
CPT2	PERHEXILINE
CREBBP	COLCHICINE
CTNNB1	DITHIAZANINE IODIDE
FGFR3	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN1A	94	4
FGFR3	64	4
CAMK2B	25	4
TUBA1A	22	4
TUBB4A	21	4
CDKL5	14	4
COQ8A	14	4
CREBBP	13	4
CASK	9	4
CTNNB1	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 18.

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

Symbol	Assays	Type breakdown
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
FGFR3	975	Binding:948, Functional:18, ADMET:9
CREBBP	687	Binding:644, Functional:43
CTNNB1	361	Binding:358, Functional:3
CAMK2B	314	Binding:313, Functional:1
CYP2U1	183	ADMET:181, Binding:2
SCN1A	149	Binding:115, Functional:18, ADMET:14, Toxicity:2
DNMT3A	120	Binding:118, ADMET:1, Functional:1
SLC22A5	97	Functional:79, ADMET:18
COQ8A	93	Binding:93
CASK	92	Binding:92
FUCA1	83	Binding:79, ADMET:4
CDKL5	74	Binding:74
KCNV2	21	Binding:20, Toxicity:1
CACNA1A	19	Binding:18, Functional:1
CPT2	12	Binding:12
SMC1A	10	Binding:10
MCOLN1	9	Binding:9
AAAS	7	Binding:7
DYNC1H1	7	Binding:7
GALC	3	Binding:2, Functional:1
ERLIN2	2	Binding:2
GAMT	2	ADMET:2
TSC2	1	Binding:1
MLC1	1	Binding:1
POMGNT1	1	Binding:1
TPP1	1	Binding:1
CLN6	1	Binding:1
SRD5A3	1	Binding:1
DCX	1	Binding:1
TMEM94	1	Binding:1
EIF2B2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDKL5	2.7.11.22	cyclin-dependent kinase
CAMK2B	2.7.11.17	Ca2+/calmodulin-dependent protein kinase
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
POMGNT1	2.4.1.312	protein O-mannose beta-1,4-N-acetylglucosaminyltransferase
TPP1	3.4.14.9	tripeptidyl-peptidase I
CPT2	2.3.1.21	carnitine O-palmitoyltransferase
CREBBP	2.3.1.48	histone acetyltransferase
RNASEH2C	3.1.26.4	ribonuclease H
RNASEH2B	3.1.26.4	ribonuclease H
SRD5A3	1.3.1.22, 1.3.1.94, 1.3.1.B13	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), polyprenal reductase,
TSEN54	4.6.1.16	tRNA-intron lyase
TRMT10A	2.1.1.221	tRNA (guanine9-N1)-methyltransferase
DNMT3A	2.1.1.37	DNA (cytosine-5-)-methyltransferase
EPM2A	3.1.3.16	protein-serine/threonine phosphatase
FGFR3	2.7.10.1	receptor protein-tyrosine kinase
FUCA1	3.2.1.51	alpha-L-fucosidase
GALC	3.2.1.46	galactosylceramidase
GAMT	2.1.1.2	guanidinoacetate N-methyltransferase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN1A	149
CAMK2B	314
CYP2U1	183
TUBA1A	1,696
TUBB4A	1,758
CREBBP	687
CTNNB1	361
DNMT3A	120
FGFR3	975

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; 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)
MEXILETINE HYDROCHLORIDE	4	SCN1A
BEPRIDIL	4	SCN1A
DIBUCAINE	4	SCN1A
ARTICAINE	4	SCN1A
BUPIVACAINE	4	SCN1A
IMIPRAMINE	4	SCN1A
DROPERIDOL	4	SCN1A
DICYCLOMINE	4	SCN1A
TETRABENAZINE	4	SCN1A
PHENIRAMINE	4	SCN1A
PRILOCAINE	4	SCN1A
PROPOXYCAINE	4	SCN1A
PROPARACAINE	4	SCN1A
HEXYLCAINE	4	SCN1A
PRAMOXINE	4	SCN1A
BENOXINATE	4	SCN1A
QUINIDINE	4	SCN1A
FELODIPINE	4	SCN1A
PHENYTOIN	4	SCN1A
QUININE	4	SCN1A
NISOLDIPINE	4	SCN1A
NIFEDIPINE	4	SCN1A
PRAZOSIN	4	SCN1A
DILTIAZEM	4	SCN1A
PRENYLAMINE	4	SCN1A
COCAINE	4	SCN1A
TRIFLUOPERAZINE	4	SCN1A
CINNARIZINE	4	SCN1A
THIORIDAZINE	4	SCN1A
ETIDOCAINE	4	SCN1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	14	SCN1A, SMC1A, CDKL5, CACNA1A, CAMK2B, CASK, COQ8A, CYP2U1, TUBA1A, TUBB4A (+4 more)
B	Phased (≥1) drug, not yet approved	2	DYNC1H1, FUCA1
C	Druggable family + PDB, no drug	11	SLC22A5, NALCN, POMGNT1, TPP1, RNASEH2C, RNASEH2B, TSEN54, TRMT10A, DNMT3A, EPM2A (+1 more)
D	Druggable family + AlphaFold only, no drug	6	ASPM, KCNV2, SRD5A3, TBCK, MFSD8, GALC
E	Difficult family or no structure, no drug	42	CRIPTO, UNC13A, ATL1, TSC2, VLDLR, WWOX, ZIC2, MCOLN1, ERLIN2, AAAS (+32 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NTNG2	0	CDKL5
ANKRD11	0	SMC1A
DNMT3A	120	—
CRIPTO	0	—
UNC13A	0	—
SLC22A5	97	—
ATL1	0	—
TSC2	1	—
VLDLR	0	—
WWOX	0	—
ZIC2	0	—
MCOLN1	9	—
ERLIN2	2	—
AAAS	7	—
ZEB2	0	—
MICU1	0	—
SETBP1	0	—
MLC1	1	—
GJC2	0	—
EXOSC3	0	—
ASPM	0	—
VPS13A	0	—
NALCN	0	—
POMGNT1	1	—
KCNV2	21	—
TPP1	1	—
CLN6	1	—
RMND1	0	—
VPS13B	0	—
ETHE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.