Choreatic disease

Summary

Choreatic disease (MONDO:0001595) is a disease (an umbrella term covering 5 Mondo subtypes) with 10 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 15
• Phenotypes (HPO): 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000	0.02	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

2 HPO clinical features (Orphanet curated; top 2 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)

Identifiers

Disease identifiers

Field	Value
Canonical name	choreatic disease
Mondo ID	MONDO:0001595
EFO	EFO:0004152
MeSH	D002819
Orphanet	1429
DOID	DOID:12859
ICD-11	829618737
NCIT	C84633
SNOMED CT	230298007, 230306001
UMLS	C0008489
MedGen	3420
GARD	0015152
Is cancer (heuristic)	no

Also known as: benign familial chorea · BHC · chorea, benign hereditary · hereditary benign chorea · hereditary progressive chorea without dementia

Data availability: 15 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 5 Mondo subtypes.

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

Related subtypes (53): cerebellar ataxia, chronic tic disorder, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, Unverricht-Lundborg syndrome, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

Subtypes (5): chorea gravidarum, choreoathetosis, familial inverted, chorea, benign familial, chorea, remitting, with nystagmus and cataract, hereditary progressive chorea without dementia

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

15 retrieved; paginated sample, class counts are floors:

7 pathogenic, 4 uncertain significance, 3 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
973107	NM_006796.3(AFG3L2):c.[1385C>T;1858C>A]		Pathogenic	no assertion criteria provided
8395	NM_000100.4(CSTB):c.67-1G>C	CSTB	Pathogenic	criteria provided, multiple submitters, no conflicts
218151	NM_014334.4(FRRS1L):c.808C>T (p.Gln270Ter)	FRRS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
218152	NM_014334.4(FRRS1L):c.692G>A (p.Trp231Ter)	FRRS1L	Pathogenic	criteria provided, single submitter
218153	NM_014334.4(FRRS1L):c.584_586del (p.Gly195del)	FRRS1L	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218154	NM_014334.4(FRRS1L):c.283dup (p.Ile95fs)	FRRS1L	Pathogenic	criteria provided, multiple submitters, no conflicts
420523	NM_020988.3(GNAO1):c.709G>A (p.Glu237Lys)	GNAO1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1801521	NM_001079668.3(NKX2-1):c.626G>C (p.Arg209Pro)	NKX2-1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689477	NM_002599.5(PDE2A):c.1180C>T (p.Gln394Ter)	PDE2A	Pathogenic	criteria provided, single submitter
545418	NM_015178.3(RHOBTB2):c.1466G>A (p.Arg489Gln)	RHOBTB2	Pathogenic	criteria provided, multiple submitters, no conflicts
812779	NM_020988.3(GNAO1):c.545C>T (p.Thr182Ile)	GNAO1	Likely pathogenic	no assertion criteria provided
397544	NM_001127222.2(CACNA1A):c.2393A>T (p.Asp798Val)	CACNA1A	Uncertain significance	criteria provided, single submitter
373927	NM_001130823.3(DNMT1):c.2718C>G (p.Phe906Leu)	DNMT1	Uncertain significance	criteria provided, single submitter
916131	NC_000006.12:g.106539151_106629957del	LOC129389600	Uncertain significance	criteria provided, single submitter
916015	NM_032730.5(RTN4IP1):c.263T>G (p.Val88Gly)	RTN4IP1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 24 · 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
ADCY5	Supportive	Autosomal dominant	choreatic disease	7
NKX2-1	Supportive	Autosomal dominant	choreatic disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NKX2-1	Orphanet:1429	Benign hereditary chorea
NKX2-1	Orphanet:146	Differentiated thyroid carcinoma
NKX2-1	Orphanet:209905	Brain-lung-thyroid syndrome
NKX2-1	Orphanet:95713	Athyreosis
ADCY5	Orphanet:1429	Benign hereditary chorea
ADCY5	Orphanet:324588	Familial dyskinesia and facial myokymia
FRRS1L	Orphanet:725	Developmental and epileptic encephalopathy with spike-wave activation in sleep
FRRS1L	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
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
RTN4IP1	Orphanet:98676	Autosomal recessive isolated optic atrophy
RHOBTB2	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
RHOBTB2	Orphanet:2131	Alternating hemiplegia of childhood
CSTB	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia
CSTB	Orphanet:308	Progressive myoclonic epilepsy type 1
DNMT1	Orphanet:314404	Autosomal dominant cerebellar ataxia-deafness-narcolepsy syndrome
DNMT1	Orphanet:456318	Hereditary sensory neuropathy-deafness-dementia syndrome
GNAO1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
GNAO1	Orphanet:592564	GNAO1-related developmental delay-seizures-movement disorder spectrum

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NKX2-1	HGNC:11825	ENSG00000136352	P43699	Homeobox protein Nkx-2.1	gencc,clinvar
ADCY5	HGNC:236	ENSG00000173175	O95622	Adenylate cyclase type 5	gencc
FRRS1L	HGNC:1362	ENSG00000260230	Q9P0K9	DOMON domain-containing protein FRRS1L	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
RTN4IP1	HGNC:18647	ENSG00000130347	Q8WWV3	NAD(P)H oxidoreductase RTN4IP1, mitochondrial	clinvar
RHOBTB2	HGNC:18756	ENSG00000008853	Q9BYZ6	Rho-related BTB domain-containing protein 2	clinvar
CSTB	HGNC:2482	ENSG00000160213	P04080	Cystatin-B	clinvar
DNMT1	HGNC:2976	ENSG00000130816	P26358	DNA (cytosine-5)-methyltransferase 1	clinvar
GNAO1	HGNC:4389	ENSG00000087258	P09471	Guanine nucleotide-binding protein G(o) subunit alpha	clinvar
PDE2A	HGNC:8777	ENSG00000186642	O00408	cGMP-dependent 3’,5’-cyclic phosphodiesterase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NKX2-1	Homeobox protein Nkx-2.1	Transcription factor that binds and activates the promoter of thyroid specific genes such as thyroglobulin, thyroperoxidase, and thyrotropin receptor.
ADCY5	Adenylate cyclase type 5	Catalyzes the formation of the signaling molecule cAMP in response to G-protein signaling.
FRRS1L	DOMON domain-containing protein FRRS1L	Important modulator of glutamate signaling pathway.
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…
RTN4IP1	NAD(P)H oxidoreductase RTN4IP1, mitochondrial	NAD(P)H oxidoreductase involved in the ubiquinone biosynthetic pathway.
RHOBTB2	Rho-related BTB domain-containing protein 2	Regulator of cell proliferation and apoptosis.
CSTB	Cystatin-B	This is an intracellular thiol proteinase inhibitor.
DNMT1	DNA (cytosine-5)-methyltransferase 1	DNA methyltransferase that methylates CpG residues.
GNAO1	Guanine nucleotide-binding protein G(o) subunit alpha	Guanine nucleotide-binding proteins (G proteins) function as transducers downstream of G protein-coupled receptors (GPCRs) in numerous signaling cascades.
PDE2A	cGMP-dependent 3’,5’-cyclic phosphodiesterase	cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.

Protein-family classification

Druggable: 2 · Difficult: 3 · Unknown: 5 · Druggable fraction: 0.2

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	1	11.2×	0.222
Transcription factor	3	2.5×	0.222
Enzyme (other)	1	1.2×	0.756
Other/Unknown	5	0.9×	0.756

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NKX2-1	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
ADCY5	Enzyme (other)	yes	4.6.1.1	A/G_cyclase, Adcy_conserved_dom, A/G_cyclase_CS
FRRS1L	Other/Unknown	no		DOMON_domain, FRRS1L
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
RTN4IP1	Other/Unknown	no		Quin_OxRdtase/zeta-crystal_CS, GroES-like_sf, ADH-like_N
RHOBTB2	Other/Unknown	no		BTB/POZ_dom, Small_GTPase, Small_GTPase_Rho
CSTB	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS
DNMT1	Transcription factor	no	2.1.1.37	BAH_dom, C5_MeTfrase, Znf_CXXC
GNAO1	Other/Unknown	no		Gprotein_alpha_su, Gprotein_alpha_I, GproteinA_insert
PDE2A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, GAF, HD/PDEase_dom

Expression context

Cohort genes with no expression data: 0.

9 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
secondary oocyte	2
right frontal lobe	2
left lobe of thyroid gland	1
right lobe of thyroid gland	1
thyroid gland	1
apex of heart	1
lower esophagus	1
lower esophagus muscularis layer	1
Brodmann (1909) area 23	1
middle temporal gyrus	1
orbitofrontal cortex	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
primordial germ cell in gonad	1
upper lobe of left lung	1
upper lobe of lung	1
lower esophagus mucosa	1
pharyngeal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NKX2-1	101	broad	marker	right lobe of thyroid gland, left lobe of thyroid gland, thyroid gland
ADCY5	193	broad	marker	apex of heart, lower esophagus muscularis layer, lower esophagus
FRRS1L	189	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, orbitofrontal cortex
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
RTN4IP1	223	ubiquitous	yes	secondary oocyte, oocyte, primordial germ cell in gonad
RHOBTB2	213	ubiquitous	marker	upper lobe of left lung, upper lobe of lung, right frontal lobe
CSTB	300	ubiquitous	marker	lower esophagus mucosa, tongue squamous epithelium, pharyngeal mucosa
DNMT1	266	ubiquitous	marker	oocyte, secondary oocyte, sural nerve
GNAO1	261	broad	marker	cortical plate, superficial temporal artery, entorhinal cortex
PDE2A	224	broad	marker	spleen, right frontal lobe, prefrontal cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DNMT1	7,179
GNAO1	3,437
RHOBTB2	2,577
NKX2-1	2,403
ADCY5	1,992
CSTB	1,987
RTN4IP1	1,969
FRRS1L	1,714
PDE2A	1,283
CACNA1A	346

Intra-cohort edges

A	B	Sources
ADCY5	PDE2A	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNAO1	P09471	86
PDE2A	O00408	44
DNMT1	P26358	27
CACNA1A	O00555	4
CSTB	P04080	3
NKX2-1	P43699	2
ADCY5	O95622	2
RTN4IP1	Q8WWV3	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RHOBTB2	Q9BYZ6	81.89
FRRS1L	Q9P0K9	80.60

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 61. Enrichment computed across 10 evidence-associated genes (7 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 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of insulin secretion	2	62.8×	0.020	CACNA1A, ADCY5
Integration of energy metabolism	2	50.2×	0.020	CACNA1A, ADCY5
Adenylate cyclase activating pathway	1	163.1×	0.045	ADCY5
STAT3 nuclear events downstream of ALK signaling	1	148.3×	0.045	DNMT1
Presynaptic depolarization and calcium channel opening	1	135.9×	0.045	CACNA1A
Adenylate cyclase inhibitory pathway	1	108.8×	0.045	ADCY5
cGMP effects	1	102.0×	0.045	PDE2A
PKA activation in glucagon signalling	1	96.0×	0.045	ADCY5
SUMOylation of DNA methylation proteins	1	96.0×	0.045	DNMT1
PKA activation	1	90.6×	0.045	ADCY5
Activation of GABAB receptors	1	85.9×	0.045	ADCY5
PKA-mediated phosphorylation of CREB	1	81.6×	0.045	ADCY5
GABA B receptor activation	1	77.7×	0.045	ADCY5
RHOBTB2 GTPase cycle	1	68.0×	0.045	RHOBTB2
Adrenaline,noradrenaline inhibits insulin secretion	1	56.3×	0.045	ADCY5
Anti-inflammatory response favouring Leishmania parasite infection	1	56.3×	0.045	ADCY5
Leishmania parasite growth and survival	1	56.3×	0.045	ADCY5
Calmodulin induced events	1	54.4×	0.045	ADCY5
CaM pathway	1	54.4×	0.045	ADCY5
Ca-dependent events	1	52.6×	0.045	ADCY5
Aquaporin-mediated transport	1	52.6×	0.045	ADCY5
Glucagon signaling in metabolic regulation	1	49.4×	0.045	ADCY5
G-protein mediated events	1	46.6×	0.045	ADCY5
Nuclear events stimulated by ALK signaling in cancer	1	46.6×	0.045	DNMT1
DAG and IP3 signaling	1	45.3×	0.045	ADCY5
GABA receptor activation	1	45.3×	0.045	ADCY5
Response of endothelial cells to shear stress	1	42.9×	0.045	ADCY5
FCGR3A-mediated IL10 synthesis	1	41.8×	0.045	ADCY5
Opioid Signalling	1	37.9×	0.045	ADCY5
PLC beta mediated events	1	37.9×	0.045	ADCY5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
locomotory behavior	3	53.8×	0.002	NKX2-1, ADCY5, GNAO1
epigenetic programming of gene expression	1	1685.2×	0.019	DNMT1
developmental induction	1	842.6×	0.019	NKX2-1
obsolete negative regulation of vascular associated smooth muscle cell differentiation involved in phenotypic switching	1	842.6×	0.019	DNMT1
cerebral cortex GABAergic interneuron differentiation	1	561.7×	0.019	NKX2-1
cellular response to 2,3,7,8-tetrachlorodibenzodioxine	1	561.7×	0.019	PDE2A
regulation of AMPA glutamate receptor clustering	1	561.7×	0.019	FRRS1L
negative regulation of vascular associated smooth muscle cell apoptotic process	1	561.7×	0.019	DNMT1
chromosomal DNA methylation maintenance following DNA replication	1	421.3×	0.019	DNMT1
adenylate cyclase-inhibiting dopamine receptor signaling pathway	1	337.0×	0.019	ADCY5
globus pallidus development	1	337.0×	0.019	NKX2-1
forebrain neuron fate commitment	1	337.0×	0.019	NKX2-1
cellular response to macrophage colony-stimulating factor stimulus	1	337.0×	0.019	PDE2A
cGMP catabolic process	1	337.0×	0.019	PDE2A
club cell differentiation	1	337.0×	0.019	NKX2-1
regulation of glutamate receptor signaling pathway	1	337.0×	0.019	FRRS1L
cellular response to bisphenol A	1	337.0×	0.019	DNMT1
adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway	2	43.8×	0.019	GNAO1, PDE2A
positive regulation of cytosolic calcium ion concentration	2	23.4×	0.019	CACNA1A, ADCY5
positive regulation of gene expression	3	11.6×	0.019	NKX2-1, DNMT1, PDE2A
negative regulation of receptor guanylyl cyclase signaling pathway	1	280.9×	0.020	PDE2A
G protein-coupled adenosine receptor signaling pathway	1	240.7×	0.022	ADCY5
forebrain dorsal/ventral pattern formation	1	210.7×	0.022	NKX2-1
lung saccule development	1	210.7×	0.022	NKX2-1
type II pneumocyte differentiation	1	210.7×	0.022	NKX2-1
cellular response to cGMP	1	210.7×	0.022	PDE2A
G protein-coupled dopamine receptor signaling pathway	1	187.2×	0.022	GNAO1
anatomical structure formation involved in morphogenesis	1	187.2×	0.022	NKX2-1
adenylate cyclase-inhibiting serotonin receptor signaling pathway	1	168.5×	0.022	GNAO1
cortical cytoskeleton organization	1	168.5×	0.022	RHOBTB2

Therapeutics

Drugs indicated for this disease

1 approved. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Tetrabenazine	Approved (phase 4)

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 7

Druggability breadth: 6 of 10 evidence-associated genes (60%) 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
CACNA1A	NIMODIPINE
DNMT1	DECITABINE
PDE2A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PDE2A	12	4
DNMT1	6	4
CACNA1A	2	4
NKX2-1	0	0
ADCY5	0	0
FRRS1L	0	0
RTN4IP1	0	0
RHOBTB2	0	0
CSTB	0	0
GNAO1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
VARDENAFIL	4	PDE2A
CLOFARABINE	4	PDE2A
SILDENAFIL	4	PDE2A
ANAGRELIDE	4	PDE2A
DIPYRIDAMOLE	4	PDE2A
EPIGALOCATECHIN GALLATE	3	DNMT1
PAPAVERINE	3	PDE2A
MOLIBRESIB	2	DNMT1
GENISTEIN	2	DNMT1
BUFROLIN	2	PDE2A
ZAPRINAST	2	PDE2A
JNJ-42396302	1	PDE2A
PF-05180999	1	PDE2A
LENRISPODUN PHOSPHATE	1	PDE2A
TAK-915	1	PDE2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 3.

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

Symbol	Assays	Type breakdown
PDE2A	346	Binding:331, ADMET:8, Functional:7
DNMT1	233	Binding:229, Functional:3, ADMET:1
ADCY5	43	Binding:33, Functional:9, ADMET:1
CACNA1A	19	Binding:18, Functional:1
GNAO1	12	Functional:10, Binding:2
CSTB	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADCY5	4.6.1.1	adenylate cyclase
DNMT1	2.1.1.37	DNA (cytosine-5-)-methyltransferase
PDE2A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
DNMT1	233
PDE2A	346

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

20 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)
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A
DECITABINE	4	DNMT1
AZACITIDINE	4	DNMT1
CEPHALOTHIN	4	DNMT1
VARDENAFIL	4	PDE2A
CLOFARABINE	4	PDE2A
SILDENAFIL	4	PDE2A
ANAGRELIDE	4	PDE2A
DIPYRIDAMOLE	4	PDE2A
EPIGALOCATECHIN GALLATE	3	DNMT1
PAPAVERINE	3	PDE2A
MOLIBRESIB	2	DNMT1
GENISTEIN	2	DNMT1
BUFROLIN	2	PDE2A
ZAPRINAST	2	PDE2A
JNJ-42396302	1	PDE2A
PF-05180999	1	PDE2A
LENRISPODUN PHOSPHATE	1	PDE2A
TAK-915	1	PDE2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CACNA1A, DNMT1, PDE2A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	ADCY5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	NKX2-1, FRRS1L, RTN4IP1, RHOBTB2, CSTB, GNAO1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NKX2-1	0	—
ADCY5	43	—
FRRS1L	0	—
RTN4IP1	0	—
RHOBTB2	0	—
CSTB	1	—
GNAO1	12	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.