Isolated cerebellar hypoplasia/agenesis

Summary

Isolated cerebellar hypoplasia/agenesis (MONDO:0008939) is a disease caused by OXR1 (GenCC Strong), with 49 cohort genes. The dominant Reactome pathway is Recycling pathway of L1 (4 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: OXR1 (GenCC Strong)
• Cohort genes: 49
• ClinVar variants: 84
• Phenotypes (HPO): 10

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0000496	Abnormality of eye movement	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001252	Hypotonia	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000256	Macrocephaly	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001276	Hypertonia	Frequent (30-79%)
HP:0002167	Abnormality of speech or vocalization	Frequent (30-79%)
HP:0100022	Abnormality of movement	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	isolated cerebellar hypoplasia/agenesis
Mondo ID	MONDO:0008939
MeSH	C562568
OMIM	213000
Orphanet	1398
DOID	DOID:0070338
NCIT	C98890
SNOMED CT	16026008
UMLS	C5231391
MedGen	1695950
GARD	0018720
MedDRA	10008033
NORD	910
Is cancer (heuristic)	no

Also known as: cerebellar hypoplasia/atrophy, epilepsy, and global developmental delay · Chiari 4 malformation · Chiari IV malformation · congenital cerebellar Hypoplasia · near total absence of cerebellum · subtotal absence of cerebellum

Data availability: 84 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › isolated cerebellar hypoplasia/agenesis

Related subtypes (216): 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, 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

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

84 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 16 pathogenic/likely pathogenic, 16 likely pathogenic, 16 pathogenic, 12 conflicting classifications of pathogenicity, 3 benign/likely benign, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
694387	NM_001198533.2(OXR1):c.1324del (p.Ser442fs)		Pathogenic/Likely pathogenic	no assertion criteria provided
632597	NM_001371928.1(AHDC1):c.997del (p.Ala333fs)	AHDC1	Pathogenic/Likely pathogenic	no assertion criteria provided
637018	NM_001170535.3(ATAD3A):c.1217T>G (p.Leu406Arg)	ATAD3A	Pathogenic	criteria provided, single submitter
632585	NM_022893.4(BCL11A):c.1601_1631del (p.Val534fs)	BCL11A	Pathogenic/Likely pathogenic	no assertion criteria provided
632586	NM_022893.4(BCL11A):c.295del (p.Val99fs)	BCL11A	Pathogenic/Likely pathogenic	no assertion criteria provided
195200	NM_001367721.1(CASK):c.79C>T (p.Arg27Ter)	CASK	Pathogenic	criteria provided, multiple submitters, no conflicts
4846757	GRCh38/hg38 Xp11.4(chrX:41727541-41757830)x1	CASK	Pathogenic	criteria provided, single submitter
632601	NM_001367721.1(CASK):c.533-2A>G	CASK	Pathogenic	criteria provided, single submitter
632602	NM_001367721.1(CASK):c.2120dup (p.Tyr708fs)	CASK	Pathogenic/Likely pathogenic	no assertion criteria provided
523448	NM_002016.2(FLG):c.544A>T (p.Lys182Ter)	CCDST	Pathogenic	criteria provided, single submitter
207813	NM_001356.5(DDX3X):c.1126C>T (p.Arg376Cys)	DDX3X	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
632603	NM_001356.5(DDX3X):c.1439G>C (p.Arg480Thr)	DDX3X	Pathogenic	criteria provided, single submitter
632588	NM_023110.3(FGFR1):c.1881G>C (p.Arg627Ser)	FGFR1	Pathogenic/Likely pathogenic	no assertion criteria provided
498786	NM_001349338.3(FOXP1):c.622C>T (p.Gln208Ter)	FOXP1	Pathogenic	criteria provided, single submitter
204593	NM_001329943.3(KIAA0586):c.392del (p.Arg131fs)	KIAA0586	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204596	NM_001329943.3(KIAA0586):c.704_705del (p.Gln235fs)	KIAA0586	Pathogenic	criteria provided, multiple submitters, no conflicts
10001	NM_001278116.2(L1CAM):c.719C>T (p.Pro240Leu)	L1CAM	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
694396	NM_001198533.2(OXR1):c.1100C>G (p.Ser367Ter)	OXR1	Pathogenic	no assertion criteria provided
694397	NM_001198533.2(OXR1):c.2163+1G>T	OXR1	Pathogenic	no assertion criteria provided
6196	NM_003560.4(PLA2G6):c.1634A>C (p.Lys545Thr)	PLA2G6	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21143	NM_000303.3(PMM2):c.415G>A (p.Glu139Lys)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
7706	NM_000303.3(PMM2):c.422G>A (p.Arg141His)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
7723	NM_000303.3(PMM2):c.338C>T (p.Pro113Leu)	PMM2	Pathogenic	criteria provided, multiple submitters, no conflicts
632596	NM_020320.5(RARS2):c.848T>A (p.Leu283Gln)	RARS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
388568	NM_014159.7(SETD2):c.5218C>T (p.Arg1740Trp)	SETD2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
429871	NM_001130438.3(SPTAN1):c.4828C>T (p.Arg1610Trp)	SPTAN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
199083	NM_001032221.6(STXBP1):c.704G>A (p.Arg235Gln)	STXBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
2120	NM_207346.3(TSEN54):c.919G>T (p.Ala307Ser)	TSEN54	Pathogenic	criteria provided, multiple submitters, no conflicts
127100	NM_001069.3(TUBB2A):c.741C>G (p.Asn247Lys)	TUBB2A	Pathogenic	criteria provided, single submitter
440948	NM_014023.4(WDR37):c.374C>T (p.Thr125Ile)	WDR37	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 99 · 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
HCRTR1	Strong	Autosomal recessive	isolated cerebellar hypoplasia/agenesis	4
OXR1	Strong	Autosomal recessive	isolated cerebellar hypoplasia/agenesis	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SEMA6B	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
SLC6A8	Orphanet:52503	X-linked creatine transporter deficiency
ARID1A	Orphanet:1465	Coffin-Siris syndrome
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
USH2A	Orphanet:231178	Usher syndrome type 2
USH2A	Orphanet:791	Retinitis pigmentosa
BCL11A	Orphanet:251380	Hereditary persistence of fetal hemoglobin-sickle cell disease syndrome
BCL11A	Orphanet:619233	Hereditary persistence of fetal hemoglobin-intellectual disability syndrome
MACF1	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome
ANO3	Orphanet:420485	Cranio-cervical dystonia with laryngeal and upper-limb involvement
CIC	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
AUTS2	Orphanet:352490	Autism spectrum disorder due to AUTS2 deficiency
AUTS2	Orphanet:641372	B-lymphoblastic leukemia/lymphoma with t(7;9)(q11.2;p13.2)
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
ARID1B	Orphanet:1465	Coffin-Siris syndrome
ARID1B	Orphanet:251056	6q25.2q25.3 microdeletion syndrome
ASXL1	Orphanet:86845	Acute myeloid leukaemia with myelodysplasia-related features
ASXL1	Orphanet:97297	Bohring-Opitz syndrome
ASXL1	Orphanet:98823	Chronic myelomonocytic leukemia
ASXL1	Orphanet:98849	Systemic mastocytosis with associated hematologic neoplasm
ASXL1	Orphanet:98850	Aggressive systemic mastocytosis
SETD2	Orphanet:597738	Luscan-Lumish syndrome
SETD2	Orphanet:597743	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
KIAA0586	Orphanet:397715	Joubert syndrome with Jeune asphyxiating thoracic dystrophy
KIAA0586	Orphanet:475	Isolated Joubert syndrome
TUBA1A	Orphanet:171680	Lissencephaly due to TUBA1A mutation
TUBA1A	Orphanet:45358	Congenital fibrosis of extraocular muscles
TUBA1A	Orphanet:467166	Tubulinopathy-associated dysgyria
TUBA1A	Orphanet:994	Fetal akinesia deformation sequence
BCOR	Orphanet:2712	Oculofaciocardiodental syndrome
BCOR	Orphanet:457246	Clear cell sarcoma of kidney
BCOR	Orphanet:520	Acute promyelocytic leukemia
BCOR	Orphanet:568	Microphthalmia, Lenz type
RARS2	Orphanet:166073	Pontocerebellar hypoplasia type 6
AHDC1	Orphanet:412069	AHDC1-related intellectual disability-obstructive sleep apnea-mild dysmorphism syndrome
ATAD3A	Orphanet:496790	Ocular anomalies-axonal neuropathy-developmental delay syndrome
ATAD3A	Orphanet:615983	Lethal pontocerebellar hypoplasia-hypotonia-respiratory insufficiency syndrome due to a point mutation
ATAD3A	Orphanet:615986	Lethal pontocerebellar hypoplasia-hypotonia-respiratory insufficiency syndrome due to biallelic deletions in the ATAD3 gene cluster
ATAD3A	Orphanet:656279	1p36.33 duplication syndrome
OFD1	Orphanet:244	Primary ciliary dyskinesia
OFD1	Orphanet:2750	Orofaciodigital syndrome type 1
OFD1	Orphanet:2754	Orofaciodigital syndrome type 6
OFD1	Orphanet:475	Isolated Joubert syndrome
OFD1	Orphanet:791	Retinitis pigmentosa
SRD5A3	Orphanet:324737	SRD5A3-CDG
DDX3X	Orphanet:3338	Toriello-Carey syndrome

Cohort genes → proteins

49 cohort genes, 48 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	49

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
OXR1	HGNC:15822	ENSG00000164830	Q8N573	Oxidation resistance protein 1	gencc,clinvar
HCRTR1	HGNC:4848	ENSG00000121764	O43613	Orexin/Hypocretin receptor type 1	gencc,clinvar
SEMA6B	HGNC:10739	ENSG00000167680	Q9H3T3	Semaphorin-6B	clinvar
SLC6A8	HGNC:11055	ENSG00000130821	P48029	Sodium- and chloride-dependent creatine transporter 1	clinvar
ARID1A	HGNC:11110	ENSG00000117713	O14497	AT-rich interactive domain-containing protein 1A	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
TUBB2A	HGNC:12412	ENSG00000137267	Q13885	Tubulin beta-2A chain	clinvar
USH2A	HGNC:12601	ENSG00000042781	O75445	Usherin	clinvar
BCL11A	HGNC:13221	ENSG00000119866	Q9H165	BCL11 transcription factor A	clinvar
KIF4A	HGNC:13339	ENSG00000090889	O95239	Chromosome-associated kinesin KIF4A	clinvar
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	clinvar
ANO3	HGNC:14004	ENSG00000134343	Q9BYT9	Anoctamin-3	clinvar
CIC	HGNC:14214	ENSG00000079432	Q96RK0	Protein capicua homolog	clinvar
AUTS2	HGNC:14262	ENSG00000158321	Q8WXX7	Autism susceptibility gene 2 protein	clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
ARID1B	HGNC:18040	ENSG00000049618	Q8NFD5	AT-rich interactive domain-containing protein 1B	clinvar
TMLHE	HGNC:18308	ENSG00000185973	Q9NVH6	Trimethyllysine dioxygenase, mitochondrial	clinvar
ASXL1	HGNC:18318	ENSG00000171456	Q8IXJ9	Polycomb group protein ASXL1	clinvar
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	clinvar
KIAA0586	HGNC:19960	ENSG00000100578	Q9BVV6	Protein TALPID3	clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar
BCOR	HGNC:20893	ENSG00000183337	Q6W2J9	BCL-6 corepressor	clinvar
KCTD3	HGNC:21305	ENSG00000136636	Q9Y597	BTB/POZ domain-containing protein KCTD3	clinvar
RARS2	HGNC:21406	ENSG00000146282	Q5T160	Probable arginine–tRNA ligase, mitochondrial	clinvar
AHDC1	HGNC:25230	ENSG00000126705	Q5TGY3	Transcription factor Gibbin	clinvar
ATAD3A	HGNC:25567	ENSG00000197785	Q9NVI7	ATPase family AAA domain-containing protein 3A	clinvar
OFD1	HGNC:2567	ENSG00000046651	O75665	Centriole and centriolar satellite protein OFD1	clinvar
SRD5A3	HGNC:25812	ENSG00000128039	Q9H8P0	Polyprenal reductase	clinvar
DDX3X	HGNC:2745	ENSG00000215301	O00571	ATP-dependent RNA helicase DDX3X	clinvar
TSEN54	HGNC:27561	ENSG00000182173	Q7Z6J9	tRNA-splicing endonuclease subunit Sen54	clinvar
DKC1	HGNC:2890	ENSG00000130826	O60832	H/ACA ribonucleoprotein complex subunit DKC1	clinvar
PRAF2	HGNC:28911	ENSG00000243279	O60831	PRA1 family protein 2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
MSTO1	HGNC:29678	ENSG00000125459	Q9BUK6	Protein misato homolog 1	clinvar
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	clinvar
ATP13A2	HGNC:30213	ENSG00000159363	Q9NQ11	Polyamine-transporting ATPase 13A2	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar
WDR37	HGNC:31406	ENSG00000047056	Q9Y2I8	WD repeat-containing protein 37	clinvar
FGFR1	HGNC:3688	ENSG00000077782	P11362	Fibroblast growth factor receptor 1	clinvar
FOXP1	HGNC:3823	ENSG00000114861	Q9H334	Forkhead box protein P1	clinvar
FZD3	HGNC:4041	ENSG00000104290	Q9NPG1	Frizzled-3	clinvar
ADGRG2	HGNC:4516	ENSG00000173698	Q8IZP9	Adhesion G-protein coupled receptor G2	clinvar
HSD17B4	HGNC:5213	ENSG00000133835	P51659	Peroxisomal multifunctional enzyme type 2	clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	clinvar
OPHN1	HGNC:8148	ENSG00000079482	O60890	Oligophrenin-1	clinvar
PLA2G6	HGNC:9039	ENSG00000184381	O60733	85/88 kDa calcium-independent phospholipase A2	clinvar
PMM2	HGNC:9115	ENSG00000140650	O15305	Phosphomannomutase 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OXR1	Oxidation resistance protein 1	May be involved in protection from oxidative damage.
HCRTR1	Orexin/Hypocretin receptor type 1	G-protein coupled receptor that binds the neuropeptide orexin-A with high affinity, and orexin-B with lower affinity, two peptides derived from a common precursor, prepro-orexin.
SEMA6B	Semaphorin-6B	Functions as a cell surface repellent for mossy fibers of developing neurons in the hippocampus where it plays a role in axon guidance.
SLC6A8	Sodium- and chloride-dependent creatine transporter 1	Creatine:sodium symporter which mediates the uptake of creatine.
ARID1A	AT-rich interactive domain-containing protein 1A	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
TUBB2A	Tubulin beta-2A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
USH2A	Usherin	Involved in hearing and vision as member of the USH2 complex.
BCL11A	BCL11 transcription factor A	Transcription factor.
KIF4A	Chromosome-associated kinesin KIF4A	Iron-sulfur (Fe-S) cluster binding motor protein that has a role in chromosome segregation during mitosis.
ANO3	Anoctamin-3	Has calcium-dependent phospholipid scramblase activity; scrambles phosphatidylcholine and galactosylceramide.
CIC	Protein capicua homolog	Transcriptional repressor which plays a role in development of the central nervous system (CNS).
AUTS2	Autism susceptibility gene 2 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.
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.
ARID1B	AT-rich interactive domain-containing protein 1B	Involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
TMLHE	Trimethyllysine dioxygenase, mitochondrial	Converts trimethyllysine (TML) into hydroxytrimethyllysine (HTML).
ASXL1	Polycomb group protein ASXL1	Probable Polycomb group (PcG) protein involved in transcriptional regulation mediated by ligand-bound nuclear hormone receptors, such as retinoic acid receptors (RARs) and peroxisome proliferator-activated receptor gamma (PPARG).
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
KIAA0586	Protein TALPID3	Required for ciliogenesis and sonic hedgehog/SHH signaling.
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.
BCOR	BCL-6 corepressor	Transcriptional corepressor.
KCTD3	BTB/POZ domain-containing protein KCTD3	Accessory subunit of potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 (HCN3) up-regulating its cell-surface expression and current density without affecting its voltage dependence and kinetics.
RARS2	Probable arginine–tRNA ligase, mitochondrial	Catalyzes the attachment of arginine to tRNA(Arg) in a two-step reaction: arginine is first activated by ATP to form Arg-AMP and then transferred to the acceptor end of tRNA(Arg).
AHDC1	Transcription factor Gibbin	Transcription factor required for the proper patterning of the epidermis, which plays a key role in early epithelial morphogenesis.
ATAD3A	ATPase family AAA domain-containing protein 3A	Essential for mitochondrial network organization, mitochondrial metabolism and cell growth at organism and cellular level.
OFD1	Centriole and centriolar satellite protein OFD1	Component of the centrioles controlling mother and daughter centrioles length.
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.
DDX3X	ATP-dependent RNA helicase DDX3X	Multifunctional ATP-dependent RNA helicase.
TSEN54	tRNA-splicing endonuclease subunit Sen54	Non-catalytic subunit of the tRNA-splicing endonuclease complex, a complex responsible for identification and cleavage of the splice sites in pre-tRNA.
DKC1	H/ACA ribonucleoprotein complex subunit DKC1	Catalytic subunit of H/ACA small nucleolar ribonucleoprotein (H/ACA snoRNP) complex, which catalyzes pseudouridylation of rRNA.
PRAF2	PRA1 family protein 2	May be involved in ER/Golgi transport and vesicular traffic.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
MSTO1	Protein misato homolog 1	Involved in the regulation of mitochondrial distribution and morphology.
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.
ATP13A2	Polyamine-transporting ATPase 13A2	ATPase which acts as a lysosomal polyamine exporter with high affinity for spermine.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
WDR37	WD repeat-containing protein 37	Required for normal ER Ca2+ handling in lymphocytes.
FGFR1	Fibroblast growth factor receptor 1	Tyrosine-protein kinase that acts as a cell-surface receptor for fibroblast growth factors and plays an essential role in the regulation of embryonic development, cell proliferation, differentiation and migration.
FOXP1	Forkhead box protein P1	Transcriptional repressor.
FZD3	Frizzled-3	Receptor for Wnt proteins.
ADGRG2	Adhesion G-protein coupled receptor G2	Adhesion G-protein coupled receptor (aGPCR) for steroid hormones, such as dehydroepiandrosterone (DHEA; also named 3beta-hydroxyandrost-5-en-17-one) and androstenedione.
HSD17B4	Peroxisomal multifunctional enzyme type 2	Bifunctional enzyme acting on the peroxisomal fatty acid beta-oxidation pathway.
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.
OPHN1	Oligophrenin-1	Stimulates GTP hydrolysis of members of the Rho family.
PLA2G6	85/88 kDa calcium-independent phospholipase A2	Calcium-independent phospholipase involved in phospholipid remodeling with implications in cellular membrane homeostasis, mitochondrial integrity and signal transduction.
PMM2	Phosphomannomutase 2	Involved in the synthesis of the GDP-mannose and dolichol-phosphate-mannose required for a number of critical mannosyl transfer reactions.

Protein-family classification

Druggable: 15 · Difficult: 12 · Unknown: 22 · Druggable fraction: 0.31

Family distribution

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

Family	Genes	Fold	FDR
Scaffold/PPI	9	3.2×	0.012
Enzyme (other)	7	1.7×	0.386
Kinase	3	1.7×	0.588
GPCR	3	1.5×	0.588
Antibody/Immunoglobulin	2	1.2×	0.706
Other/Unknown	22	0.8×	0.954
Transcription factor	3	0.5×	0.954

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OXR1	Other/Unknown	no		TLDc_dom, LysM, LysM_dom_sf
HCRTR1	GPCR	yes		Orexin_rcpt, GPCR_Rhodpsn, OX1R
SEMA6B	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
SLC6A8	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_creatine, SNS_sf
ARID1A	Other/Unknown	no		ARID_dom, ARM-like, ARM-type_fold
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
TUBB2A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
USH2A	Antibody/Immunoglobulin	yes		Laminin_G, LE_dom, FN3_dom
BCL11A	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Dev/Hematopoietic_TF
KIF4A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom
ANO3	Other/Unknown	no		Anoctamin, Anoct_dimer, Anoctamin_TM
CIC	Other/Unknown	no		HMG_box_dom, Cic_dom, HMG_box_dom_sf
AUTS2	Other/Unknown	no		AUTS2
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
ARID1B	Other/Unknown	no		ARID_dom, BAF250/Osa, BAF250_C
TMLHE	Enzyme (other)	yes	1.14.11.8	TauD/TfdA-like, GBBH-like_N, Trimethyllysine_dOase
ASXL1	Other/Unknown	no		Asxl_HARE-HTH, ASX/ASX-like, ASX-like_PHD
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
KIAA0586	Other/Unknown	no		TALPID3
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
BCOR	Scaffold/PPI	no		Ankyrin_rpt, BCOR, PUFD
KCTD3	Scaffold/PPI	no		BTB/POZ_dom, WD40_rpt, T1-type_BTB
RARS2	Other/Unknown	no		Arg-tRNA-ligase, aa-tRNA-synth_I_CS, DALR_anticod-bd
AHDC1	Other/Unknown	no		DUF4683, AHDC1
ATAD3A	Other/Unknown	no		AAA+_ATPase, ATPase_AAA_core, ATAD3_N
OFD1	Other/Unknown	no		LisH, OFD1
SRD5A3	Enzyme (other)	yes	1.3.1.22	3-oxo-5_a-steroid_4-DH_C, Dfg10/SRD5A3
DDX3X	Enzyme (other)	yes	3.6.4.13	RNA-helicase_DEAD-box_CS, Helicase_C-like, DEAD/DEAH_box_helicase_dom
TSEN54	Enzyme (other)	yes	4.6.1.16	tRNA_splic_suSen54_N, tRNA_splic_suSen54
DKC1	Other/Unknown	no		PUA, PsdUridine_synth_N, Uncharacterised_CHP00451
PRAF2	Other/Unknown	no		Prenylated_rab_accept_PRA1
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
MSTO1	Other/Unknown	no		Misato_II_tubulin-like, DML1/Misato_tubulin, Tubulin/FtsZ_GTPase_sf
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold
ATP13A2	Transcription factor	no		P_typ_ATPase, P-type_TPase_V, ATPase_P-typ_transduc_dom_A_sf
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
WDR37	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_CS
FGFR1	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Ig_sub2
FOXP1	Transcription factor	no		Fork_head_dom, TF_fork_head_CS_2, FOXP-CC
FZD3	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
ADGRG2	GPCR	yes		GPS, GPCR_2_secretin-like, GPCR_2-like_7TM
HSD17B4	Enzyme (other)	yes	4.2.1.119	SDR_fam, MaoC-like_dom, SCP2_sterol-bd_dom
CCDST	Other/Unknown	no
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
OPHN1	Scaffold/PPI	no		RhoGAP_dom, PH_domain, BAR_dom
PLA2G6	Scaffold/PPI	no	3.1.1.4	Ankyrin_rpt, PNPLA_dom, Acyl_Trfase/lysoPLipase
PMM2	Enzyme (other)	yes	5.4.2.8	PMM, HAD-SF_hydro_IIB, HAD_sf

Expression context

Cohort genes with no expression data: 0.

46 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)	49
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	7
ganglionic eminence	5
sural nerve	5
calcaneal tendon	4
cerebellar hemisphere	4
right hemisphere of cerebellum	4
buccal mucosa cell	4
male germ line stem cell (sensu Vertebrata) in testis	4
secondary oocyte	4
ileal mucosa	3
ventricular zone	3
endothelial cell	3
right lobe of liver	3
corpus epididymis	3
sperm	3
lateral nuclear group of thalamus	2
pons	2
apex of heart	2
quadriceps femoris	2
right frontal lobe	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OXR1	287	ubiquitous	marker	pons, calcaneal tendon, lateral nuclear group of thalamus
HCRTR1	113	tissue_specific	yes	vastus lateralis, quadriceps femoris, apex of heart
SEMA6B	177	ubiquitous	marker	right frontal lobe, anterior cingulate cortex, cingulate cortex
SLC6A8	291	ubiquitous	marker	inferior olivary complex, apex of heart, ileal mucosa
ARID1A	286	ubiquitous	marker	bone marrow cell, ventricular zone, embryo
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
TUBB2A	293	ubiquitous	marker	endothelial cell, dorsal root ganglion, pons
USH2A	30	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver, buccal mucosa cell
BCL11A	247	ubiquitous	marker	cortical plate, ganglionic eminence, primary visual cortex
KIF4A	179	broad	marker	oocyte, secondary oocyte, ventricular zone
MACF1	303	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, right lung
ANO3	189	broad	marker	corpus epididymis, lateral globus pallidus, putamen
CIC	274	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
AUTS2	292	ubiquitous	marker	cortical plate, tibia, ganglionic eminence
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
ARID1B	256	ubiquitous	marker	bone marrow cell, colonic epithelium, sural nerve
TMLHE	136	ubiquitous	marker	skeletal muscle tissue, hindlimb stylopod muscle, muscle of leg
ASXL1	294	ubiquitous	marker	sural nerve, sperm, adrenal tissue
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium
KIAA0586	247	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, right testis, left testis
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence
BCOR	265	ubiquitous	marker	buccal mucosa cell, ganglionic eminence, cortical plate
KCTD3	284	ubiquitous	marker	jejunal mucosa, right adrenal gland cortex, right adrenal gland
RARS2	255	ubiquitous	marker	ileal mucosa, adrenal tissue, tibialis anterior
AHDC1	232	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, frontal pole
ATAD3A	247	ubiquitous	marker	sural nerve, gastrocnemius, mucosa of transverse colon
OFD1	288	ubiquitous	marker	sperm, bronchial epithelial cell, cervix squamous epithelium
SRD5A3	254	ubiquitous	marker	palpebral conjunctiva, gall bladder, olfactory segment of nasal mucosa
DDX3X	294	ubiquitous	marker	choroid plexus epithelium, oocyte, sperm

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DDX3X	6,454
FGFR1	5,693
TUBB2A	5,621
DKC1	4,882
SETD2	4,668
CASK	4,223
DYNC1H1	4,215
ARID1A	3,476
COASY	3,273
SPTAN1	3,083

Intra-cohort edges

A	B	Sources
ARID1A	ARID1B	biogrid_interaction, string_interaction
ARID1A	BCL11A	string_interaction
ATP13A2	PLA2G6	string_interaction
FGFR1	L1CAM	biogrid_interaction
HCRTR1	OXR1	string_interaction
HSD17B4	TUBA1A	intact
KCTD3	USH2A	string_interaction
KIAA0586	OFD1	string_interaction
KIF4A	TUBA1A	intact
L1CAM	SLC6A8	string_interaction
PMM2	SRD5A3	string_interaction
RARS2	TSEN54	string_interaction
SEPSECS	TSEN54	string_interaction
SETD2	WDR37	biogrid_interaction, intact
SPTAN1	STXBP1	string_interaction

Structural data

PDB: 28 · AlphaFold-only: 20 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
FGFR1	P11362	83
SETD2	Q9BYW2	43
ATP13A2	Q9NQ11	25
CASK	O14936	22
BCL11A	Q9H165	17
DDX3X	O00571	17
TUBA1A	Q71U36	15
HCRTR1	O43613	14
ARID1A	O14497	7
SPTAN1	Q13813	7
CIC	Q96RK0	7
DKC1	O60832	7
SEPSECS	Q9HD40	7
HSD17B4	P51659	7
PMM2	O15305	7
SLC6A8	P48029	6
BCOR	Q6W2J9	5
TSEN54	Q7Z6J9	5
ASXL1	Q8IXJ9	4
FZD3	Q9NPG1	4
TUBB2A	Q13885	3
MACF1	O94854	3
ARID1B	Q8NFD5	2
L1CAM	P32004	2
STXBP1	P61764	1
KIF4A	O95239	1
FOXP1	Q9H334	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51
RARS2	Q5T160	89.18
TMLHE	Q9NVH6	89.10
SRD5A3	Q9H8P0	89.07
PLA2G6	O60733	86.16
MSTO1	Q9BUK6	83.83
PRAF2	O60831	83.44
ATAD3A	Q9NVI7	82.35
WDR37	Q9Y2I8	78.86
ANO3	Q9BYT9	76.30
OPHN1	O60890	74.86
SEMA6B	Q9H3T3	74.81
KCTD3	Q9Y597	70.88
OFD1	O75665	68.41
ADGRG2	Q8IZP9	62.76
OXR1	Q8N573	60.31
KIAA0586	Q9BVV6	47.61
AUTS2	Q8WXX7	41.89
AHDC1	Q5TGY3	38.82
USH2A	O75445

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 237. Enrichment computed across 49 evidence-associated genes (35 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 35 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recycling pathway of L1	4	25.6×	0.002	TUBB2A, KIF4A, TUBA1A, L1CAM
COPI-independent Golgi-to-ER retrograde traffic	4	23.7×	0.002	TUBB2A, TUBA1A, DYNC1H1, PLA2G6
L1CAM interactions	5	17.2×	0.002	SPTAN1, TUBB2A, KIF4A, TUBA1A, L1CAM
Formation of neuronal progenitor and neuronal BAF (npBAF and nBAF)	3	39.1×	0.003	ARID1A, BCL11A, ARID1B
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	3	25.8×	0.009	ARID1A, AUTS2, ARID1B
Recruitment of NuMA to mitotic centrosomes	4	13.3×	0.009	TUBB2A, TUBA1A, OFD1, DYNC1H1
COPI-mediated anterograde transport	4	12.6×	0.009	SPTAN1, TUBB2A, TUBA1A, DYNC1H1
Assembly and cell surface presentation of NMDA receptors	3	21.8×	0.010	TUBB2A, CASK, TUBA1A
Aggrephagy	3	21.3×	0.010	TUBB2A, TUBA1A, DYNC1H1
MHC class II antigen presentation	4	10.2×	0.014	TUBB2A, KIF4A, TUBA1A, DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	3	16.6×	0.016	TUBB2A, TUBA1A, DYNC1H1
Hedgehog ‘off’ state	3	15.3×	0.016	TUBB2A, TUBA1A, OFD1
Kinesins	3	15.3×	0.016	TUBB2A, KIF4A, TUBA1A
Axon guidance	5	6.5×	0.016	SPTAN1, TUBB2A, KIF4A, TUBA1A, L1CAM
Formation of the canonical BAF (cBAF) complex	2	36.2×	0.018	ARID1A, ARID1B
Formation of the embryonic stem cell BAF (esBAF) complex	2	34.4×	0.018	ARID1A, BCL11A
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	2	31.1×	0.018	TUBB2A, TUBA1A
Transport of connexons to the plasma membrane	2	31.1×	0.018	TUBB2A, TUBA1A
Signal transduction by L1	2	29.7×	0.018	FGFR1, L1CAM
Dopamine Neurotransmitter Release Cycle	2	28.4×	0.018	STXBP1, CASK
Gap junction trafficking and regulation	2	27.2×	0.018	TUBB2A, TUBA1A
Gap junction trafficking	2	27.2×	0.018	TUBB2A, TUBA1A
Nephrin family interactions	2	27.2×	0.018	SPTAN1, CASK
Post-chaperonin tubulin folding pathway	2	27.2×	0.018	TUBB2A, TUBA1A
Loss of Nlp from mitotic centrosomes	3	13.6×	0.018	TUBA1A, OFD1, DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	3	13.6×	0.018	TUBA1A, OFD1, DYNC1H1
AURKA Activation by TPX2	3	13.1×	0.018	TUBA1A, OFD1, DYNC1H1
Transcriptional regulation by RUNX1	3	12.6×	0.018	ARID1A, AUTS2, ARID1B
Recruitment of mitotic centrosome proteins and complexes	3	11.7×	0.018	TUBA1A, OFD1, DYNC1H1
ER to Golgi Anterograde Transport	3	11.4×	0.018	SPTAN1, TUBB2A, TUBA1A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 48 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
polyprenol catabolic process	1	351.1×	0.063	SRD5A3
specification of axis polarity	1	351.1×	0.063	BCOR
obsolete positive regulation of vesicle docking	1	351.1×	0.063	STXBP1
regulation of macrophage colony-stimulating factor production	1	351.1×	0.063	FOXP1
spermine transmembrane transport	1	351.1×	0.063	ATP13A2
negative regulation of neuron remodeling	1	351.1×	0.063	BCL11A
negative regulation of branching morphogenesis of a nerve	1	351.1×	0.063	BCL11A
regulation of acrosomal vesicle exocytosis	1	351.1×	0.063	STXBP1
box H/ACA sno(s)RNA 3’-end processing	1	175.5×	0.063	DKC1
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	175.5×	0.063	SEPSECS
regulation of kidney size	1	175.5×	0.063	ASXL1
very long-chain fatty-acyl-CoA metabolic process	1	175.5×	0.063	HSD17B4
regulation of monocyte differentiation	1	175.5×	0.063	FOXP1
negative regulation of mitotic cell cycle, embryonic	1	175.5×	0.063	FZD3
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	175.5×	0.063	PMM2
negative regulation of tooth mineralization	1	175.5×	0.063	BCOR
vitamin D3 metabolic process	1	175.5×	0.063	FGFR1
negative regulation of cellular response to growth factor stimulus	1	175.5×	0.063	CASK
extracellular exosome biogenesis	1	175.5×	0.063	ATP13A2
regulation of defense response to bacterium	1	175.5×	0.063	FOXP1
positive regulation of glutamate secretion, neurotransmission	1	175.5×	0.063	STXBP1
positive regulation of mitotic cell cycle DNA replication	1	175.5×	0.063	FGFR1
protein localization to Cajal body	1	175.5×	0.063	DKC1
obsolete negative regulation of fibroblast growth factor receptor signaling pathway involved in neural plate anterior/posterior pattern formation	1	175.5×	0.063	OFD1
positive regulation of parathyroid hormone secretion	1	175.5×	0.063	FGFR1
regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	175.5×	0.063	FGFR1
tRNA-type intron splice site recognition and cleavage	1	117.0×	0.063	TSEN54
arginyl-tRNA aminoacylation	1	117.0×	0.063	RARS2
axon target recognition	1	117.0×	0.063	STXBP1
regulation of phosphate transport	1	117.0×	0.063	FGFR1

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 8 · Phased (≥1): 14 · Undrugged: 35

Druggability breadth: 27 of 49 evidence-associated genes (55%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
HCRTR1	SUVOREXANT
TUBB2A	COLCHICINE
CASK	FEDRATINIB
TUBA1A	COLCHICINE
DDX3X	IMATINIB
FGFR1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FGFR1	93	4
TUBA1A	22	4
TUBB2A	21	4
HCRTR1	13	4
CASK	9	4
SETD2	3	2
SLC6A8	1	3
SPTAN1	1	2
DDX3X	1	4
DKC1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SUVOREXANT	4	HCRTR1
NALFURAFINE	4	HCRTR1
LEMBOREXANT	4	HCRTR1
DARIDOREXANT	4	HCRTR1
NALFURAFINE HYDROCHLORIDE	4	HCRTR1
COLCHICINE	4	TUBA1A, TUBB2A
VINBLASTINE	4	TUBA1A, TUBB2A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A, TUBB2A
DOCETAXEL	4	TUBA1A, TUBB2A
NOSCAPINE	4	TUBA1A, TUBB2A
VINBLASTINE SULFATE	4	TUBA1A, TUBB2A
PACLITAXEL	4	TUBA1A, TUBB2A
LEVOFLOXACIN	4	TUBA1A, TUBB2A
VINORELBINE	4	TUBA1A, TUBB2A
TIRBANIBULIN	4	TUBA1A, TUBB2A
PODOFILOX	4	TUBA1A, TUBB2A
VINCRISTINE	4	TUBA1A, TUBB2A
DOCETAXEL ANHYDROUS	4	TUBA1A, TUBB2A
FEDRATINIB	4	CASK, FGFR1
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
IMATINIB	4	DDX3X
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 12.

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

Symbol	Assays	Type breakdown
TUBB2A	1,758	Binding:1718, Functional:34, ADMET:6
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
FGFR1	1,465	Binding:1428, Functional:24, ADMET:13
HCRTR1	280	Binding:154, Functional:126
CASK	92	Binding:92
SETD2	64	Binding:64
PLA2G6	47	Binding:47
DDX3X	32	Binding:31, ADMET:1
KIF4A	20	Binding:20
HSD17B4	11	Binding:10, Functional:1
COASY	10	Binding:10
DKC1	8	Binding:8
SPTAN1	7	Binding:7
DYNC1H1	7	Binding:7
ARID1A	6	Binding:6
PMM2	3	Binding:3
OXR1	2	Binding:2
BCOR	2	Binding:2
ADGRG2	2	Binding:2
L1CAM	2	Binding:2
SLC6A8	1	Functional:1
STXBP1	1	Binding:1
RARS2	1	Binding:1
ATAD3A	1	Binding:1
SRD5A3	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
TMLHE	1.14.11.8	trimethyllysine dioxygenase
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
SRD5A3	1.3.1.22, 1.3.1.94, 1.3.1.B13	3-oxo-5alpha-steroid 4-dehydrogenase (NADP+), polyprenal reductase,
DDX3X	3.6.4.13	RNA helicase
TSEN54	4.6.1.16	tRNA-intron lyase
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase
FGFR1	2.7.10.1	receptor protein-tyrosine kinase
HSD17B4	4.2.1.119	enoyl-CoA hydratase 2
PLA2G6	3.1.1.4	phospholipase A2
PMM2	5.4.2.8	phosphomannomutase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HCRTR1	280
TUBB2A	1,758
TUBA1A	1,696
FGFR1	1,465

Pharmacogenomics

Cohort genes with a PharmGKB record: 48; 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)
SUVOREXANT	4	HCRTR1
NALFURAFINE	4	HCRTR1
LEMBOREXANT	4	HCRTR1
DARIDOREXANT	4	HCRTR1
NALFURAFINE HYDROCHLORIDE	4	HCRTR1
COLCHICINE	4	TUBA1A, TUBB2A
VINBLASTINE	4	TUBA1A, TUBB2A
LEVOFLOXACIN ANHYDROUS	4	TUBA1A, TUBB2A
DOCETAXEL	4	TUBA1A, TUBB2A
NOSCAPINE	4	TUBA1A, TUBB2A
VINBLASTINE SULFATE	4	TUBA1A, TUBB2A
PACLITAXEL	4	TUBA1A, TUBB2A
LEVOFLOXACIN	4	TUBA1A, TUBB2A
VINORELBINE	4	TUBA1A, TUBB2A
TIRBANIBULIN	4	TUBA1A, TUBB2A
PODOFILOX	4	TUBA1A, TUBB2A
VINCRISTINE	4	TUBA1A, TUBB2A
DOCETAXEL ANHYDROUS	4	TUBA1A, TUBB2A
FEDRATINIB	4	CASK, FGFR1
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
IMATINIB	4	DDX3X
PONATINIB	4	FGFR1
PEMIGATINIB	4	FGFR1
NINTEDANIB	4	FGFR1
TIVOZANIB	4	FGFR1
LENVATINIB	4	FGFR1
AXITINIB	4	FGFR1
SORAFENIB	4	FGFR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	HCRTR1, TUBB2A, CASK, TUBA1A, DDX3X, FGFR1
B	Phased (≥1) drug, not yet approved	8	SLC6A8, SPTAN1, SETD2, DKC1, DYNC1H1, COASY, PLA2G6, PMM2
C	Druggable family + PDB, no drug	5	TSEN54, SEPSECS, FZD3, HSD17B4, L1CAM
D	Druggable family + AlphaFold only, no drug	4	USH2A, TMLHE, SRD5A3, ADGRG2
E	Difficult family or no structure, no drug	26	OXR1, SEMA6B, ARID1A, STXBP1, BCL11A, KIF4A, MACF1, ANO3, CIC, AUTS2 (+16 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OXR1	2	HCRTR1
SRD5A3	1	PMM2
SEMA6B	0	—
ARID1A	6	—
STXBP1	1	—
USH2A	0	—
BCL11A	0	—
KIF4A	20	—
MACF1	0	—
ANO3	0	—
CIC	0	—
AUTS2	0	—
ARID1B	0	—
TMLHE	0	—
ASXL1	0	—
KIAA0586	0	—
BCOR	2	—
KCTD3	0	—
RARS2	1	—
AHDC1	0	—
ATAD3A	1	—
OFD1	0	—
TSEN54	0	—
PRAF2	0	—
MSTO1	0	—
ATP13A2	0	—
SEPSECS	0	—
WDR37	0	—
FOXP1	0	—
FZD3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.