PTS

Summary

PTS (6-pyruvoyltetrahydropterin synthase, HGNC:9689) is a protein-coding gene on chromosome 11q23.1, encoding 6-pyruvoyl tetrahydrobiopterin synthase (Q03393). Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases.

The enzyme encoded by this gene catalyzes the elimination of inorganic triphosphate from dihydroneopterin triphosphate, which is the second and irreversible step in the biosynthesis of tetrahydrobiopterin from GTP. Tetrahydrobiopterin, also known as BH(4), is an essential cofactor and regulator of various enzyme activities, including enzymes involved in serotonin biosynthesis and NO synthase activity. Mutations in this gene result in hyperphenylalaninemia.

Source: NCBI Gene 5805 — RefSeq curated summary.

At a glance

• Gene–disease (curated): BH4-deficient hyperphenylalaninemia A (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 313 total — 36 pathogenic, 34 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000317

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9689
Approved symbol	PTS
Name	6-pyruvoyltetrahydropterin synthase
Location	11q23.1
Locus type	gene with protein product
Status	Approved
Aliases	PTPS
Ensembl gene	ENSG00000150787
Ensembl biotype	protein_coding
OMIM	612719
Entrez	5805

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding, 4 retained_intron, 2 nonsense_mediated_decay

ENST00000280362, ENST00000524931, ENST00000525645, ENST00000525803, ENST00000527428, ENST00000527635, ENST00000528679, ENST00000531175, ENST00000531673, ENST00000889305

RefSeq mRNA: 1 — MANE Select: NM_000317 NM_000317

CCDS: CCDS8359

Canonical transcript exons

ENST00000280362 — 6 exons

Exon	Start	End
ENSE00000996309	112226428	112226526
ENSE00001105394	112233432	112233973
ENSE00003480730	112228594	112228673
ENSE00003497580	112230208	112230230
ENSE00003550257	112233163	112233233
ENSE00003649024	112230626	112230682

Expression profiles

Bgee: expression breadth ubiquitous, 298 present calls, max score 98.95.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.3473 / max 177.2784, expressed in 1801 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
116716	17.3473	1801

Top tissues by expression

298 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.95	gold quality
right adrenal gland	UBERON:0001233	97.60	gold quality
left adrenal gland cortex	UBERON:0035825	97.38	gold quality
left adrenal gland	UBERON:0001234	97.34	gold quality
adrenal cortex	UBERON:0001235	97.25	gold quality
right lobe of liver	UBERON:0001114	97.10	gold quality
right adrenal gland cortex	UBERON:0035827	97.08	gold quality
adrenal gland	UBERON:0002369	96.89	gold quality
pons	UBERON:0000988	96.57	gold quality
hypothalamus	UBERON:0001898	95.98	gold quality
superior vestibular nucleus	UBERON:0007227	95.90	gold quality
metanephros cortex	UBERON:0010533	95.73	gold quality
tongue squamous epithelium	UBERON:0006919	95.70	gold quality
gluteal muscle	UBERON:0002000	95.68	gold quality
biceps brachii	UBERON:0001507	95.67	gold quality
gingival epithelium	UBERON:0001949	95.58	gold quality
vastus lateralis	UBERON:0001379	95.56	gold quality
substantia nigra pars compacta	UBERON:0001965	95.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.46	gold quality
substantia nigra	UBERON:0002038	95.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.39	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.36	gold quality
quadriceps femoris	UBERON:0001377	95.29	gold quality
adenohypophysis	UBERON:0002196	95.24	gold quality
midbrain	UBERON:0001891	95.21	gold quality
squamous epithelium	UBERON:0006914	95.10	gold quality
pituitary gland	UBERON:0000007	95.06	gold quality
amygdala	UBERON:0001876	95.03	gold quality
spinal cord	UBERON:0002240	95.03	gold quality
diaphragm	UBERON:0001103	94.83	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.54
E-GEOD-100618	no	195.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1

miRNA regulators (miRDB)

33 targeting PTS, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-3616-5P	99.55	67.02	989
HSA-MIR-573	99.55	67.44	955
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-520F-5P	99.34	70.40	1632
HSA-MIR-190B-3P	99.33	68.29	1382
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-550A-3P	98.37	69.61	632

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 13)

• mutational analysis in Chinese hyperphenylalaninemia caused by tetrahydrobiopterin synthesis deficiency (PMID:11438997)
• Our data show that PTPS induction is necessary for optimized BH4 synthesis in cytokine-stimulated human coronary artery endothelial cells and point to IL-1beta as a leading cytokine in this process. (PMID:14551150)
• Hyperphenylalaninemia may be caused by deficiency of Phe hydroxylase or by deficiency of co-factor BH(4). (PMID:16086286)
• Human PTS was efficiently expressed in noradrenergic regions but only in a small number of dopaminergic neurons. (PMID:16135092)
• Expression of PTS was significantly decreased in PD cases. (PMID:17270157)
• We suggest that the serum prolactin level may be a more sensitive marker than the CSF HVA level to guide the dose adjustment of L-Dopa/carbidopa in the management of patients with PTPS deficiency. (PMID:17590551)
• The mutant characterization of PTPS gene was coincident with other early studies in Chinese. The novel mutation L127F was considered as a pathogenetic mutation and associated with severe clinical phenotype. (PMID:18505119)
• Severe neurological impairment from BH4 deficiency could be prevented by newborn screening for hyperphenylalaninemia (HPA) and proper metabolic management. (PMID:19830588)
• A total of 43 mutations were identified in the PTS gene in a screen of East Asian populations, comprising 22 previously reported mutations and 21 new discovered mutations. (PMID:22237589)
• Long-term clinical outcome of 6-pyruvoyl-tetrahydropterin synthase-deficient patients. (PMID:32651154)
• Retrospective analysis of 19 patients with 6-Pyruvoyl Tetrahydropterin Synthase Deficiency: Prolactin levels inversely correlate with growth. (PMID:33234470)
• BH4-deficient hyperphenylalaninemia in Russia. (PMID:33822819)
• Molecular and metabolic bases of tetrahydrobiopterin (BH4) deficiencies. (PMID:33903016)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pts	ENSDARG00000045269
mus_musculus	Pts	ENSMUSG00000032067
rattus_norvegicus	Pts	ENSRNOG00000009250
drosophila_melanogaster	pr	FBGN0003141
caenorhabditis_elegans	ptps-1	WBGENE00015010

Protein

Protein identifiers

6-pyruvoyl tetrahydrobiopterin synthase — Q03393 (reviewed: Q03393)

All UniProt accessions (4): Q03393, E9PJM0, E9PKY8, E9PNN3

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases. Catalyzes the transformation of 7,8-dihydroneopterin triphosphate into 6-pyruvoyl tetrahydropterin.

Subunit / interactions. Homohexamer formed of two homotrimers in a head to head fashion.

Post-translational modifications. Phosphorylation of Ser-19 is required for maximal enzyme activity.

Disease relevance. Hyperphenylalaninemia, BH4-deficient, A (HPABH4A) [MIM:261640] An autosomal recessive disorder characterized by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits. Neurological symptoms are unresponsive to the classic phenylalanine-low diet. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Pathway. Cofactor biosynthesis; tetrahydrobiopterin biosynthesis; tetrahydrobiopterin from 7,8-dihydroneopterin triphosphate: step 1/3.

Miscellaneous. The active site is at the interface between 2 subunits. The proton acceptor Cys is on one subunit, and the charge relay system is on the other subunit.

Similarity. Belongs to the PTPS family.

RefSeq proteins (1): NP_000308* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007115	6-PTP_synth/QueD	Family
IPR022469	PTPS_His_AS	Active_site
IPR022470	PTPS_Cys_AS	Active_site
IPR038418	6-PTP_synth/QueD_sf	Homologous_superfamily

Pfam: PF01242

Enzyme classification (BRENDA):

• EC 4.2.3.12 — 6-pyruvoyltetrahydropterin synthase (BRENDA: 19 organisms, 23 substrates, 26 inhibitors, 31 Km, 6 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
6-(L-ERYTHRO-1,2-DIHYDROXYPROPYL 3-TRIPHOSPHATE)	0.0022–17.7	15
7,8-DIHYDRONEOPTERIN TRIPHOSPHATE	0.0005–0.164	14
6-(L-ERYTHRO-1,2-DIHYDROXYPROPYL 3-MONOPHOSPHATE	1.8	1
SEPIAPTERIN	0.92	1

Catalyzed reactions (Rhea), 1 shown:

• 7,8-dihydroneopterin 3’-triphosphate = 6-pyruvoyl-5,6,7,8-tetrahydropterin + triphosphate + H(+) (RHEA:22048)

UniProt features (50 total): sequence variant 25, helix 7, strand 5, active site 3, binding site 3, modified residue 3, chain 1, mutagenesis site 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3I2B	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03393-F1	96.01	0.94

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 43 (proton acceptor); 90 (charge relay system); 134 (charge relay system)

Ligand- & substrate-binding residues (3): 24; 49; 51

Post-translational modifications (3): 19, 28, 128

Mutagenesis-validated functional residues (1):

Position	Phenotype
19	decrease in activity; abolishes phosphorylation by pkg.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1474151	Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation

MSigDB gene sets: 276 (showing top): MODULE_52, TGCGCANK_UNKNOWN, GOBP_POLYOL_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, BROWNE_HCMV_INFECTION_16HR_UP, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, WANG_LMO4_TARGETS_DN, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, CAIRO_HEPATOBLASTOMA_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP

GO Biological Process (4): amino acid metabolic process (GO:0006520), tetrahydrobiopterin biosynthetic process (GO:0006729), central nervous system development (GO:0007417), tetrahydrobiopterin metabolic process (GO:0046146)

GO Molecular Function (5): 6-pyruvoyltetrahydropterin synthase activity (GO:0003874), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of cofactors	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoplasm	2
primary metabolic process	1
diol biosynthetic process	1
pteridine-containing compound biosynthetic process	1
tetrahydrobiopterin metabolic process	1
nervous system development	1
system development	1
diol metabolic process	1
pteridine-containing compound metabolic process	1
carbon-oxygen lyase activity, acting on phosphates	1
protein binding	1
cation binding	1
binding	1
catalytic activity	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1760 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PTS	PTPRA	P18433	948
PTS	PTPN12	Q05209	936
PTS	PTPN7	P35236	923
PTS	PSTPIP1	O43586	901
PTS	PTP4A2	Q12974	897
PTS	PTPN1	P18031	896
PTS	PTPRR	Q15256	889
PTS	PTPN5	P54829	881
PTS	PTPRB	P23467	858
PTS	PTPN21	Q16825	857
PTS	SRC	P12931	853
PTS	PTPN3	P26045	852
PTS	PTPRS	Q13332	850
PTS	PTPN4	P29074	844
PTS	SPR	P35270	840

IntAct

76 interactions, top by confidence:

A	B	Type	Score
PTS	PTS	psi-mi:“MI:0915”(physical association)	0.950
PTS	SDCBP	psi-mi:“MI:0915”(physical association)	0.670
SDCBP	PTS	psi-mi:“MI:0915”(physical association)	0.670
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
NTAQ1	PTS	psi-mi:“MI:0915”(physical association)	0.620
FXR2	PTS	psi-mi:“MI:0915”(physical association)	0.620
PTS	FXR2	psi-mi:“MI:0915”(physical association)	0.620
COIL	PTS	psi-mi:“MI:0915”(physical association)	0.560
PTS	LNX1	psi-mi:“MI:0915”(physical association)	0.560
THAP10	PTS	psi-mi:“MI:0915”(physical association)	0.560
LNX1	PTS	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (61): PTS (Two-hybrid), SDCBP (Two-hybrid), COIL (Two-hybrid), THAP10 (Two-hybrid), LNX1 (Two-hybrid), PTS (Affinity Capture-MS), PTS (Affinity Capture-MS), PTS (Two-hybrid), AHCYL1 (Co-fractionation), PTS (Affinity Capture-Western), NIT1 (Co-fractionation), PTS (Two-hybrid), PTS (Two-hybrid), PTS (Affinity Capture-MS), PTS (Affinity Capture-MS)

ESM2 similar proteins: A1USJ5, A2REL9, A6LFE8, A6LWG6, A7GW42, A7ZB36, A8F1F2, A8GRW0, A8GUB6, A9KHU4, B0BXB8, B5XLE8, C4K2D8, O02058, O27296, O29809, O31676, O66626, P0A3E9, P0C0C2, P0DB30, P0DB31, P27213, P44123, P48611, Q03393, Q04NF4, Q04WN5, Q1RHI6, Q1RID0, Q1ZXI0, Q4UKI6, Q55798, Q5GSM7, Q5REZ5, Q5XCA9, Q65TR0, Q68XI9, Q6AMT5, Q6G3J8

Diamond homologs: E7FHF1, O29809, P27213, Q03393, Q5REZ5, Q90W95, Q9R1Z7, O02058, P48611, P65870, P65871, P65872, P80081, Q1ZXI0, O31676, O27296, Q55798, Q8K9D8, Q9UXZ4

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PRKG1	up-regulates	PTS	phosphorylation
PRKG2	up-regulates	PTS	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

313 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	36
Likely pathogenic	34
Uncertain significance	53
Likely benign	126
Benign	14

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068717	NC_000011.9:g.(?112096088)(112105696_?)del	Pathogenic
1076000	NM_000317.3(PTS):c.236_239del (p.Tyr79fs)	Pathogenic
1417019	NM_000317.3(PTS):c.314+2T>C	Pathogenic
1451742	NM_000317.3(PTS):c.384T>A (p.Tyr128Ter)	Pathogenic
1452334	NC_000011.9:g.(?112097157)(112104288_?)del	Pathogenic
1453091	NM_000317.3(PTS):c.399C>A (p.Tyr133Ter)	Pathogenic
1458067	NM_000317.3(PTS):c.200C>A (p.Thr67Lys)	Pathogenic
2032318	NM_000317.3(PTS):c.292_293insATACTTTG (p.Pro98fs)	Pathogenic
2046210	NM_000317.3(PTS):c.85A>T (p.Lys29Ter)	Pathogenic
2137247	NM_000317.3(PTS):c.186+1G>A	Pathogenic
2422868	NC_000011.9:g.(?112103876)(112104288_?)del	Pathogenic
2678101	NM_000317.3(PTS):c.276T>A (p.Asn92Lys)	Pathogenic
2766927	NM_000317.3(PTS):c.370G>C (p.Val124Leu)	Pathogenic
2809631	NM_000317.3(PTS):c.189dup (p.Asp64Ter)	Pathogenic
2910294	NM_000317.3(PTS):c.322G>T (p.Glu108Ter)	Pathogenic
3240235	NM_000317.3(PTS):c.244-2A>G	Pathogenic
3685851	NM_000317.3(PTS):c.187-2A>T	Pathogenic
3895739	NC_000011.9:g.(112101406_112103885)(112104697?)del	Pathogenic
463151	NM_000317.3(PTS):c.200C>T (p.Thr67Met)	Pathogenic
478	NM_000317.3(PTS):c.361_374del (p.Val121fs)	Pathogenic
479	NM_000317.3(PTS):c.155A>G (p.Asn52Ser)	Pathogenic
480	NM_000317.3(PTS):c.259C>T (p.Pro87Ser)	Pathogenic
484	NM_000317.3(PTS):c.286G>A (p.Asp96Asn)	Pathogenic
485	NM_000317.3(PTS):c.163+696_163+750del	Pathogenic
550850	NM_000317.3(PTS):c.118_121del (p.Phe40fs)	Pathogenic
552046	NM_000317.3(PTS):c.164-7T>A	Pathogenic
552175	NM_000317.3(PTS):c.317C>T (p.Thr106Met)	Pathogenic
553378	NM_000317.3(PTS):c.84-3C>G	Pathogenic
553441	NM_000317.3(PTS):c.296A>G (p.Tyr99Cys)	Pathogenic
553829	NM_000317.3(PTS):c.260C>T (p.Pro87Leu)	Pathogenic

SpliceAI

1257 predictions. Top by Δscore:

Variant	Effect	Δscore
11:112228587:T:TA	acceptor_gain	1.0000
11:112228590:TCAGT:T	acceptor_loss	1.0000
11:112228591:CAG:C	acceptor_loss	1.0000
11:112228592:A:AG	acceptor_gain	1.0000
11:112228593:G:GT	acceptor_gain	1.0000
11:112228593:GT:G	acceptor_gain	1.0000
11:112228593:GTA:G	acceptor_gain	1.0000
11:112228593:GTAA:G	acceptor_gain	1.0000
11:112228593:GTAAA:G	acceptor_gain	1.0000
11:112230207:GTT:G	acceptor_gain	1.0000
11:112230620:CTTTA:C	acceptor_loss	1.0000
11:112230621:TTTAG:T	acceptor_loss	1.0000
11:112230622:TTAGA:T	acceptor_loss	1.0000
11:112230623:TAGAT:T	acceptor_loss	1.0000
11:112230624:A:AG	acceptor_gain	1.0000
11:112230624:A:T	acceptor_loss	1.0000
11:112230625:G:GG	acceptor_gain	1.0000
11:112230625:GATT:G	acceptor_gain	1.0000
11:112230680:G:GT	donor_gain	1.0000
11:112233157:CTCTA:C	acceptor_loss	1.0000
11:112233159:CTAG:C	acceptor_loss	1.0000
11:112233160:TA:T	acceptor_loss	1.0000
11:112233161:A:AC	acceptor_loss	1.0000
11:112233161:A:AG	acceptor_gain	1.0000
11:112233162:G:GA	acceptor_loss	1.0000
11:112233162:G:GG	acceptor_gain	1.0000
11:112233162:GGA:G	acceptor_gain	1.0000
11:112255386:A:AC	donor_gain	1.0000
11:112255387:C:CC	donor_gain	1.0000
11:112226525:AGG:A	donor_loss	0.9900

AlphaMissense

971 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:112233232:A:C	S105R	0.994
11:112233432:C:A	S105R	0.994
11:112233432:C:G	S105R	0.994
11:112226513:C:G	H24D	0.991
11:112226517:G:C	R25P	0.991
11:112230666:T:C	L76P	0.990
11:112226507:G:C	A22P	0.989
11:112228663:C:A	H51Q	0.988
11:112228663:C:G	H51Q	0.988
11:112226508:C:A	A22E	0.987
11:112228628:T:C	F40L	0.987
11:112228630:T:A	F40L	0.987
11:112228630:T:G	F40L	0.987
11:112228659:G:A	G50E	0.987
11:112233448:G:C	A111P	0.987
11:112233470:T:C	L118P	0.986
11:112233218:T:C	F100S	0.985
11:112233449:C:A	A111D	0.985
11:112228657:T:A	H49Q	0.984
11:112228657:T:G	H49Q	0.984
11:112233519:A:C	E134D	0.984
11:112233519:A:T	E134D	0.984
11:112230214:T:A	V57E	0.983
11:112233188:A:C	H90P	0.983
11:112233440:A:T	E108V	0.983
11:112233441:A:C	E108D	0.983
11:112233441:A:T	E108D	0.983
11:112233521:C:T	T135I	0.983
11:112226502:T:C	F20S	0.982
11:112233170:T:A	I84N	0.982

dbSNP variants (sampled 300 via entrez): RS1000143269 (11:112233121 G>A,T), RS1000175432 (11:112229825 C>T), RS1000965379 (11:112226309 G>A,C,T), RS1001114970 (11:112231999 A>C,G), RS1001118073 (11:112226640 C>T), RS1001314754 (11:112232675 C>T), RS1001546561 (11:112231679 G>A,T), RS1001682263 (11:112233001 C>T), RS1001755758 (11:112226819 G>T), RS1002198918 (11:112224839 C>A,T), RS1002276668 (11:112231487 A>G), RS1002488567 (11:112233991 A>G), RS1002799375 (11:112225767 T>C), RS1003283225 (11:112229933 A>G), RS1003315701 (11:112229732 C>T)

Disease associations

OMIM: gene MIM:612719 | disease phenotypes: MIM:261640, MIM:163950, MIM:233910

GenCC curated gene-disease

Disease	Classification	Inheritance
BH4-deficient hyperphenylalaninemia A	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
BH4-deficient hyperphenylalaninemia A	Definitive	AR

Mondo (5): BH4-deficient hyperphenylalaninemia A (MONDO:0009863), Noonan syndrome 1 (MONDO:0008104), GTP cyclohydrolase I deficiency with hyperphenylalaninemia (MONDO:0100186), metabolic disease (MONDO:0005066), hyperphenylalaninemia due to tetrahydrobiopterin deficiency (MONDO:0016543)

Orphanet (4): 6-pyruvoyl-tetrahydropterin synthase deficiency (Orphanet:13), Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet:238583), Noonan syndrome (Orphanet:648), GTP cyclohydrolase I deficiency (Orphanet:2102)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000508	Ptosis
HP:0000711	Restlessness
HP:0000713	Agitation
HP:0000716	Depression
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001262	Excessive daytime somnolence
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001300	Parkinsonism
HP:0001332	Dystonia
HP:0001336	Myoclonus
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001518	Small for gestational age
HP:0001954	Recurrent fever
HP:0002015	Dysphagia
HP:0002033	Poor suck
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002071	Abnormality of extrapyramidal motor function

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST003159_1	Objective response to lithium treatment	1.000000e-08
GCST006979_419	Heel bone mineral density	2.000000e-18

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008659	Metabolic Diseases	C18.452
C535325	6-pyruvoyl-tetrahydropterin synthase deficiency (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4630823 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	affects methylation, increases expression	2
Benzo(a)pyrene	increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	increases expression	1
abrine	increases expression	1
MT19c compound	increases expression	1
Temozolomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Diethylhexyl Phthalate	increases expression	1
Gold	decreases expression	1
Lead	affects splicing	1
Methyl Methanesulfonate	increases expression	1
Sarin	decreases expression	1
Smoke	decreases expression	1
Dihydrotestosterone	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Zinc	decreases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Isotretinoin	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Asbestos, Crocidolite	increases expression	1
Cadmium Chloride	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4626313	ADMET	Inhibition of PTPS (unknown origin) expressed in Escherichia coli BL21 using p-nitrophenyl phosphate as substrate measured after 30 mins by UV-vis spectrophotometric method	Highly Potent and Selective N-Aryl Oxamic Acid-Based Inhibitors for Mycobacterium tuberculosis Protein Tyrosine Phosphatase B. — J Med Chem

Cellosaurus cell lines

6 cell lines: 4 transformed cell line, 1 cancer cell line, 1 finite cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2CU	Abcam HeLa PTS KO	Cancer cell line	Female
CVCL_LG38	CG0020	Finite cell line	Male
CVCL_LG65	CG1149	Transformed cell line	Female
CVCL_LG66	CG1150	Transformed cell line	Male
CVCL_LG67	CG1151	Transformed cell line	Female
CVCL_LG69	CG1164	Transformed cell line	Male

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00192621	PHASE4	COMPLETED	Seronegatives and Metabolic Abnormalities Protocol 2 (SAMA002): Study to Compare the Effect of Kaletra and Combivir® in HIV-Negative Healthy Subjects
NCT01443806	PHASE4	COMPLETED	Characterisation of the Human Carboxylesterase 1 (CES1) Mutations in Thailand
NCT02645279	PHASE4	UNKNOWN	Comparison of Oral 30 % Dextrose and iv Midazolam Sedation During MRI in Neonates
NCT04653779	PHASE4	UNKNOWN	A Clinical Trial to Evaluate the Preference Regarding Convenience of Medication and Efficacy/Safety of SUGAMET®XR Tablet 5/1000mg
NCT05084079	PHASE4	UNKNOWN	Different Initial Insulin Dose Regimens on Time to Achieve Glycemic Targets and Treatment Safety in SIIT
NCT05855577	PHASE4	NOT_YET_RECRUITING	Motor Function Efficacy of Pharmacological Treatments Targeting Energy Metabolism, in Parkinson’s Patients
NCT06003153	PHASE4	RECRUITING	GLUCOSE-MGH: Genetic Links Understood Through Challenge With Oral Semaglutide Exposure at MGH
NCT06009653	PHASE4	WITHDRAWN	Effects of Tirzepatide Plus Intensive Lifestyle Therapy on Body Weight and Metabolic Health in Latinos With Obesity
NCT00387114	PHASE3	TERMINATED	Effect of an Anti-Oxidant Treatment on Resistin Serum Levels.A Randomized Study
NCT00546052	PHASE3	COMPLETED	A 52 Week Study to Evaluate the Effects of Losartan With or Without HCTZ on Plasma Glucose, Metabolic Parameters, Blood Pressure in Hypertensive Patients With Metabolic Syndrome (0954A-331)
NCT00607373	PHASE3	COMPLETED	Study to Assess the Safety and Efficacy of ISIS 301012 (Mipomersen) in Homozygous Familial Hypercholesterolemia
NCT00694109	PHASE3	COMPLETED	An Open-label Extension Study to Assess the Long-term Safety and Efficacy of ISIS 301012 (Mipomersen) in Patients With Familial Hypercholesterolemia or Severe-Hypercholesterolemia
NCT00935766	PHASE3	TERMINATED	Effect of Fish Oil (Omega-3 Fatty Acids) on Arteries
NCT01286909	PHASE3	UNKNOWN	Efficacy of Laflavon in Lowering Triglycerides and Raising High-Density Lipoprotein (HDL)
NCT01343680	PHASE3	TERMINATED	Trial of Two Central Venous Catheter (CVC) Flushing Schemes in Pediatric Hematology and Oncology Patients
NCT04371978	PHASE3	TERMINATED	Efficacy and Safety of Dipeptidyl Peptidase-4 Inhibitors in Diabetic Patients With Established COVID-19
NCT04809220	PHASE3	COMPLETED	A Study of Two Doses of Dulaglutide (LY2189265) in Japanese Patients With Type 2 Diabetes
NCT05260021	PHASE3	COMPLETED	A Study to Evaluate Tirzepatide (LY3298176) in Pediatric and Adolescent Participants With Type 2 Diabetes Mellitus Inadequately Controlled With Metformin or Basal Insulin or Both
NCT05425745	PHASE3	COMPLETED	Evaluate the Effect of Obicetrapib in Patients With HeFH on Top of Maximum Tolerated Lipid-Modifying Therapies.
NCT05505994	PHASE3	UNKNOWN	The Efficacy and Safety of DWP16001 in Combination With Metformin in T2DM Patients Inadequately Controlled on Metformin
NCT05691712	PHASE3	COMPLETED	A Study of Tirzepatide (LY3298176) in Chinese Participants With Type 2 Diabetes
NCT06568471	PHASE3	RECRUITING	A Study on Efficacy and Safety of HST101 in Chinese Patients with Hypercholesterolemia
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT07613307	PHASE3	NOT_YET_RECRUITING	A Study of Orforglipron (LY3502970) in Participants With Type 2 Diabetes Who Observe Ramadan Fasting
NCT00001723	PHASE2	COMPLETED	Safety and Efficacy of Xenical in Children and Adolescents With Obesity-Related Diseases
NCT00119379	PHASE2	COMPLETED	Effectiveness of Nucleoside Supplementation or Switch to Tenofovir in Reversing Fat Loss in HIV Infected Adults
NCT00362180	PHASE2	COMPLETED	Measure Liver Fat Content After ISIS 301012 (Mipomersen) Administration
NCT00446264	PHASE2	COMPLETED	Islet Allotransplantation With Steroid Free Immunosuppression
NCT00477594	PHASE2	COMPLETED	Open Label Extension of ISIS 301012 (Mipomersen) to Treat Familial Hypercholesterolemia
NCT00622765	PHASE2	COMPLETED	A Study of the Safety and Effectiveness of JNJ-16269110 (R256918) in Overweight and Obese Patients
NCT00707746	PHASE2	COMPLETED	Safety and Efficacy Study of ISIS 301012 (Mipomersen) Administration in High Risk Statin Intolerant Subjects
NCT01041677	PHASE2	COMPLETED	A Study of the Safety of R256918 in Obese Patients
NCT01135537	PHASE2	TERMINATED	Pharmacokinetics of Thymoglobulin in Paediatric Haematopoietic Stem-cell Transplants
NCT01596699	PHASE2	TERMINATED	Pilot Trial of Clofarabine Added to Standard Busulfan and Fludarabine for Conditioning Prior to Allogeneic Hematopoietic Cell Transplantation
NCT01927913	PHASE2	WITHDRAWN	Treatment of Iron Overload Requiring Chelation Therapy
NCT01968720	PHASE2	COMPLETED	Pilot Study To Assess CAT-2003 in Patients With Severe Hypertriglyceridemia
NCT02019667	PHASE2	COMPLETED	Phase 2 Clinical Trial of SGS-742 Therapy in Succinic Semialdehyde Dehydrogenase Deficiency
NCT02102737	PHASE2	COMPLETED	Comparison of A New Technique of Measure of the Insulin Resistance By Scintigraphy With the Reference Technique
NCT02512679	PHASE2	TERMINATED	Related Hematopoietic Stem Cell Transplantation (HSCT) for Genetic Diseases of Blood Cells
NCT02587572	PHASE2	WITHDRAWN	Safety and Efficacy Trial Using Allogeneic Human Mesenchymal Stem Cells: The SIRONA Trial