Cerebral palsy

Summary

Cerebral palsy (MONDO:0006497) is a disease (an umbrella term covering 5 Mondo subtypes) caused by FBXO31 (GenCC Strong), with 55 cohort genes (1 GWAS associations across 3 studies) and 1,347 clinical trials. Top therapeutic interventions include baclofen, botulinum toxin type a, and alendronic acid.

At a glance

• Causal gene: FBXO31 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 55
• GWAS associations: 1
• ClinVar variants: 58
• Clinical trials: 1,347

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	cerebral palsy
Mondo ID	MONDO:0006497
EFO	EFO:1000632
MeSH	D002547
DOID	DOID:1969
ICD-10-CM	G80
ICD-11	76906748
NCIT	C34460
SNOMED CT	128188000
UMLS	C0007789
MedGen	854
Is cancer (heuristic)	no

Also known as: infantile cerebral palsy

Data availability: 58 ClinVar variants · 1 GWAS association (3 studies) · 9 GenCC gene-disease records · 1 HPO phenotype · 19 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › palsy › cerebral palsy

Related subtypes (9): hemiplegia, quadriplegia, facial paralysis, ophthalmoplegia, paraplegia, progressive bulbar palsy, klumpke’s paralysis, respiratory paralysis, Erb palsy

Subtypes (5): spastic cerebral palsy, ataxic cerebral palsy, mixed cerebral palsy, hypotonic cerebral palsy, athetoid cerebral palsy

Genetics & variants

GWAS landscape

1 GWAS associations across 3 studies. Top hits map to 2 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs74384846	2e-08	ENTPD4, LOXL2	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90473360	UK Biobank Whole-Genome Sequencing Consortium	2025	305	458,135	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90651560	Liu TY	2025	184	218,635	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90435924	Zhou W	2018	145	395,209	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
rs74384846	8	23394306	T>C		intron_variant	ENTPD4, LOXL2	2e-08	Tier 4: intronic/intergenic

ClinVar germline variants

58 retrieved; paginated sample, class counts are floors:

13 likely pathogenic, 12 pathogenic, 11 pathogenic/likely pathogenic, 7 conflicting classifications of pathogenicity, 7 uncertain significance, 3 risk factor, 1 uncertain significance; risk factor, 1 likely pathogenic; risk factor, 1 conflicting classifications of pathogenicity; risk factor, 1 pathogenic/likely pathogenic/pathogenic, low penetrance/established risk allele; risk factor, 1 benign/likely benign; other; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172820	Single allele	ADAP2	Pathogenic	criteria provided, single submitter
242273	NM_016824.5(ADD3):c.1100G>A (p.Gly367Asp)	ADD3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172811	GRCh37/hg19 22q11.21(chr22:18873001-21469900)	AIFM3	Pathogenic	criteria provided, single submitter
1638	NM_000382.3(ALDH3A2):c.941_943delinsGGGCTAAAAGTACTGTTGGGG (p.Ala314_Pro315delinsGlyAlaLysSerThrValGlyAla)	ALDH3A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
52603	NM_000059.4(BRCA2):c.8487+3A>G	BRCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17545	NM_000083.3(CLCN1):c.2680C>T (p.Arg894Ter)	CLCN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172810	NM_001845.6(COL4A1):c.4114G>C (p.Gly1372Arg)	COL4A1	Pathogenic	criteria provided, single submitter
13310	NM_000506.5(F2):c.*97G>A	F2	Pathogenic/Likely pathogenic/Pathogenic, low penetrance/Established risk allele; risk factor	criteria provided, multiple submitters, no conflicts
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
9589	NC_012920.1(MT-TL1):m.3243A>G	MT-TL1	Pathogenic	reviewed by expert panel
983221	NM_022474.4(PALS1):c.1289A>G (p.Glu430Gly)	PALS1	Pathogenic	criteria provided, single submitter
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
1172822	Single allele	PNPLA4	Pathogenic	criteria provided, single submitter
665	NM_000312.4(PROC):c.226G>A (p.Val76Met)	PROC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1262	NM_024570.4(RNASEH2B):c.529G>A (p.Ala177Thr)	RNASEH2B	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
997718	NM_015474.4(SAMHD1):c.109G>T (p.Glu37Ter)	SAMHD1	Pathogenic	criteria provided, single submitter
209188	NM_015046.7(SETX):c.5821_5830del (p.Ala1941fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172817	NM_014946.4(SPAST):c.1099-4371_1245+1010del	SPAST	Pathogenic	criteria provided, single submitter
1172818	NM_182914.3(SYNE2):c.16153C>T (p.Gln5385Ter)	SYNE2	Pathogenic	criteria provided, single submitter
1172808	NM_006009.4(TUBA1A):c.50G>A (p.Gly17Asp)	TUBA1A	Pathogenic	criteria provided, single submitter
265378	NM_006009.4(TUBA1A):c.367C>T (p.Arg123Cys)	TUBA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
135658	NM_006087.4(TUBB4A):c.1228G>A (p.Glu410Lys)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217025	NM_006087.4(TUBB4A):c.763G>A (p.Val255Ile)	TUBB4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1172805	Multiple alleles		Likely pathogenic	criteria provided, single submitter
267832	46;XX;t(1;5)(p31;q33)dn		Likely pathogenic	criteria provided, single submitter
1172804	NM_020754.4(ARHGAP31):c.1700del (p.Pro567fs)	ARHGAP31	Likely pathogenic	criteria provided, single submitter
1172824	NM_001127222.2(CACNA1A):c.7249G>T (p.Glu2417Ter)	CACNA1A	Likely pathogenic	criteria provided, single submitter
812928	NM_017721.5(CC2D1A):c.378+137_1641+1157del	CC2D1A	Likely pathogenic	no assertion criteria provided
1172807	NM_001845.6(COL4A1):c.1258G>A (p.Gly420Arg)	COL4A1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 21 · Orphanet: 125 · 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
FBXO31	Strong	Autosomal dominant	cerebral palsy	6
FBXO5	Strong	Autosomal dominant	cerebral palsy	6
AGAP1	Moderate	Autosomal dominant	cerebral palsy
RHOB	Moderate	Autosomal dominant	cerebral palsy
TEP1	Moderate	Autosomal dominant	cerebral palsy
KDM7A	Limited	Autosomal dominant	cerebral palsy
MAOB	Limited	Autosomal dominant	cerebral palsy
RFX2	Limited	Autosomal dominant	cerebral palsy
TENM1	Limited	X-linked	cerebral palsy	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXO31	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
TENM1	Orphanet:88620	Isolated congenital anosmia
BRCA2	Orphanet:1331	Familial prostate cancer
BRCA2	Orphanet:1333	Familial pancreatic carcinoma
BRCA2	Orphanet:145	Hereditary breast and/or ovarian cancer syndrome
BRCA2	Orphanet:178	Chordoma
BRCA2	Orphanet:227535	Hereditary breast cancer
BRCA2	Orphanet:319462	Inherited cancer-predisposing syndrome due to biallelic BRCA2 mutations
BRCA2	Orphanet:440437	Familial colorectal cancer Type X
BRCA2	Orphanet:654	Nephroblastoma
BRCA2	Orphanet:667662	Breast implant-associated anaplastic large cell lymphoma
BRCA2	Orphanet:694963	Inflammatory breast cancer
BRCA2	Orphanet:70567	Cholangiocarcinoma
BRCA2	Orphanet:84	Fanconi anemia
SMARCA4	Orphanet:1465	Coffin-Siris syndrome
SMARCA4	Orphanet:231108	Rhabdoid tumor predisposition syndrome
SMARCA4	Orphanet:370396	Small cell carcinoma of the ovary
SMARCA4	Orphanet:466962	SMARCA4-deficient sarcoma of thorax
SPAST	Orphanet:100985	Autosomal dominant spastic paraplegia type 4
BUB1B	Orphanet:1052	Mosaic variegated aneuploidy syndrome
TTN	Orphanet:140922	Titin-related limb-girdle muscular dystrophy R10
TTN	Orphanet:154	Familial isolated dilated cardiomyopathy
TTN	Orphanet:169186	Autosomal recessive centronuclear myopathy
TTN	Orphanet:178464	Hereditary myopathy with early respiratory failure
TTN	Orphanet:289377	Early-onset myopathy with fatal cardiomyopathy
TTN	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
TTN	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
TTN	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
TTN	Orphanet:324604	Classic multiminicore myopathy
TTN	Orphanet:334	Hereditary atrial fibrillation
TTN	Orphanet:466921	Childhood-onset progressive contractures-limb-girdle weakness-muscle dystrophy syndrome
TTN	Orphanet:609	Tibial muscular dystrophy
TTN	Orphanet:707983	Early-onset autosomal recessive TTN-related distal myopathy
ATP10A	Orphanet:411515	Angelman syndrome due to imprinting defect in 15q11-q13
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
CACNA1C	Orphanet:101016	Romano-Ward syndrome
CACNA1C	Orphanet:130	Brugada syndrome
CACNA1C	Orphanet:528084	Non-specific syndromic intellectual disability
CACNA1C	Orphanet:595098	Timothy syndrome type 1
CACNA1C	Orphanet:595105	Timothy syndrome type 2
CACNA1C	Orphanet:595109	Atypical Timothy syndrome
SAMHD1	Orphanet:481662	Familial Chilblain lupus
SAMHD1	Orphanet:51	Aicardi-Goutières syndrome
MFN2	Orphanet:2398	Multiple symmetric lipomatosis

Cohort genes → proteins

55 cohort genes, 54 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	55

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TEP1	HGNC:11726	ENSG00000129566	Q99973	Telomerase protein component 1	gencc
FBXO5	HGNC:13584	ENSG00000112029	Q9UKT4	F-box only protein 5	gencc
FBXO31	HGNC:16510	ENSG00000103264	Q5XUX0	F-box only protein 31	gencc
AGAP1	HGNC:16922	ENSG00000157985	Q9UPQ3	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1	gencc
KDM7A	HGNC:22224	ENSG00000006459	Q6ZMT4	Lysine-specific demethylase 7A	gencc
RHOB	HGNC:668	ENSG00000143878	P62745	Rho-related GTP-binding protein RhoB	gencc
MAOB	HGNC:6834	ENSG00000069535	P27338	Amine oxidase [flavin-containing] B	gencc
TENM1	HGNC:8117	ENSG00000009694	Q9UKZ4	Teneurin-1	gencc
RFX2	HGNC:9983	ENSG00000087903	P48378	DNA-binding protein RFX2	gencc
BRCA2	HGNC:1101	ENSG00000139618	P51587	Breast cancer type 2 susceptibility protein	clinvar
SLC6A4	HGNC:11050	ENSG00000108576	P31645	Sodium-dependent serotonin transporter	clinvar
SMARCA4	HGNC:11100	ENSG00000127616	P51532	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	clinvar
SPAST	HGNC:11233	ENSG00000021574	Q9UBP0	Spastin	clinvar
BUB1B	HGNC:1149	ENSG00000156970	O60566	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	clinvar
TTN	HGNC:12403	ENSG00000155657	Q8WZ42	Titin	clinvar
ATP10A	HGNC:13542	ENSG00000206190	O60312	Phospholipid-transporting ATPase VA	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
CACNA1C	HGNC:1390	ENSG00000151067	Q13936	Voltage-dependent L-type calcium channel subunit alpha-1C	clinvar
SAMHD1	HGNC:15925	ENSG00000101347	Q9Y3Z3	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	clinvar
ADAP2	HGNC:16487	ENSG00000184060	Q9NPF8	Arf-GAP with dual PH domain-containing protein 2	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
ASTN2	HGNC:17021	ENSG00000148219	O75129	Astrotactin-2	clinvar
SYNE2	HGNC:17084	ENSG00000054654	Q8WXH0	Nesprin-2	clinvar
PALS1	HGNC:18669	ENSG00000072415	Q8N3R9	Protein PALS1	clinvar
CLCN1	HGNC:2019	ENSG00000188037	P35523	Chloride channel protein 1	clinvar
CLCN2	HGNC:2020	ENSG00000114859	P51788	Chloride channel protein 2	clinvar
TUBA1A	HGNC:20766	ENSG00000167552	Q71U36	Tubulin alpha-1A chain	clinvar
TUBB4A	HGNC:20774	ENSG00000104833	P04350	Tubulin beta-4A chain	clinvar
COL4A1	HGNC:2202	ENSG00000187498	P02462	Collagen alpha-1(IV) chain	clinvar
COL4A2	HGNC:2203	ENSG00000134871	P08572	Collagen alpha-2(IV) chain	clinvar
ADD3	HGNC:245	ENSG00000148700	Q9UEY8	Gamma-adducin	clinvar
PNPLA4	HGNC:24887	ENSG00000006757	P41247	Patatin-like phospholipase domain-containing protein 4	clinvar
RNASEH2B	HGNC:25671	ENSG00000136104	Q5TBB1	Ribonuclease H2 subunit B	clinvar
PIEZO2	HGNC:26270	ENSG00000154864	Q9H5I5	Piezo-type mechanosensitive ion channel component 2	clinvar
AIFM3	HGNC:26398	ENSG00000183773	Q96NN9	Apoptosis-inducing factor 3	clinvar
ANKRD34A	HGNC:27639	ENSG00000272031	Q69YU3	Ankyrin repeat domain-containing protein 34A	clinvar
ARHGAP31	HGNC:29216	ENSG00000031081	Q2M1Z3	Rho GTPase-activating protein 31	clinvar
KIDINS220	HGNC:29508	ENSG00000134313	Q9ULH0	Kinase D-interacting substrate of 220 kDa	clinvar
CC2D1A	HGNC:30237	ENSG00000132024	Q6P1N0	Coiled-coil and C2 domain-containing protein 1A	clinvar
EGFR	HGNC:3236	ENSG00000146648	P00533	Epidermal growth factor receptor	clinvar
NKX2-6	HGNC:32940	ENSG00000180053	A6NCS4	Homeobox protein Nkx-2.6	clinvar
F2	HGNC:3535	ENSG00000180210	P00734	Prothrombin	clinvar
F8	HGNC:3546	ENSG00000185010	P00451	Coagulation factor VIII	clinvar
FMR1	HGNC:3775	ENSG00000102081	Q06787	Fragile X messenger ribonucleoprotein 1	clinvar
ALDH3A2	HGNC:403	ENSG00000072210	P51648	Aldehyde dehydrogenase family 3 member A2	clinvar
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	clinvar
HTT	HGNC:4851	ENSG00000197386	P42858	Huntingtin	clinvar
KLHL3	HGNC:6354	ENSG00000146021	Q9UH77	Kelch-like protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TEP1	Telomerase protein component 1	Component of the telomerase ribonucleoprotein complex that is essential for the replication of chromosome termini.
FBXO5	F-box only protein 5	Regulator of APC activity during mitotic and meiotic cell cycle.
FBXO31	F-box only protein 31	Substrate-recognition component of the SCF(FBXO31) protein ligase complex, which specifically mediates the ubiquitination of proteins amidated at their C-terminus in response to oxidative stress, leading to their degradation by the proteas…
AGAP1	Arf-GAP with GTPase, ANK repeat and PH domain-containing protein 1	GTPase-activating protein for ARF1 and, to a lesser extent, ARF5.
KDM7A	Lysine-specific demethylase 7A	Histone demethylase required for brain development.
RHOB	Rho-related GTP-binding protein RhoB	Mediates apoptosis in neoplastically transformed cells after DNA damage.
MAOB	Amine oxidase [flavin-containing] B	Catalyzes the oxidative deamination of primary and some secondary amines such as neurotransmitters, and exogenous amines including the tertiary amine, neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), with concomitant reducti…
TENM1	Teneurin-1	Involved in neural development, regulating the establishment of proper connectivity within the nervous system.
RFX2	DNA-binding protein RFX2	Transcription factor that acts as a key regulator of spermatogenesis.
BRCA2	Breast cancer type 2 susceptibility protein	Involved in double-strand break repair and/or homologous recombination.
SLC6A4	Sodium-dependent serotonin transporter	Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle.
SMARCA4	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SPAST	Spastin	ATP-dependent microtubule severing protein that specifically recognizes and cuts microtubules that are polyglutamylated.
BUB1B	Mitotic checkpoint serine/threonine-protein kinase BUB1 beta	Essential component of the mitotic checkpoint.
TTN	Titin	Key component in the assembly and functioning of vertebrate striated muscles.
ATP10A	Phospholipid-transporting ATPase VA	Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane.
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…
CACNA1C	Voltage-dependent L-type calcium channel subunit alpha-1C	Pore-forming, alpha-1C subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents.
SAMHD1	Deoxynucleoside triphosphate triphosphohydrolase SAMHD1	Protein that acts both as a host restriction factor involved in defense response to virus and as a regulator of DNA end resection at stalled replication forks.
ADAP2	Arf-GAP with dual PH domain-containing protein 2	GTPase-activating protein for the ADP ribosylation factor family (Potential).
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
ASTN2	Astrotactin-2	Mediates recycling of the neuronal cell adhesion molecule ASTN1 to the anterior pole of the cell membrane in migrating neurons.
SYNE2	Nesprin-2	Multi-isomeric modular protein which forms a linking network between organelles and the actin cytoskeleton to maintain the subcellular spatial organization.
PALS1	Protein PALS1	Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells.
CLCN1	Chloride channel protein 1	Voltage-gated chloride channel involved in skeletal muscle excitability.
CLCN2	Chloride channel protein 2	Voltage-gated and osmosensitive chloride channel.
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.
COL4A1	Collagen alpha-1(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
COL4A2	Collagen alpha-2(IV) chain	Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a ‘chicken-wire’ meshwork together with laminins, proteoglycans and entactin/nidogen.
ADD3	Gamma-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.
PNPLA4	Patatin-like phospholipase domain-containing protein 4	Has abundant triacylglycerol lipase activity.
RNASEH2B	Ribonuclease H2 subunit B	Non catalytic subunit of RNase H2, an endonuclease that specifically degrades the RNA of RNA:DNA hybrids.
PIEZO2	Piezo-type mechanosensitive ion channel component 2	Pore-forming subunit of the mechanosensitive non-specific cation Piezo channel required for rapidly adapting mechanically activated (MA) currents and has a key role in sensing touch and tactile pain.
AIFM3	Apoptosis-inducing factor 3	Induces apoptosis through a caspase dependent pathway.
ARHGAP31	Rho GTPase-activating protein 31	Functions as a GTPase-activating protein (GAP) for RAC1 and CDC42.
KIDINS220	Kinase D-interacting substrate of 220 kDa	Promotes a prolonged MAP-kinase signaling by neurotrophins through activation of a Rap1-dependent mechanism.
CC2D1A	Coiled-coil and C2 domain-containing protein 1A	Transcription factor that binds specifically to the DRE (dual repressor element) and represses HTR1A gene transcription in neuronal cells.
EGFR	Epidermal growth factor receptor	Receptor tyrosine kinase binding ligands of the EGF family and activating several signaling cascades to convert extracellular cues into appropriate cellular responses.
NKX2-6	Homeobox protein Nkx-2.6	Acts as a transcriptional activator.
F2	Prothrombin	Thrombin, which cleaves bonds after Arg and Lys, converts fibrinogen to fibrin and activates factors V, VII, VIII, XIII, and, in complex with thrombomodulin, protein C.
F8	Coagulation factor VIII	Factor VIII, along with calcium and phospholipid, acts as a cofactor for F9/factor IXa when it converts F10/factor X to the activated form, factor Xa.
FMR1	Fragile X messenger ribonucleoprotein 1	Multifunctional polyribosome-associated RNA-binding protein that plays a central role in neuronal development and synaptic plasticity through the regulation of alternative mRNA splicing, mRNA stability, mRNA dendritic transport and postsyn…
ALDH3A2	Aldehyde dehydrogenase family 3 member A2	Catalyzes the oxidation of medium and long chain aliphatic aldehydes to fatty acids.
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
GRIN2B	Glutamate receptor ionotropic, NMDA 2B	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
HTT	Huntingtin	May play a role in microtubule-mediated transport or vesicle function.
KLHL3	Kelch-like protein 3	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin ligase complex that acts as a regulator of ion transport in the distal nephron.
PDGFRB	Platelet-derived growth factor receptor beta	Tyrosine-protein kinase that acts as a cell-surface receptor for homodimeric PDGFB and PDGFD and for heterodimers formed by PDGFA and PDGFB, and plays an essential role in the regulation of embryonic development, cell proliferation, surviv…

Protein-family classification

Druggable: 17 · Difficult: 10 · Unknown: 28 · Druggable fraction: 0.31

Family distribution

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

Family	Genes	Fold	FDR
Ion channel	2	4.1×	0.290
Kinase	5	2.5×	0.290
Scaffold/PPI	6	1.9×	0.290
Complement	1	4.9×	0.419
Enzyme (other)	6	1.3×	0.555
Protease	2	1.3×	0.668
Other/Unknown	28	0.9×	0.913
Transcription factor	4	0.6×	0.913
Antibody/Immunoglobulin	1	0.5×	0.913

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TEP1	Scaffold/PPI	no		WD40_rpt, NACHT_NTPase, TEP1_N
FBXO5	Other/Unknown	no		F-box_dom, ZF_ZBR, FBX5_43
FBXO31	Other/Unknown	no		F-box_dom, F-box-like_dom_sf, FBXO31/39
AGAP1	Scaffold/PPI	no		ArfGAP_dom, Small_GTPase, PH_domain
KDM7A	Transcription factor	no	1.14.11.65	Znf_PHD, JmjC_dom, Znf_FYVE_PHD
RHOB	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
MAOB	Enzyme (other)	yes	1.4.3.4	Flavin_amine_oxidase, Amino_oxidase, FAD/NAD-bd_sf
TENM1	Other/Unknown	no		EGF, YD, Ten_N
RFX2	Other/Unknown	no		DNA-bd_RFX, RFX1_trans_act, WH-like_DNA-bd_sf
BRCA2	Other/Unknown	no		BRCA2_repeat, NA-bd_OB-fold, BRCA2_OB_1
SLC6A4	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_serotonin_N, SNS_sf
SMARCA4	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SPAST	Enzyme (other)	yes	5.6.1.1	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS
BUB1B	Kinase	yes	2.7.11.1	Kinase-like_dom_sf, Mad3/Bub1_I, Bub1/Mad3
TTN	Kinase	yes	2.7.11.1	Prot_kinase_dom, Ig_sub2, Ig_sub
ATP10A	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
CACNA1C	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1csu
SAMHD1	Transcription factor	no	3.1.5.B1	SAM, HD/PDEase_dom, HD_domain
ADAP2	Scaffold/PPI	no		ArfGAP_dom, PH_domain, PH-like_dom_sf
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
ASTN2	Complement	yes		MACPF, Astrotactin, FN3_sf
SYNE2	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, Spectrin_repeat
PALS1	Kinase	yes		SH3_domain, PDZ, L27_dom
CLCN1	Other/Unknown	no		ClC, Cl_channel-1, Cl-channel_core
CLCN2	Other/Unknown	no		ClC, Cl-channel-2, Cl-channel_core
TUBA1A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
TUBB4A	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
COL4A1	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
COL4A2	Other/Unknown	no		Collagen_IV_NC, Collagen, CTDL_fold
ADD3	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf
PNPLA4	Other/Unknown	no		PNPLA_dom, Acyl_Trfase/lysoPLipase, PLPL
RNASEH2B	Enzyme (other)	yes	3.1.26.4	RNase_H2_suB_wHTH, RNase_H2_suB, Rnh202_N
PIEZO2	Other/Unknown	no		Piezo, Piezo_cap_dom, Piezo_TM25-28
AIFM3	Other/Unknown	no		FAD/NAD-linked_Rdtase_dimer_sf, Rieske_2Fe-2S, FAD/NAD-binding_dom
ANKRD34A	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, AN34A/B/C
ARHGAP31	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, PX-Rho_GAP
KIDINS220	Scaffold/PPI	no		Ankyrin_rpt, KAP_P-loop, SAM/pointed_sf
CC2D1A	Other/Unknown	no		C2_dom, CC2D1A/B_DM14, C2_domain_sf
EGFR	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
NKX2-6	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
F2	Protease	yes	3.4.21.5	Kringle, GLA_domain, Trypsin_dom
F8	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
FMR1	Other/Unknown	no		KH_dom, KH_dom_type_1, Agenet-like_dom
ALDH3A2	Enzyme (other)	yes	1.2.1.48	Aldehyde_DH_NAD(P), Aldehyde_DH_dom, Ald_DH_CS_CYS
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
HTT	Other/Unknown	no		Huntingtin, ARM-like, ARM-type_fold
KLHL3	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf

Expression context

Cohort genes with no expression data: 0.

52 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)	1
broad (>20)	54
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	7
ganglionic eminence	6
secondary oocyte	6
ventricular zone	6
right hemisphere of cerebellum	6
cerebellar hemisphere	5
mucosa of transverse colon	4
oocyte	4
sural nerve	4
monocyte	3
mononuclear cell	3
cerebellar cortex	3
paraflocculus	3
saphenous vein	3
endothelial cell	3
right coronary artery	3
calcaneal tendon	3
gluteal muscle	2
decidua	2
cerebellar vermis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TEP1	247	ubiquitous	marker	monocyte, mucosa of transverse colon, mononuclear cell
FBXO5	225	ubiquitous	marker	ventricular zone, ganglionic eminence, secondary oocyte
FBXO31	261	ubiquitous	marker	cerebellar hemisphere, cerebellar cortex, right hemisphere of cerebellum
AGAP1	287	ubiquitous	marker	frontal pole, cortical plate, paraflocculus
KDM7A	287	ubiquitous	marker	cartilage tissue, tendon of biceps brachii, gluteal muscle
RHOB	299	ubiquitous	marker	mucosa of stomach, saphenous vein, vein
MAOB	268	broad	marker	saphenous vein, lateral globus pallidus, decidua
TENM1	218	tissue_specific	marker	cerebellar vermis, paraflocculus, endothelial cell
RFX2	255	ubiquitous	marker	right uterine tube, left testis, right testis
BRCA2	184	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, secondary oocyte, ventricular zone
SLC6A4	162	tissue_specific	marker	right lung, jejunal mucosa, ileal mucosa
SMARCA4	295	ubiquitous	marker	ganglionic eminence, cortical plate, cervix squamous epithelium
SPAST	284	ubiquitous	marker	cortical plate, oocyte, secondary oocyte
BUB1B	210	ubiquitous	marker	secondary oocyte, oocyte, ventricular zone
TTN	223	broad	marker	biceps brachii, gluteal muscle, skeletal muscle tissue of biceps brachii
ATP10A	229	broad	marker	endothelial cell, descending thoracic aorta, thoracic aorta
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
CACNA1C	134	broad	marker	apex of heart, right coronary artery, muscle layer of sigmoid colon
SAMHD1	291	ubiquitous	marker	monocyte, mononuclear cell, pericardium
ADAP2	253	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
ASTN2	236	ubiquitous	marker	buccal mucosa cell, trigeminal ganglion, dorsal root ganglion
SYNE2	284	ubiquitous	marker	ventricular zone, skeletal muscle tissue of biceps brachii, ganglionic eminence
PALS1	272	ubiquitous	marker	jejunal mucosa, ventricular zone, germinal epithelium of ovary
CLCN1	108	tissue_specific	marker	hindlimb stylopod muscle, triceps brachii, skeletal muscle tissue of rectus abdominis
CLCN2	181	broad	yes	mucosa of transverse colon, tibial nerve, sural nerve
TUBA1A	288	ubiquitous	marker	endothelial cell, cortical plate, ganglionic eminence
TUBB4A	201	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
COL4A1	283	ubiquitous	marker	visceral pleura, placenta, right coronary artery
COL4A2	284	ubiquitous	marker	saphenous vein, decidua, placenta

Protein interactions among cohort

Intra-cohort edges: 15.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EGFR	18,421
HTT	13,156
SMARCA4	8,138
TUBB4A	5,138
PDGFRB	5,111
BRCA2	4,839
ALDH3A2	4,773
FMR1	4,726
TEP1	4,398
TTN	4,237

Intra-cohort edges

A	B	Sources
ADD3	HTT	intact
AGAP1	ANKRD34A	biogrid_interaction
ARHGAP31	TUBB4A	biogrid_interaction
ASTN2	TENM1	string_interaction
COL4A1	COL4A2	intact, string_interaction
EGFR	PDGFRB	string_interaction
EGFR	TUBA1A	intact
F2	F8	intact, string_interaction
F8	PROC	string_interaction
FBXO31	FBXO5	string_interaction
GNB1	HTT	intact
HTT	TUBA1A	intact
MAOB	SLC6A4	string_interaction
RNASEH2B	SAMHD1	string_interaction
RNASEH2B	SYNE2	biogrid_interaction

Structural data

PDB: 42 · AlphaFold-only: 12 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
F2	P00734	475
EGFR	P00533	388
SAMHD1	Q9Y3Z3	76
TTN	Q8WZ42	64
MAOB	P27338	57
GRIN2B	Q13224	36
CACNA1C	Q13936	33
SMARCA4	P51532	31
HTT	P42858	31
SLC6A4	P31645	30
F8	P00451	25
TUBA1A	Q71U36	15
BRCA2	P51587	14
FMR1	Q06787	12
PROC	P04070	12
BUB1B	O60566	9
PALS1	Q8N3R9	9
CLCN1	P35523	9
CLCN2	P51788	8
PDGFRB	P09619	8
SPAST	Q9UBP0	7
AIFM3	Q96NN9	7
PMM2	O15305	7
NECTIN2	Q92692	7
KDM7A	Q6ZMT4	6
CACNA1A	O00555	4
COL4A1	P02462	4
COL4A2	P08572	4
RNASEH2B	Q5TBB1	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PNPLA4	P41247	94.38
ADAP2	Q9NPF8	92.49
TUBB4A	P04350	92.25
CC2D1A	Q6P1N0	74.71
ATP10A	O60312	71.30
RFX2	P48378	68.73
ADD3	Q9UEY8	66.83
NKX2-6	A6NCS4	64.31
ANKRD34A	Q69YU3	57.86
SETX	Q7Z333	52.93
ARHGAP31	Q2M1Z3	43.32
TENM1	Q9UKZ4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 377. Enrichment computed across 55 evidence-associated genes (40 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 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective F8 cleavage by thrombin	2	190.3×	0.007	F2, F8
Amplification and propagation of coagulation cascade	3	47.6×	0.007	F2, F8, PROC
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	2	63.4×	0.017	F2, PROC
Gamma-carboxylation of protein precursors	2	57.1×	0.017	F2, PROC
Removal of aminoterminal propeptides from gamma-carboxylated proteins	2	57.1×	0.017	F2, PROC
Sealing of the nuclear envelope (NE) by ESCRT-III	3	25.9×	0.017	SPAST, TUBA1A, TUBB4A
Nuclear Envelope (NE) Reassembly	3	22.0×	0.017	SPAST, TUBA1A, TUBB4A
Selective autophagy	3	20.9×	0.017	MFN2, TUBA1A, TUBB4A
Signaling by PDGF	3	19.0×	0.017	COL4A1, COL4A2, PDGFRB
Assembly and cell surface presentation of NMDA receptors	3	19.0×	0.017	TUBA1A, TUBB4A, GRIN2B
NCAM1 interactions	3	18.6×	0.017	CACNA1C, COL4A1, COL4A2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	7	5.9×	0.017	BUB1B, MFN2, TUBA1A, TUBB4A, ADD3, KIDINS220, ALDH3A2
Regulation of clotting cascade	3	17.5×	0.018	F2, F8, PROC
Mitotic Metaphase and Anaphase	4	9.7×	0.018	SPAST, BUB1B, TUBA1A, TUBB4A
Mitotic Anaphase	4	9.7×	0.018	SPAST, BUB1B, TUBA1A, TUBB4A
Cell Cycle	6	5.4×	0.018	BRCA2, SPAST, BUB1B, SYNE2, TUBA1A, TUBB4A
Fibrin formation	2	43.9×	0.020	F2, PROC
Signaling by Rho GTPases	6	5.1×	0.021	BUB1B, TUBA1A, TUBB4A, ADD3, KIDINS220, ALDH3A2
Anchoring fibril formation	2	38.1×	0.024	COL4A1, COL4A2
RHO GTPases Activate Formins	4	7.8×	0.032	BUB1B, TUBA1A, TUBB4A, RHOB
Transmission across Chemical Synapses	4	7.6×	0.032	SLC6A4, CACNA1A, TUBA1A, TUBB4A
Gamma-carboxylation, transport, and amino-terminal cleavage of proteins	1	285.5×	0.033	F2
Defective PMM2 causes PMM2-CDG	1	285.5×	0.033	PMM2
Defective factor VIII causes hemophilia A	1	285.5×	0.033	F2
Defective F8 accelerates dissociation of the A2 domain	1	285.5×	0.033	F8
Defective F8 binding to the cell membrane	1	285.5×	0.033	F8
Defective F8 secretion	1	285.5×	0.033	F8
SARS-CoV-1 targets PDZ proteins in cell-cell junction	1	285.5×	0.033	PALS1
Scavenging by Class A Receptors	2	30.1×	0.033	COL4A1, COL4A2
Fibronectin matrix formation	2	28.6×	0.033	COL4A1, COL4A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 53 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sesquiterpenoid metabolic process	1	318.0×	0.068	ALDH3A2
ribonucleotide metabolic process	1	318.0×	0.068	RNASEH2B
regulation of aldosterone biosynthetic process	1	318.0×	0.068	CLCN2
protein localization to myelin sheath abaxonal region	1	318.0×	0.068	PALS1
hexadecanal metabolic process	1	318.0×	0.068	ALDH3A2
coreceptor-mediated virion attachment to host cell	1	318.0×	0.068	NECTIN2
positive regulation of termination of DNA-templated transcription	1	318.0×	0.068	SETX
cell migration involved in coronary angiogenesis	1	318.0×	0.068	PDGFRB
metanephric glomerular mesangial cell proliferation involved in metanephros development	1	318.0×	0.068	PDGFRB
apical dendrite arborization	1	318.0×	0.068	CC2D1A
positive regulation of intracellular transport of viral material	1	318.0×	0.068	FMR1
negative regulation of cardiocyte differentiation	1	318.0×	0.068	EGFR
negative regulation of snRNA transcription by RNA polymerase II	1	318.0×	0.068	CC2D1A
dGTP catabolic process	1	159.0×	0.068	SAMHD1
deoxyribonucleotide catabolic process	1	159.0×	0.068	SAMHD1
positive regulation of serotonin secretion	1	159.0×	0.068	SLC6A4
nuclear migration along microfilament	1	159.0×	0.068	SYNE2
obsolete positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity	1	159.0×	0.068	HTT
negative regulation of DNA endoreduplication	1	159.0×	0.068	FBXO5
phytol metabolic process	1	159.0×	0.068	ALDH3A2
cell migration involved in vasculogenesis	1	159.0×	0.068	PDGFRB
dATP catabolic process	1	159.0×	0.068	SAMHD1
susceptibility to T cell mediated cytotoxicity	1	159.0×	0.068	NECTIN2
cell differentiation involved in salivary gland development	1	159.0×	0.068	CLCN2
obsolete GDP-D-mannose biosynthetic process from fructose-6-phosphate	1	159.0×	0.068	PMM2
smooth muscle cell chemotaxis	1	159.0×	0.068	PDGFRB
distal tubule morphogenesis	1	159.0×	0.068	KLHL3
regulation of thalamus size	1	159.0×	0.068	SLC6A4
regulation of membrane depolarization during action potential	1	159.0×	0.068	CLCN2
mitotic recombination-dependent replication fork processing	1	159.0×	0.068	BRCA2

Therapeutics

Drugs indicated for this disease

2 approved, 4 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Baclofen	Approved (phase 4)
Diazepam	Approved (phase 4)
Ibuprofen	Phase 3 (in late-stage trials)
Magnesium Sulfate Anhydrous	Phase 3 (in late-stage trials)
Nabiximols	Phase 3 (in late-stage trials)
Onabotulinumtoxina	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Autologous Cord Blood, Epoetin Beta, Filgrastim, Incobotulinumtoxina, Metformin, Sodium Chloride.

Drug target analysis

Approved (phase 4): 14 · Phase ≥3: 15 · Phased (≥1): 17 · Undrugged: 38

Druggability breadth: 28 of 55 evidence-associated genes (51%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
KDM7A	AMIODARONE
MAOB	CLOTRIMAZOLE
SLC6A4	CETIRIZINE
BUB1B	CERITINIB
CACNA1A	NIMODIPINE
CACNA1C	REMIFENTANIL
TUBA1A	COLCHICINE
TUBB4A	COLCHICINE
EGFR	LEVODOPA
F2	INDIGOTINDISULFONATE
GRIN2B	HALOPERIDOL
HTT	BEPRIDIL
PDGFRB	PONATINIB
PROC	MELAGATRAN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A4	422	4
EGFR	175	4
HTT	165	4
PDGFRB	102	4
CACNA1C	85	4
MAOB	52	4
F2	48	4
GRIN2B	35	4
TUBA1A	22	4
TUBB4A	21	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
AMIODARONE	4	CACNA1C, HTT, KDM7A, SLC6A4
CLOTRIMAZOLE	4	CACNA1C, EGFR, HTT, MAOB, SLC6A4
PHENELZINE	4	MAOB
SELEGILINE HYDROCHLORIDE	4	MAOB
RASAGILINE MESYLATE	4	MAOB
ROSIGLITAZONE	4	MAOB
TEDIZOLID	4	MAOB
LINEZOLID	4	MAOB
TOLOXATONE	4	MAOB
METHYLENE BLUE CATION	4	MAOB
SAFINAMIDE	4	MAOB
TRANYLCYPROMINE	4	MAOB
TROGLITAZONE	4	MAOB
ISTRADEFYLLINE	4	MAOB
DONEPEZIL	4	CACNA1C, MAOB
PRIMAQUINE	4	MAOB, SLC6A4
DANTHRON	4	HTT, MAOB
MENADIONE	4	MAOB
PIOGLITAZONE	4	MAOB
PARGYLINE	4	MAOB
ZONISAMIDE	4	MAOB
MOCLOBEMIDE	4	MAOB
RASAGILINE	4	MAOB
MICONAZOLE	4	EGFR, MAOB, SLC6A4
IPRONIAZID	4	MAOB
SELEGILINE	4	MAOB
FENTANYL	4	MAOB
CETIRIZINE	4	SLC6A4
BEPRIDIL	4	CACNA1C, HTT, SLC6A4
ACETOPHENAZINE	4	SLC6A4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

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

Symbol	Assays	Type breakdown
EGFR	6,531	Binding:6211, Functional:173, ADMET:138, Toxicity:9
TUBB4A	1,758	Binding:1718, Functional:34, ADMET:6
TUBA1A	1,696	Binding:1655, Functional:35, ADMET:6
MAOB	1,620	Binding:1587, Functional:14, ADMET:13, Toxicity:6
F2	1,269	Binding:1216, Functional:38, ADMET:13, Toxicity:2
PDGFRB	1,237	Binding:1213, Functional:16, ADMET:8
SLC6A4	1,055	Binding:1021, Functional:18, ADMET:9, Toxicity:6, Unclassified:1
CACNA1C	575	Binding:319, Functional:211, Toxicity:26, ADMET:19
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1
SMARCA4	230	Binding:207, ADMET:12, Functional:11
PROC	117	Binding:117
HTT	77	Binding:72, Functional:5
CACNA1A	19	Binding:18, Functional:1
BUB1B	12	Binding:12
GNB1	12	Binding:12
KDM7A	10	Binding:9, Functional:1
F8	8	Binding:8
RHOB	6	Binding:6
SAMHD1	4	Binding:3, Functional:1
MFN2	3	Binding:3
ALDH3A2	3	Binding:3
KLHL3	3	Binding:3
PMM2	3	Binding:3
SPAST	1	Binding:1
TTN	1	Binding:1
CLCN2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KDM7A	1.14.11.65	[histone H3]-dimethyl-L-lysine9 demethylase
RHOB	3.6.5.2	small monomeric GTPase
MAOB	1.4.3.4	monoamine oxidase
SPAST	5.6.1.1	microtubule-severing ATPase
BUB1B	2.7.11.1	non-specific serine/threonine protein kinase
TTN	2.7.11.1	non-specific serine/threonine protein kinase
ATP10A	7.6.2.1	P-type phospholipid transporter
SAMHD1	3.1.5.B1
RNASEH2B	3.1.26.4	ribonuclease H
EGFR	2.7.10.1	receptor protein-tyrosine kinase
F2	3.4.21.5	thrombin
ALDH3A2	1.2.1.48	long-chain-aldehyde dehydrogenase
PDGFRB	2.7.10.1	receptor protein-tyrosine kinase
PMM2	5.4.2.8	phosphomannomutase
PROC	3.4.21.69	activated protein C (thrombin-activated peptidase)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
MAOB	1,620
SLC6A4	1,055
SMARCA4	230
CACNA1C	575
TUBA1A	1,696
TUBB4A	1,758
EGFR	6,531
F2	1,269
GRIN2B	471
PDGFRB	1,237
PROC	117

Pharmacogenomics

Cohort genes with a PharmGKB record: 55; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
SLC6A4	1

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)
AMIODARONE	4	CACNA1C, HTT, KDM7A, SLC6A4
CLOTRIMAZOLE	4	CACNA1C, EGFR, HTT, MAOB, SLC6A4
PHENELZINE	4	MAOB
SELEGILINE HYDROCHLORIDE	4	MAOB
RASAGILINE MESYLATE	4	MAOB
ROSIGLITAZONE	4	MAOB
TEDIZOLID	4	MAOB
LINEZOLID	4	MAOB
TOLOXATONE	4	MAOB
METHYLENE BLUE CATION	4	MAOB
SAFINAMIDE	4	MAOB
TRANYLCYPROMINE	4	MAOB
TROGLITAZONE	4	MAOB
ISTRADEFYLLINE	4	MAOB
DONEPEZIL	4	CACNA1C, MAOB
PRIMAQUINE	4	MAOB, SLC6A4
DANTHRON	4	HTT, MAOB
MENADIONE	4	MAOB
PIOGLITAZONE	4	MAOB
PARGYLINE	4	MAOB
ZONISAMIDE	4	MAOB
MOCLOBEMIDE	4	MAOB
RASAGILINE	4	MAOB
MICONAZOLE	4	EGFR, MAOB, SLC6A4
IPRONIAZID	4	MAOB
SELEGILINE	4	MAOB
FENTANYL	4	MAOB
CETIRIZINE	4	SLC6A4
BEPRIDIL	4	CACNA1C, HTT, SLC6A4
ACETOPHENAZINE	4	SLC6A4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	14	KDM7A, MAOB, SLC6A4, BUB1B, CACNA1A, CACNA1C, TUBA1A, TUBB4A, EGFR, F2 (+4 more)
B	Phased (≥1) drug, not yet approved	3	SMARCA4, GNB1, PMM2
C	Druggable family + PDB, no drug	8	RHOB, SPAST, TTN, ASTN2, PALS1, RNASEH2B, ALDH3A2, NECTIN2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	30	TEP1, FBXO5, FBXO31, AGAP1, TENM1, RFX2, BRCA2, ATP10A, SAMHD1, ADAP2 (+20 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TEP1	0	—
FBXO5	0	—
FBXO31	0	—
AGAP1	0	—
RHOB	6	—
TENM1	0	—
RFX2	0	—
BRCA2	0	—
SPAST	1	—
TTN	1	—
ATP10A	0	—
SAMHD1	4	—
ADAP2	0	—
MFN2	3	—
ASTN2	0	—
SYNE2	0	—
PALS1	0	—
CLCN1	0	—
CLCN2	1	—
COL4A1	0	—
COL4A2	0	—
ADD3	0	—
PNPLA4	0	—
RNASEH2B	0	—
PIEZO2	0	—
AIFM3	0	—
ANKRD34A	0	—
ARHGAP31	0	—
KIDINS220	0	—
CC2D1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,347.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	957
PHASE2	37
PHASE3	31
PHASE1	24
PHASE4	16
PHASE1/PHASE2	16
EARLY_PHASE1	11
PHASE2/PHASE3	8

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT07524972	PHASE3	RECRUITING	Antenatal Magnesium Sulphate in High-Risk Preterm Patients
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00133861	PHASE2/PHASE3	COMPLETED	Botulinum Toxin Efficiency on Spasticity of Rectus Femoris and Semitendinosus Muscles as Functional Agonist and Antagonist Muscles
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01189058	PHASE2/PHASE3	UNKNOWN	Modulation of Brain Plasticity After Perinatal Stroke
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01489904	PHASE2/PHASE3	UNKNOWN	Application of Botulinum Toxin Type A in Salivary Glands in the Treatment of Drooling in Patients With Cerebral Palsy
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity
NCT01603628	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Lower Limb Spasticity
NCT01603641	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Lower Limb Spasticity
NCT01633736	PHASE3	UNKNOWN	Targeted Hip Strength Training in Children With Cerebral Palsy (CP)
NCT01832454	PHASE2/PHASE3	UNKNOWN	Safety and Efficacy of Bone Marrow MNC for the Treatment of Cerebral Palsy in Subjects Below 15 Years
NCT01898520	PHASE3	COMPLETED	A Safety, Efficacy and Tolerability Study of Sativex for the Treatment of Spasticity in Children Aged 8 to 18 Years
NCT01929434	PHASE3	COMPLETED	Efficacy of Stem Cell Transplantation Compared to Rehabilitation Treatment of Patients With Cerebral Paralysis
NCT02002884	PHASE3	COMPLETED	Dose-response Study of Efficacy and Safety of Botulinum Toxin Type A to Treat Spasticity of the Arm(s) or of Arm(s) and Leg(s) in Cerebral Palsy

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BACLOFEN	4	6
BOTULINUM TOXIN TYPE A	4	6
ALENDRONIC ACID	4	3
GLYCOPYRRONIUM	4	3
MAGNESIUM SULFATE	4	3
ROPIVACAINE	4	3
LIDOCAINE	4	2
AMANTADINE HYDROCHLORIDE	4	1
ATROPINE	4	1
CLONAZEPAM	4	1
DIAZEPAM	4	1
GABAPENTIN	4	1
HYDROCORTISONE	4	1
INCOBOTULINUMTOXINA	4	1
INULIN	4	1
LAMOTRIGINE	4	1
MANNITOL	4	1
NIFEDIPINE	4	1
ONABOTULINUMTOXINA	4	1
PAMIDRONIC ACID	4	1
RIMABOTULINUMTOXINB	4	1
SODIUM CHLORIDE	4	1
SORBITOL	4	1
TETRABENAZINE	4	1
TOPIRAMATE	4	1
TRIHEXYPHENIDYL	4	1
VALBENAZINE	4	1
LEUCINE	3	1
MAGNESIUM	3	1
MALTODEXTRIN	3	1