BH4-deficient hyperphenylalaninemia A

Summary

BH4-deficient hyperphenylalaninemia A (MONDO:0009863) is a disease caused by variants in PTS and SPR, with 7 cohort genes. The dominant Reactome pathway is Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation (3 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal genes: PTS (GenCC Definitive), SPR (GenCC Strong)
• Cohort genes: 7
• ClinVar variants: 326
• Phenotypes (HPO): 31

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	<1 / 1 000 000		Europe	Validated
Prevalence at birth	<1 / 1 000 000	0.0854	Brazil	Validated
Prevalence at birth	1-9 / 1 000 000	0.3094	China	Validated
Prevalence at birth	1-9 / 100 000	2.5258	Hong Kong	Validated

Signs & symptoms

Clinical features (HPO)

31 HPO clinical features (Orphanet curated; top 31 by frequency):

HPO ID	Term	Frequency
HP:0001252	Hypotonia	Frequent (30-79%)
HP:0002179	Opisthotonus	Frequent (30-79%)
HP:0001332	Dystonia	Occasional (5-29%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000711	Restlessness	Occasional (5-29%)
HP:0000713	Agitation	Occasional (5-29%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0002015	Dysphagia	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002067	Bradykinesia	Occasional (5-29%)
HP:0002071	Abnormality of extrapyramidal motor function	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0002421	Poor head control	Occasional (5-29%)
HP:0002487	Hyperkinetic movements	Occasional (5-29%)
HP:0002521	Hypsarrhythmia	Occasional (5-29%)
HP:0002527	Falls	Occasional (5-29%)
HP:0003781	Excessive salivation	Occasional (5-29%)
HP:0010553	Oculogyric crisis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	BH4-deficient hyperphenylalaninemia A
Mondo ID	MONDO:0009863
MeSH	C535325
OMIM	261640
Orphanet	13
DOID	DOID:0090106
NCIT	C138171
SNOMED CT	237914002
UMLS	C0878676
MedGen	209234
GARD	0005682
Is cancer (heuristic)	no

Also known as: 6-pyruvoyl tetrahydropterin synthase deficiency · 6-pyruvoyl-tetrahydropterin synthase deficiency · BH4-deficient hyperphenylalaninemia A · Bh4-deficient hyperphenylalaninemia type A · HPABH4A · hyperphenylalanemia, BH4-deficient, A · hyperphenylalaninemia due to 6-pyruvoyl-tetrahydropterin synthase deficiency · hyperphenylalaninemia due to 6-pyruvoyltetrahydropterin synthase deficiency · hyperphenylalaninemia, BH4-deficient A · hyperphenylalaninemia, BH4-deficient, A · hyperphenylalaninemia, BH4-deficient, type A · hyperphenylalaninemia, Bh4-deficient, type a · hyperphenylalaninemia, tetrahydrobiopterin-deficient, due to PTS deficiency · PTS deficiency · PTS deficiency hyperphenylalaninemia, BH4-deficient, due to partial PTS deficiency, included

Data availability: 326 ClinVar variants · 6 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 › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › hyperphenylalaninemia due to tetrahydrobiopterin deficiency › BH4-deficient hyperphenylalaninemia A

Related subtypes (3): dihydropteridine reductase deficiency, pterin-4 alpha-carbinolamine dehydratase 1 deficiency, GTP cyclohydrolase I deficiency with hyperphenylalaninemia

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

326 retrieved; paginated sample, class counts are floors:

131 likely benign, 48 uncertain significance, 47 pathogenic, 43 likely pathogenic, 29 pathogenic/likely pathogenic, 20 conflicting classifications of pathogenicity, 6 benign, 2 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1067052	NM_000317.3(PTS):c.-24_9del	LOC130006765	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067348	NM_000317.3(PTS):c.1A>G (p.Met1Val)	LOC130006765	Pathogenic	criteria provided, single submitter
1073651	NM_000317.3(PTS):c.74_76dup (p.Leu26Ter)	LOC130006765	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1308635	NM_000317.3(PTS):c.78G>T (p.Leu26Phe)	LOC130006765	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2704000	NM_000317.3(PTS):c.3G>T (p.Met1Ile)	LOC130006765	Pathogenic	criteria provided, single submitter
463153	NM_000317.3(PTS):c.73C>G (p.Arg25Gly)	LOC130006765	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
476	NM_000317.3(PTS):c.74G>A (p.Arg25Gln)	LOC130006765	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4818153	NM_000317.3(PTS):c.3G>A (p.Met1Ile)	LOC130006765	Pathogenic	criteria provided, single submitter
552463	NM_000317.3(PTS):c.26G>A (p.Arg9His)	LOC130006765	Pathogenic	criteria provided, multiple submitters, no conflicts
859996	NM_000317.3(PTS):c.73C>T (p.Arg25Ter)	LOC130006765	Pathogenic	criteria provided, multiple submitters, no conflicts
102677	NM_000277.3(PAH):c.442-5C>G	PAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102724	NM_000277.3(PAH):c.527G>A (p.Arg176Gln)	PAH	Pathogenic	reviewed by expert panel
102766	NM_000277.3(PAH):c.631C>A (p.Pro211Thr)	PAH	Pathogenic	reviewed by expert panel
102912	NM_000277.3(PAH):c.964G>A (p.Ala322Thr)	PAH	Pathogenic	reviewed by expert panel
628	NM_000277.3(PAH):c.1139C>T (p.Thr380Met)	PAH	Pathogenic	reviewed by expert panel
631	NM_000277.3(PAH):c.527G>T (p.Arg176Leu)	PAH	Pathogenic	reviewed by expert panel
92746	NM_000277.3(PAH):c.533A>G (p.Glu178Gly)	PAH	Pathogenic	reviewed by expert panel
1067696	NM_000317.3(PTS):c.367C>T (p.Pro123Ser)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068717	NC_000011.9:g.(?112096088)(112105696_?)del	PTS	Pathogenic	criteria provided, single submitter
1073772	NM_000317.3(PTS):c.407A>T (p.Asp136Val)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076000	NM_000317.3(PTS):c.236_239del (p.Tyr79fs)	PTS	Pathogenic	criteria provided, single submitter
1378622	NM_000317.3(PTS):c.174_175del (p.Val59fs)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1417019	NM_000317.3(PTS):c.314+2T>C	PTS	Pathogenic	criteria provided, single submitter
1451742	NM_000317.3(PTS):c.384T>A (p.Tyr128Ter)	PTS	Pathogenic	criteria provided, single submitter
1452334	NC_000011.9:g.(?112097157)(112104288_?)del	PTS	Pathogenic	criteria provided, single submitter
1453083	NM_000317.3(PTS):c.331G>A (p.Ala111Thr)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453091	NM_000317.3(PTS):c.399C>A (p.Tyr133Ter)	PTS	Pathogenic	criteria provided, single submitter
1455604	NM_000317.3(PTS):c.379C>T (p.Leu127Phe)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458067	NM_000317.3(PTS):c.200C>A (p.Thr67Lys)	PTS	Pathogenic	criteria provided, single submitter
1458069	NM_000317.3(PTS):c.243G>A (p.Glu81=)	PTS	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 10 · 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
PTS	Definitive	Autosomal recessive	BH4-deficient hyperphenylalaninemia A	5
SPR	Strong	Autosomal recessive	BH4-deficient hyperphenylalaninemia A	7
TACR1	Strong	Autosomal recessive	BH4-deficient hyperphenylalaninemia A	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PTS	Orphanet:13	6-pyruvoyl-tetrahydropterin synthase deficiency
SPR	Orphanet:70594	Dopa-responsive dystonia due to sepiapterin reductase deficiency
ALG9	Orphanet:730	Autosomal dominant polycystic kidney disease
ALG9	Orphanet:79328	ALG9-CDG
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria
QDPR	Orphanet:226	Dihydropteridine reductase deficiency

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PTS	HGNC:9689	ENSG00000150787	Q03393	6-pyruvoyl tetrahydrobiopterin synthase	gencc,clinvar
SPR	HGNC:11257	ENSG00000116096	P35270	Sepiapterin reductase	gencc
TACR1	HGNC:11526	ENSG00000115353	P25103	Substance-P receptor	gencc
ALG9	HGNC:15672	ENSG00000086848	Q9H6U8	Alpha-1,2-mannosyltransferase ALG9	clinvar
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	clinvar
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	clinvar
QDPR	HGNC:9752	ENSG00000151552	P09417	Dihydropteridine reductase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PTS	6-pyruvoyl tetrahydrobiopterin synthase	Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases.
SPR	Sepiapterin reductase	Catalyzes the final one or two reductions in tetra-hydrobiopterin biosynthesis to form 5,6,7,8-tetrahydrobiopterin.
TACR1	Substance-P receptor	Receptor for the tachykinin substance P, also able to bind and respond to tachynins neurokinin A/substance K and neurokinin B/neuromedin-K.
ALG9	Alpha-1,2-mannosyltransferase ALG9	Mannosyltransferase that operates in the biosynthetic pathway of dolichol-linked oligosaccharides, the glycan precursors employed in protein asparagine (N)-glycosylation.
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
QDPR	Dihydropteridine reductase	Catalyzes the conversion of quinonoid dihydrobiopterin into tetrahydrobiopterin.

Protein-family classification

Druggable: 7 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	6	10.3×	4e-06
GPCR	1	3.4×	0.258

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PTS	Enzyme (other)	yes	4.2.3.12	6-PTP_synth/QueD, PTPS_His_AS, PTPS_Cys_AS
SPR	Enzyme (other)	yes	1.1.1.153	SDR_fam, Sepiapterin_red, NAD(P)-bd_dom_sf
TACR1	GPCR	yes		NK1_rcpt, GPCR_Rhodpsn, Neurokn_rcpt
ALG9	Enzyme (other)	yes	2.4.1.259	GPI_mannosylTrfase
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra
QDPR	Enzyme (other)	yes	1.5.1.34	SDR_fam, Sc_DH/Rdtase_CS, NAD(P)-bd_dom_sf

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right adrenal gland	2
right lobe of liver	2
adrenal tissue	1
left adrenal gland cortex	1
mucosa of transverse colon	1
endocervix	1
male germ line stem cell (sensu Vertebrata) in testis	1
subcutaneous adipose tissue	1
body of pancreas	1
endothelial cell	1
ganglionic eminence	1
oocyte	1
secondary oocyte	1
type B pancreatic cell	1
gall bladder	1
liver	1
inferior vagus X ganglion	1
lateral globus pallidus	1
superior vestibular nucleus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PTS	298	ubiquitous	marker	adrenal tissue, right adrenal gland, left adrenal gland cortex
SPR	255	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, right adrenal gland
TACR1	183	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, endocervix, subcutaneous adipose tissue
ALG9	240	ubiquitous	marker	endothelial cell, body of pancreas, ganglionic eminence
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell
PAH	175	broad	marker	right lobe of liver, liver, gall bladder
QDPR	283	ubiquitous	marker	inferior vagus X ganglion, lateral globus pallidus, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 10.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
QDPR	3,732
SPR	3,029
GCH1	2,123
PAH	1,953
PTS	1,897
TACR1	1,350
ALG9	1,167

Intra-cohort edges

A	B	Sources
GCH1	PAH	string_interaction
GCH1	PTS	string_interaction
GCH1	QDPR	string_interaction
GCH1	SPR	string_interaction
PAH	PTS	string_interaction
PAH	QDPR	biogrid_interaction, string_interaction
PAH	SPR	string_interaction
PTS	QDPR	string_interaction
PTS	SPR	string_interaction
QDPR	SPR	biogrid_interaction, string_interaction

Structural data

PDB: 7 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PAH	P00439	20
TACR1	P25103	15
SPR	P35270	14
GCH1	P30793	11
ALG9	Q9H6U8	2
QDPR	P09417	2
PTS	Q03393	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 7 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
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	3	489.4×	4e-07	PTS, SPR, GCH1
Phenylalanine metabolism	2	543.8×	5e-05	PAH, QDPR
Phenylketonuria	1	1631.4×	0.003	PAH
Defective ALG9 causes CDG-1l	1	1631.4×	0.003	ALG9
Metabolism of nitric oxide: NOS3 activation and regulation	1	326.3×	0.011	SPR
Tachykinin receptors bind tachykinins	1	271.9×	0.011	TACR1
Metabolism of cofactors	1	271.9×	0.011	SPR
eNOS activation	1	125.5×	0.021	SPR
Diseases associated with N-glycosylation of proteins	1	90.6×	0.026	ALG9
Biosynthesis of the N-glycan precursor (dolichol lipid-linked oligosaccharide, LLO) and transfer to a nascent protein	1	29.7×	0.070	ALG9
Diseases of glycosylation	1	18.8×	0.100	ALG9
Metabolism of vitamins and cofactors	1	16.6×	0.102	SPR
Cargo recognition for clathrin-mediated endocytosis	1	15.0×	0.105	TACR1
Clathrin-mediated endocytosis	1	12.2×	0.117	TACR1
Diseases of metabolism	1	11.5×	0.117	ALG9
Asparagine N-linked glycosylation	1	8.6×	0.143	ALG9
G alpha (q) signalling events	1	8.2×	0.143	TACR1
Post-translational protein modification	1	2.7×	0.365	ALG9
Disease	1	1.9×	0.468	ALG9
Metabolism of proteins	1	1.8×	0.468	ALG9
Metabolism	1	1.7×	0.468	SPR

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tetrahydrobiopterin biosynthetic process	4	1375.7×	2e-11	PTS, SPR, GCH1, QDPR
L-phenylalanine catabolic process	2	601.9×	1e-04	PAH, QDPR
amino acid metabolic process	2	229.3×	7e-04	PTS, QDPR
nitric oxide biosynthetic process	2	200.6×	7e-04	SPR, GCH1
L-tyrosine biosynthetic process	1	2407.4×	0.003	PAH
amino acid biosynthetic process	1	2407.4×	0.003	PAH
pteridine-containing compound biosynthetic process	1	2407.4×	0.003	GCH1
dihydrobiopterin metabolic process	1	2407.4×	0.003	QDPR
regulation of lung blood pressure	1	1203.7×	0.006	GCH1
angiotensin-mediated drinking behavior	1	802.5×	0.007	TACR1
catecholamine biosynthetic process	1	802.5×	0.007	PAH
positive regulation of nitric-oxide synthase activity	1	802.5×	0.007	GCH1
aggressive behavior	1	601.9×	0.007	TACR1
phospholipase C-activating tachykinin receptor signaling pathway	1	601.9×	0.007	TACR1
smooth muscle contraction involved in micturition	1	601.9×	0.007	TACR1
detection of abiotic stimulus	1	481.5×	0.007	TACR1
response to ozone	1	481.5×	0.007	TACR1
positive regulation of synaptic transmission, cholinergic	1	481.5×	0.007	TACR1
sperm ejaculation	1	481.5×	0.007	TACR1
tetrahydrofolate biosynthetic process	1	401.2×	0.008	GCH1
regulation of removal of superoxide radicals	1	401.2×	0.008	GCH1
regulation of smooth muscle cell migration	1	343.9×	0.008	TACR1
operant conditioning	1	343.9×	0.008	TACR1
positive regulation of action potential	1	300.9×	0.008	TACR1
positive regulation of uterine smooth muscle contraction	1	300.9×	0.008	TACR1
tachykinin receptor signaling pathway	1	267.5×	0.009	TACR1
dopamine biosynthetic process	1	267.5×	0.009	GCH1
positive regulation of lymphocyte proliferation	1	267.5×	0.009	TACR1
positive regulation of hormone secretion	1	240.7×	0.009	TACR1
positive regulation of vascular permeability	1	185.2×	0.011	TACR1

Therapeutics

Drug target analysis

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

Druggability breadth: 5 of 7 evidence-associated genes (71%) 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
TACR1	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TACR1	42	4
PTS	0	0
SPR	0	0
ALG9	0	0
GCH1	0	0
PAH	0	0
QDPR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	TACR1
ARIPIPRAZOLE	4	TACR1
AMOXAPINE	4	TACR1
THIOTHIXENE	4	TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	TACR1
ASTEMIZOLE	4	TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	TACR1
PAROXETINE	4	TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	TACR1
NEFAZODONE	4	TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	TACR1
ECONAZOLE	4	TACR1
TAMOXIFEN	4	TACR1
MICONAZOLE	4	TACR1
CASOPITANT	3	TACR1
SAREDUTANT	3	TACR1
SERLOPITANT	3	TACR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
TACR1	620	Binding:506, Functional:111, ADMET:3
SPR	10	Binding:10
QDPR	5	Binding:5
PAH	4	Binding:4
PTS	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PTS	4.2.3.12	6-pyruvoyltetrahydropterin synthase
SPR	1.1.1.153	sepiapterin reductase (L-erythro-7,8-dihydrobiopterin-forming)
ALG9	2.4.1.259, 2.4.1.261	dolichyl-P-Man:Man6GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase, dolichyl-P-Man:Man8GlcNAc2-PP-dolichol alpha-1,2-mannosyltransferase
GCH1	3.5.4.16	GTP cyclohydrolase I
PAH	1.14.16.1	phenylalanine 4-monooxygenase
QDPR	1.5.1.34	6,7-dihydropteridine reductase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TACR1	620

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CLOTRIMAZOLE	4	TACR1
ARIPIPRAZOLE	4	TACR1
AMOXAPINE	4	TACR1
THIOTHIXENE	4	TACR1
FIDAXOMICIN	4	TACR1
APREPITANT	4	TACR1
CYCLOSPORINE	4	TACR1
RITONAVIR	4	TACR1
TERFENADINE	4	TACR1
NETUPITANT	4	TACR1
NILOTINIB	4	TACR1
BOSUTINIB	4	TACR1
ASTEMIZOLE	4	TACR1
ROLAPITANT	4	TACR1
LANSOPRAZOLE	4	TACR1
PAROXETINE	4	TACR1
DEXTROMETHORPHAN	4	TACR1
HALOPERIDOL	4	TACR1
ACLIDINIUM BROMIDE	4	TACR1
TRAZODONE	4	TACR1
NEFAZODONE	4	TACR1
ITRACONAZOLE	4	TACR1
DOXAZOSIN	4	TACR1
CARVEDILOL	4	TACR1
ECONAZOLE	4	TACR1
TAMOXIFEN	4	TACR1
MICONAZOLE	4	TACR1
CASOPITANT	3	TACR1
SAREDUTANT	3	TACR1
SERLOPITANT	3	TACR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	TACR1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	6	PTS, SPR, ALG9, GCH1, PAH, QDPR
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
PTS	1	—
SPR	10	—
ALG9	0	—
GCH1	0	—
PAH	4	—
QDPR	5	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.