TH-deficient dopa-responsive dystonia

Summary

TH-deficient dopa-responsive dystonia (MONDO:0011551) is a disease caused by TH (GenCC Definitive), with 6 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: TH (GenCC Definitive)
• Cohort genes: 6
• ClinVar variants: 1,150
• Phenotypes (HPO): 33

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		50	Worldwide	Validated
Point prevalence	1-9 / 1 000 000		Europe	Validated

Signs & symptoms

Clinical features (HPO)

33 HPO clinical features (Orphanet curated; top 33 by frequency):

HPO ID	Term	Frequency
HP:0000508	Ptosis	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0001254	Lethargy	Frequent (30-79%)
HP:0001270	Motor delay	Frequent (30-79%)
HP:0001300	Parkinsonism	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001348	Brisk reflexes	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001762	Talipes equinovarus	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002063	Rigidity	Frequent (30-79%)
HP:0002066	Gait ataxia	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002071	Abnormality of extrapyramidal motor function	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002375	Hypokinesia	Frequent (30-79%)
HP:0002395	Lower limb hyperreflexia	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003781	Excessive salivation	Frequent (30-79%)
HP:0003785	Decreased CSF homovanillic acid concentration	Frequent (30-79%)
HP:0004373	Focal dystonia	Frequent (30-79%)
HP:0010553	Oculogyric crisis	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0030166	Night sweats	Frequent (30-79%)
HP:0001256	Intellectual disability, mild	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0007325	Generalized dystonia	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Very rare (<1-4%)
HP:0002448	Progressive encephalopathy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	TH-deficient dopa-responsive dystonia
Mondo ID	MONDO:0011551
OMIM	605407
Orphanet	101150
DOID	DOID:0051059
SNOMED CT	715827001
UMLS	C2673535
MedGen	382128
GARD	0001902
NORD	1810
Is cancer (heuristic)	no

Also known as: autosomal recessive dopa-responsive dystonia · autosomal recessive Segawa syndrome · DOPA responsive dystonia, autosomal recessive · Dopa-responsive dystonia, autosomal recessive · dopa-responsive dystonia, autosomal recessive · dystonia, DOPA responsive, autosomal recessive · DYT5b · Segawa syndrome, recessive · Tyrosine Hydroxylase Deficiency · tyrosine hydroxylase-deficient dopa-responsive dystonia

Data availability: 1,150 ClinVar variants · 5 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › TH-deficient dopa-responsive dystonia

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, autosomal recessive osteopetrosis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

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

600 retrieved; paginated sample, class counts are floors:

304 likely benign, 170 uncertain significance, 44 likely pathogenic, 27 pathogenic, 24 benign, 16 pathogenic/likely pathogenic, 11 conflicting classifications of pathogenicity, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1457228	NC_000011.9:g.(?2181023)(2193087_?)del	INS	Pathogenic	criteria provided, single submitter
1004173	NM_000360.4(TH):c.1382C>T (p.Pro461Leu)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068293	NM_000360.4(TH):c.488-1G>A	TH	Pathogenic	criteria provided, multiple submitters, no conflicts
1072805	NM_000360.4(TH):c.788del (p.Gly263fs)	TH	Pathogenic	criteria provided, single submitter
12324	NM_000360.4(TH):c.1141C>A (p.Gln381Lys)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12325	NM_000360.4(TH):c.614T>C (p.Leu205Pro)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12327	NM_000360.4(TH):c.605G>A (p.Arg202His)	TH	Pathogenic	criteria provided, multiple submitters, no conflicts
12328	NM_000360.4(TH):c.917G>A (p.Arg306His)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12331	NM_000360.4(TH):c.1105-24T>A	TH	Pathogenic	no assertion criteria provided
12332	NM_000360.4(TH):c.202del (p.Leu68fs)	TH	Pathogenic	no assertion criteria provided
1359133	NM_000360.4(TH):c.1138A>T (p.Lys380Ter)	TH	Pathogenic	criteria provided, single submitter
1371019	NM_000360.4(TH):c.281C>A (p.Ser94Ter)	TH	Pathogenic	criteria provided, single submitter
1390521	NM_000360.4(TH):c.1354C>T (p.Gln452Ter)	TH	Pathogenic	criteria provided, single submitter
1425111	NM_000360.4(TH):c.1210_1213del (p.Ser404fs)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452491	NM_000360.4(TH):c.374_387dup (p.Tyr130fs)	TH	Pathogenic	criteria provided, single submitter
1452616	NM_000360.4(TH):c.1189G>A (p.Gly397Arg)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1455671	NM_000360.4(TH):c.1125del (p.Glu375fs)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456177	NM_000360.4(TH):c.1122_1123delinsTT (p.Glu375Ter)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457222	NM_000360.4(TH):c.584C>A (p.Ser195Ter)	TH	Pathogenic	criteria provided, single submitter
1458504	NC_000011.9:g.(?2191910)(2193087_?)del	TH	Pathogenic	criteria provided, single submitter
1460233	NC_000011.9:g.(?2187460)(2191953_?)del	TH	Pathogenic	criteria provided, single submitter
188890	NM_000360.4(TH):c.1282C>T (p.Gln428Ter)	TH	Pathogenic	criteria provided, multiple submitters, no conflicts
1947375	NM_000360.4(TH):c.507del (p.Val170fs)	TH	Pathogenic	criteria provided, single submitter
1998536	NM_000360.4(TH):c.91-833dup	TH	Pathogenic	criteria provided, single submitter
2019062	NM_000360.4(TH):c.982_991del (p.Cys328fs)	TH	Pathogenic	criteria provided, single submitter
2025524	NM_000360.4(TH):c.837del (p.Lys280fs)	TH	Pathogenic	criteria provided, single submitter
2033133	NM_000360.4(TH):c.778del (p.Arg260fs)	TH	Pathogenic	criteria provided, single submitter
2039753	NM_000360.4(TH):c.1341T>A (p.Tyr447Ter)	TH	Pathogenic	criteria provided, single submitter
2052457	NM_000360.4(TH):c.1252dup (p.Ala418fs)	TH	Pathogenic	criteria provided, single submitter
2077702	NM_000360.4(TH):c.1147G>A (p.Gly383Arg)	TH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 4 · 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
TH	Definitive	Autosomal recessive	TH-deficient dopa-responsive dystonia	6
TSPOAP1	Strong	Autosomal recessive	dystonia 22, juvenile-onset	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TH	Orphanet:101150	Autosomal recessive dopa-responsive dystonia
TSPOAP1	Orphanet:101150	Autosomal recessive dopa-responsive dystonia
INS	Orphanet:552	MODY
INS	Orphanet:99885	Isolated permanent neonatal diabetes mellitus

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TH	HGNC:11782	ENSG00000180176	P07101	Tyrosine 3-monooxygenase	gencc,clinvar
TSPOAP1	HGNC:16831	ENSG00000005379	O95153	Peripheral-type benzodiazepine receptor-associated protein 1	gencc
KRTAP5-1	HGNC:23596	ENSG00000205869	Q6L8H4	Keratin-associated protein 5-1	clinvar
KRTAP5-9	HGNC:23604	ENSG00000254997	P26371	Keratin-associated protein 5-9	clinvar
INS	HGNC:6081	ENSG00000254647	P01308	Insulin	clinvar
LSP1	HGNC:6707	ENSG00000130592	P33241	Lymphocyte-specific protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TH	Tyrosine 3-monooxygenase	Catalyzes the conversion of L-tyrosine to L-dihydroxyphenylalanine (L-Dopa), the rate-limiting step in the biosynthesis of catecholamines, dopamine, noradrenaline, and adrenaline.
TSPOAP1	Peripheral-type benzodiazepine receptor-associated protein 1	Required for synaptic transmission regulation.
KRTAP5-1	Keratin-associated protein 5-1	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated protein (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through th…
KRTAP5-9	Keratin-associated protein 5-9	In the hair cortex, hair keratin intermediate filaments are embedded in an interfilamentous matrix, consisting of hair keratin-associated protein (KRTAP), which are essential for the formation of a rigid and resistant hair shaft through th…
INS	Insulin	Insulin decreases blood glucose concentration.
LSP1	Lymphocyte-specific protein 1	May play a role in mediating neutrophil activation and chemotaxis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.33

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
Antibody/Immunoglobulin	1	4.9×	0.458
Enzyme (other)	1	2.0×	0.458
Other/Unknown	4	1.2×	0.458

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TH	Enzyme (other)	yes	1.14.16.2	ArAA_hydroxylase, Tyr_3_mOase, ArAA_hydroxylase_Fe/CU_BS
TSPOAP1	Antibody/Immunoglobulin	yes		SH3_domain, FN3_dom, Ig-like_fold
KRTAP5-1	Other/Unknown	no
KRTAP5-9	Other/Unknown	no
INS	Other/Unknown	no		Insulin, Insulin-like, Ins/IGF/rlx
LSP1	Other/Unknown	no		Lymphspecific, Caldesmon_LSP

Expression context

Cohort genes with no expression data: 0.

4 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
type B pancreatic cell	2
male germ line stem cell (sensu Vertebrata) in testis	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
right frontal lobe	1
right uterine tube	1
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1
cervix squamous epithelium	1
endometrium epithelium	1
body of pancreas	1
islet of Langerhans	1
blood	1
leukocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TH	147	tissue_specific	marker	substantia nigra pars reticulata, substantia nigra pars compacta, male germ line stem cell (sensu Vertebrata) in testis
TSPOAP1	253	broad	marker	right uterine tube, right frontal lobe, granulocyte
KRTAP5-1	122		yes	cerebellar hemisphere, cerebellum, cerebellar cortex
KRTAP5-9	141		yes	cervix squamous epithelium, type B pancreatic cell, endometrium epithelium
INS	137	tissue_specific	marker	type B pancreatic cell, islet of Langerhans, body of pancreas
LSP1	140	broad	marker	granulocyte, blood, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
INS	11,670
TH	3,526
LSP1	1,243
KRTAP5-9	1,112
TSPOAP1	708
KRTAP5-1	108

Structural data

PDB: 3 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
INS	P01308	382
TH	P07101	7
LSP1	P33241	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TSPOAP1	O95153	57.91
KRTAP5-9	P26371	40.70
KRTAP5-1	Q6L8H4	38.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 44. Enrichment computed across 6 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Catecholamine biosynthesis	1	571.0×	0.025	TH
IRS activation	1	456.8×	0.025	INS
Signal attenuation	1	207.6×	0.025	INS
Signaling by Insulin receptor	1	175.7×	0.025	INS
Pregnenolone biosynthesis	1	163.1×	0.025	TSPOAP1
Regulation of beta-cell development	1	142.8×	0.025	INS
Acetylcholine Neurotransmitter Release Cycle	1	134.3×	0.025	TSPOAP1
Insulin receptor signalling cascade	1	134.3×	0.025	INS
Serotonin Neurotransmitter Release Cycle	1	126.9×	0.025	TSPOAP1
Norepinephrine Neurotransmitter Release Cycle	1	126.9×	0.025	TSPOAP1
Synthesis, secretion, and deacylation of Ghrelin	1	120.2×	0.025	INS
Transcriptional Regulation by NPAS4	1	114.2×	0.025	INS
Regulation of gene expression in beta cells	1	103.8×	0.025	INS
Dopamine Neurotransmitter Release Cycle	1	99.3×	0.025	TSPOAP1
NPAS4 regulates expression of target genes	1	99.3×	0.025	INS
Glutamate Neurotransmitter Release Cycle	1	91.4×	0.025	TSPOAP1
Insulin processing	1	91.4×	0.025	INS
Keratinization	2	22.3×	0.025	KRTAP5-1, KRTAP5-9
Developmental Biology	3	8.7×	0.025	KRTAP5-1, KRTAP5-9, INS
Insulin receptor recycling	1	76.1×	0.027	INS
FOXO-mediated transcription of oxidative stress, metabolic and neuronal genes	1	76.1×	0.027	INS
FOXO-mediated transcription	1	67.2×	0.030	INS
Negative regulation of the PI3K/AKT network	1	55.7×	0.033	INS
Peptide hormone metabolism	1	54.4×	0.033	INS
Regulation of insulin secretion	1	43.9×	0.040	INS
Integration of energy metabolism	1	35.1×	0.048	INS
ER to Golgi Anterograde Transport	1	26.6×	0.060	INS
COPI-mediated anterograde transport	1	22.0×	0.070	INS
Transport to the Golgi and subsequent modification	1	20.6×	0.070	INS
Amyloid fiber formation	1	20.6×	0.070	INS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dopamine biosynthetic process from tyrosine	1	3370.4×	0.010	TH
epinephrine biosynthetic process	1	1685.2×	0.010	TH
negative regulation of glycogen catabolic process	1	1685.2×	0.010	INS
positive regulation of nitric-oxide synthase activity	1	1123.5×	0.010	INS
obsolete positive regulation of nitric oxide mediated signal transduction	1	842.6×	0.010	INS
serotonin biosynthetic process	1	842.6×	0.010	TH
negative regulation of fatty acid metabolic process	1	842.6×	0.010	INS
negative regulation of feeding behavior	1	842.6×	0.010	INS
alpha-beta T cell activation	1	674.1×	0.010	INS
negative regulation of respiratory burst involved in inflammatory response	1	674.1×	0.010	INS
positive regulation of respiratory burst	1	674.1×	0.010	INS
positive regulation of dendritic spine maintenance	1	674.1×	0.010	INS
cognition	2	114.2×	0.010	TH, INS
mating behavior	1	561.7×	0.011	TH
negative regulation of acute inflammatory response	1	481.5×	0.011	INS
hyaloid vascular plexus regression	1	481.5×	0.011	TH
synaptic transmission, dopaminergic	1	421.3×	0.011	TH
norepinephrine biosynthetic process	1	421.3×	0.011	TH
dopamine biosynthetic process	1	374.5×	0.012	TH
nitric oxide-cGMP-mediated signaling	1	306.4×	0.012	INS
regulation of protein secretion	1	306.4×	0.012	INS
positive regulation of peptide hormone secretion	1	306.4×	0.012	INS
cellular response to interleukin-7	1	259.3×	0.014	LSP1
embryonic camera-type eye morphogenesis	1	224.7×	0.014	TH
neuron projection maintenance	1	224.7×	0.014	INS
positive regulation of glycogen biosynthetic process	1	198.3×	0.014	INS
positive regulation of brown fat cell differentiation	1	198.3×	0.014	INS
negative regulation of reactive oxygen species biosynthetic process	1	198.3×	0.014	INS
fatty acid homeostasis	1	187.2×	0.014	INS
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	187.2×	0.014	INS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 3 of 6 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TH	0	0
TSPOAP1	0	0
KRTAP5-1	0	0
KRTAP5-9	0	0
INS	0	0
LSP1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
TH	8	Binding:8
INS	8	Binding:7, ADMET:1
TSPOAP1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TH	1.14.16.2	tyrosine 3-monooxygenase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	TH
D	Druggable family + AlphaFold only, no drug	1	TSPOAP1
E	Difficult family or no structure, no drug	4	KRTAP5-1, KRTAP5-9, INS, LSP1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TH	8	—
TSPOAP1	1	—
KRTAP5-1	0	—
KRTAP5-9	0	—
INS	8	—
LSP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.