PAH

Summary

PAH (phenylalanine hydroxylase, HGNC:8582) is a protein-coding gene on chromosome 12q23.2, encoding Phenylalanine-4-hydroxylase (P00439). Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

This gene encodes a member of the biopterin-dependent aromatic amino acid hydroxylase protein family. The encoded phenylalanine hydroxylase enzyme hydroxylates phenylalanine to tyrosine and is the rate-limiting step in phenylalanine catabolism. Deficiency of this enzyme activity results in the autosomal recessive disorder phenylketonuria.

Source: NCBI Gene 5053 — RefSeq curated summary.

At a glance

• Gene–disease (curated): phenylketonuria (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 1,626 total — 437 pathogenic, 378 likely-pathogenic
• Phenotypes (HPO): 58
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_000277

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8582
Approved symbol	PAH
Name	phenylalanine hydroxylase
Location	12q23.2
Locus type	gene with protein product
Status	Approved
Aliases	PH
Ensembl gene	ENSG00000171759
Ensembl biotype	protein_coding
OMIM	612349
Entrez	5053

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 12 protein_coding, 8 protein_coding_CDS_not_defined, 4 retained_intron

ENST00000307000, ENST00000546708, ENST00000546844, ENST00000547319, ENST00000548677, ENST00000548928, ENST00000549111, ENST00000549247, ENST00000550405, ENST00000550978, ENST00000551114, ENST00000551337, ENST00000551988, ENST00000552251, ENST00000553106, ENST00000635477, ENST00000635500, ENST00000635528, ENST00000906692, ENST00000906693, ENST00000906694, ENST00000906695, ENST00000906696, ENST00000906697

RefSeq mRNA: 2 — MANE Select: NM_000277 NM_000277, NM_001354304

CCDS: CCDS9092

Canonical transcript exons

ENST00000553106 — 13 exons

Exon	Start	End
ENSE00001141448	102917071	102917244
ENSE00002263892	102840400	102840515
ENSE00002303890	102852815	102852950
ENSE00002316008	102855136	102855332
ENSE00002376391	102836889	102839218
ENSE00003459904	102877462	102877550
ENSE00003487848	102844336	102844431
ENSE00003503140	102912791	102912898
ENSE00003628312	102894735	102894918
ENSE00003632465	102866596	102866663
ENSE00003638223	102846895	102846951
ENSE00003643679	102843646	102843779
ENSE00003693050	102851687	102851756

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 99.66.

FANTOM5 (CAGE): breadth broad, TPM avg 5.8218 / max 1725.1094, expressed in 292 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
132955	3.6426	113
132954	1.2218	30
132956	0.3747	77
132959	0.2907	135
132953	0.1269	14
132958	0.1136	58
132957	0.0291	4
132951	0.0223	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.66	gold quality
liver	UBERON:0002107	99.51	gold quality
gall bladder	UBERON:0002110	98.92	gold quality
nephron tubule	UBERON:0001231	98.38	gold quality
renal glomerulus	UBERON:0000074	96.92	gold quality
kidney epithelium	UBERON:0004819	96.89	gold quality
adult organism	UBERON:0007023	96.69	gold quality
metanephric glomerulus	UBERON:0004736	96.28	gold quality
adult mammalian kidney	UBERON:0000082	94.98	gold quality
kidney	UBERON:0002113	92.43	gold quality
adrenal tissue	UBERON:0018303	90.43	gold quality
body of pancreas	UBERON:0001150	87.80	gold quality
renal medulla	UBERON:0000362	87.41	gold quality
cortex of kidney	UBERON:0001225	87.09	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.35	gold quality
sperm	CL:0000019	84.13	gold quality
right adrenal gland	UBERON:0001233	83.33	gold quality
metanephros	UBERON:0000081	83.09	gold quality
pancreas	UBERON:0001264	82.89	gold quality
right testis	UBERON:0004534	82.29	gold quality
left testis	UBERON:0004533	81.90	gold quality
male germ cell	CL:0000015	81.25	gold quality
left adrenal gland	UBERON:0001234	79.69	gold quality
testis	UBERON:0000473	78.96	gold quality
adrenal gland	UBERON:0002369	78.72	gold quality
right adrenal gland cortex	UBERON:0035827	78.04	gold quality
pancreatic ductal cell	CL:0002079	77.93	silver quality
adrenal cortex	UBERON:0001235	77.67	gold quality
epithelial cell of pancreas	CL:0000083	77.16	silver quality
islet of Langerhans	UBERON:0000006	77.10	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-131882	yes	1726.04
E-CURD-119	yes	1398.39
E-MTAB-8495	yes	553.49
E-CURD-135	no	1084.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, CREB1, HNF1A

miRNA regulators (miRDB)

54 targeting PAH, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4729	99.69	72.18	4233

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• Sixteen different mutations have been detected, two mutations were found at unexpectedly high frequencies, E280K and R261Q. (PMID:11524738)
• The spectrum of PAH gene mutations in Sicily reflects the complex demographic history of this island at the crossroad of prehistoric and historical migrations in the Mediterranean sea. (PMID:11708866)
• X ray cystallography of the catalytic domain in its catalytically active Fe(II) form and binary complex with tetrahydrobiopterin ytic domain (PMID:11718561)
• Tetrahydrobiopterin regulates gene’s expression in phenylalanine hydroxylase deficiency. (PMID:11855940)
• Identification and characterization of a novel liver-specific enhancer of the human phenylalanine hydroxylase gene. (PMID:11935335)
• Analysis of differential scanning calorimetry thermograms shows that thermal denaturation of PAH occurs in three stages: unfolding of the four regulatory domains; unfolding of two (out of the four) catalytic domains; and irreversible protein denaturation. (PMID:12056888)
• Structural comparison of bacterial and human iron-dependent phenylalanine hydroxylases: similar fold, different stability and reaction rates. (PMID:12096915)
• crystal structure of the ternary complex of the catalytic domain of human phenylalanine hydroxylase with tetrahydrobiopterin and 3-(2-thienyl)-L-alanine (PMID:12126628)
• the mutation spectrum in the Republic of Ireland (PMID:12173030)
• determination of molecular basis for the effects of phosphorylation on the catalytic efficiency and enzyme stability (PMID:12185072)
• Genetic evaluation of the family members of subjects with the PAH K274E mutation showed that all individuals with the K274E mutation also exhibited the PAH L321L polymorphism in the catalytic domain of the PAH enzyme. (PMID:12210276)
• Both the on- and off-rates for the conformational transition were biphasic, which is interpreted in terms of a difference in the energy barrier and the rate by which the two domains (catalytic and regulatory) undergo a conformational change. (PMID:12379147)
• study of deamidation of labile asparagine residues in the autoregulatory sequence (PMID:12603326)
• studies on the regulatory properties of the pterin cofactor and dopamine bound at the active site (PMID:12603331)
• To investigate further the involvement of Cys237 and Arg68 in the activation of the enzyme, we have prepared mutants of hPAH at these positions, with substitutions of different charge and size. (PMID:12653545)
• A review of studies of PAH gene mutations causing hyper-phenylalaninemia points in particular to a prevalent general mechanism that appears to play a major role in the pathogenicity of many PAH mutations. (PMID:12655545)
• Two catalytic mutations (Y277D and E280K) and two severe structural defects (IVS10-11G>A and L311P) have been found to abolish PAH specific activity. (PMID:12655546)
• Two novel amino acid subsittutions, L249P in exon 7 and F402L in exon 12 and one nucleotide substitution 912T>C in intron 8 of the PAH gene in Phenylketonuria families. (PMID:12655552)
• mutations and polymorphisms of phenylalanine hydroxylase are associated with phenylketonuria (PMID:12765842)
• Variation is not a highly penetrant autosomal dominant susceptibility locus for mood disorder in families. (PMID:12782966)
• Parental attitudes regarding newborn screening of PKU were compiled and evaluated. (PMID:12833401)
• Results describe the crystal structures of the catalytic domain of human phenylalanine hydroxylase in complex with 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin and 3-(2-thienyl)-L-alanine or L-norleucine at 2.0A resolution. (PMID:14568534)
• mutant forms revealed a variably reduced global conformational stability compared with wild-type human PAH, as measured by thermal denaturation and limited proteolysis (PMID:15060071)
• the denatured state properties of the AAAHs (TH, TPH and PAH) contribute significantly to the stability of these enzymes and their tolerance towards missense mutations (PMID:15135070)
• Eleven mutations and 3 polymorphisms in PAH gene were found in 40 phenylketonuria (PKU) patients. (PMID:15300621)
• Hence, generation of H(2)O(2) by UVB can activate epidermal PAH leading to an increased L-tyrosine pool for melanogenesis. (PMID:15313177)
• seven mild PKU mutations resulted in catalytic defects; I65T, R68S, P244L, and most probably A309V, showed reduced binding affinity for tetrahydrobiopterin (PMID:15459954)
• Tetrahydrobopterin protects PAH activity in vitro and has implications for phenylketonurias. (PMID:15556637)
• Study demonstrated the variety of the mutation type PAH gene of PKU in Inner Mongolia population, and confirmed that R243Q, Y356X, Y204C were the hot spots of PAH gene mutation. (PMID:15793771)
• Tyr325 appears to have an important role ensuring stoichiometric binding of iron, correct geometry of the complexes with substrate and cofactor and, consequently, a right coupling efficiency of the PAH reaction. (PMID:15917086)
• Hyperphenylalaninemia may be caused by deficiency of Phe hydroxylase or by deficiency of co-factor BH(4). (PMID:16086286)
• both subunits of phenylalanine hydroxylase were expressed and that the purified heteroallelic enzymes, were catalytically active (PMID:16545551)
• Results showed that both arginine amino acid and exon 7 is of great significance with regards to the structure and function of the enzyme. (PMID:16765994)
• A recurrent mutation (c.1222C>T) within the PAH gene is explained by spontaneous methylation-mediated deamination of a CpG dinucleotide in a hypermutable codon. (PMID:16917891)
• Both 7(R)- and 7(S)BH4 function as poor cofactors for PAH, whereas only 7(S)BH4 acts as a potent competitive inhibitor (PMID:16935936)
• In phenylalanine hydroxylase deficiency, mutations were identified in 240/249 PAH alleles (detection rate: 96.4%). Of 60 gene variants, the most frequent were p.R261Q (15.7% of alleles), p.A403V (11.6% of alleles) and c.1066-11G > A (8.8% of alleles). (PMID:17096675)
• Mutations in the regulatory domain responded to tetrahydrobiopterin even in patients with classical phenylketonuria. (PMID:17627389)
• A PAH mutational analysis in phenylketonuria patients in two large old order Amish settlements. (PMID:17630668)
• The prediction of the energetic impact on PAH native-state stability of 318 PKU-associated missense mutations, was studied. (PMID:17924342)
• The birth prevalence of PKU in populations of European, South Asian, and sub-Saharn African ancestry living in South East England is reported. (PMID:18184144)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pah	ENSDARG00000020143
mus_musculus	Pah	ENSMUSG00000020051
rattus_norvegicus	Pah	ENSRNOG00000004302
drosophila_melanogaster	Hn	FBGN0001208
caenorhabditis_elegans		WBGENE00000240

Paralogs (3): TPH1 (ENSG00000129167), TPH2 (ENSG00000139287), TH (ENSG00000180176)

Protein

Protein identifiers

Phenylalanine-4-hydroxylase — P00439 (reviewed: P00439)

Alternative names: Phe-4-monooxygenase

All UniProt accessions (6): P00439, A0A0U1RQI3, A0A0U1RQY4, F8W0A0, F8W1D4, J3KND8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.

Subunit / interactions. Homodimer and homotetramer.

Post-translational modifications. Phosphorylation at Ser-16 increases basal activity and facilitates activation by the substrate phenylalanine.

Disease relevance. Phenylalanine hydroxylase deficiency (PAH deficiency) [MIM:261600] An autosomal recessive inborn error of phenylalanine metabolism characterized by intolerance to dietary intake of the essential amino acid phenylalanine. The disease spectrum depends on the degree of PAH deficiency and the phenylalanine levels in plasma. Severe deficiency causes classic phenylketonuria (PKU) that is characterized by plasma concentrations of phenylalanine persistently above 1200 umol/L. PKU patients develop profound and irreversible intellectual disability, unless low phenylalanine diet is introduced early in life. They tend to have light pigmentation, rashes similar to eczema, epilepsy, extreme hyperactivity, psychotic states and an unpleasant ‘mousy’ odor. Less severe forms of PAH deficiency are characterized by phenylalanine levels above normal (120 umol/L) but below 1200 umol/L and include moderate PKU, mild PKU, non-PKU hyperphenylalaninemia (non-PKU HPA) and mild hyperphenylalaninemia. Individuals with PAH deficiency who have plasma phenylalanine concentrations consistently below 600 umol/L on an unrestricted diet are not at higher risk of developing intellectual, neurologic, and neuropsychological impairment than are individuals without PAH deficiency. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. N-terminal region of PAH is thought to contain allosteric binding sites for phenylalanine and to constitute an ‘inhibitory’ domain that regulates the activity of a catalytic domain in the C-terminal portion of the molecule.

Pathway. Amino-acid degradation; L-phenylalanine degradation; acetoacetate and fumarate from L-phenylalanine: step 1/6.

Polymorphism. The Glu-274 variant occurs on approximately 4% of African-American PAH alleles. The enzyme activity of the variant protein is indistinguishable from that of the wild-type form.

Similarity. Belongs to the biopterin-dependent aromatic amino acid hydroxylase family.

RefSeq proteins (2): NP_000268, NP_001341233 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001273	ArAA_hydroxylase	Family
IPR002912	ACT_dom	Domain
IPR005961	Phe-4-hydroxylase_tetra	Family
IPR018301	ArAA_hydroxylase_Fe/CU_BS	Binding_site
IPR019773	Tyrosine_3-monooxygenase-like	Family
IPR019774	Aromatic-AA_hydroxylase_C	Domain
IPR036329	Aro-AA_hydroxylase_C_sf	Homologous_superfamily
IPR036951	ArAA_hydroxylase_sf	Homologous_superfamily
IPR041912	Euk_PheOH_cat	Domain
IPR045865	ACT-like_dom_sf	Homologous_superfamily

Pfam: PF00351, PF01842

Enzyme classification (BRENDA):

• EC 1.14.16.1 — phenylalanine 4-monooxygenase (BRENDA: 25 organisms, 126 substrates, 89 inhibitors, 304 Km, 60 kcat entries)

Substrate kinetics (BRENDA)

36 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
L-PHENYLALANINE	0.022–500	66
TETRAHYDROBIOPTERIN	0.002–0.5	41
S-CARBOXYMETHYL-L-CYSTEINE	0.0728–25.24	35
5,6,7,8-TETRAHYDROBIOPTERIN	0.001–0.155	21
PHENYLALANINE	0.043–1.3	18
L-PHE	0.1–6.9	14
6-METHYLTETRAHYDROPTERIN	0.043–0.1	12
(6R)-L-ERYTHRO-5,6,7,8-TETRAHYDROBIOPTERIN	0.008–0.094	10
6-METHYLTETRAHYDROBIOPTERIN	0.43–6.9	7
6,7-DIMETHYL-5,6,7,8-TETRAHYDROPTERIN	0.0344–0.262	6
ABZ-VAA	0.008–0.028	6
L-TRYPTOPHAN	1–8.5	6
S-METHYL-L-CYSTEINE	18.32–51.6	6
6,7-DIMETHYLTETRAHYDROBIOPTERIN	0.065–0.105	4
THIENYLALANINE	0.47–1.7	4

Catalyzed reactions (Rhea), 1 shown:

• (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin + L-phenylalanine + O2 = (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin + L-tyrosine (RHEA:20273)

UniProt features (259 total): sequence variant 212, helix 19, strand 17, binding site 3, turn 3, chain 1, domain 1, mutagenesis site 1, sequence conflict 1, modified residue 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
1J8U	X-RAY DIFFRACTION	1.5
6HPO	X-RAY DIFFRACTION	1.67
1J8T	X-RAY DIFFRACTION	1.7
5FII	X-RAY DIFFRACTION	1.8
1DMW	X-RAY DIFFRACTION	2
1MMK	X-RAY DIFFRACTION	2
1MMT	X-RAY DIFFRACTION	2
1PAH	X-RAY DIFFRACTION	2
3PAH	X-RAY DIFFRACTION	2
4PAH	X-RAY DIFFRACTION	2
1LRM	X-RAY DIFFRACTION	2.1
1TDW	X-RAY DIFFRACTION	2.1
5PAH	X-RAY DIFFRACTION	2.1
4ANP	X-RAY DIFFRACTION	2.11
6PAH	X-RAY DIFFRACTION	2.15
1TG2	X-RAY DIFFRACTION	2.2
1KW0	X-RAY DIFFRACTION	2.5
6N1K	X-RAY DIFFRACTION	3.06
2PAH	X-RAY DIFFRACTION	3.1
6HYC	X-RAY DIFFRACTION	3.18

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P00439-F1	89.04	0.63

Functional residue map

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

Ligand- & substrate-binding residues (3): 285; 290; 330

Post-translational modifications (1): 16

Mutagenesis-validated functional residues (1):

Position	Phenotype
283	loss of positive cooperativity and reduction of fold-activation by l-phe preincubation.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-2160456	Phenylketonuria
R-HSA-8964208	Phenylalanine metabolism

MSigDB gene sets: 289 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, MODULE_93, GOBP_PHENOL_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, GRANDVAUX_IRF3_TARGETS_DN, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, DIERICK_SEROTONIN_FUNCTION_GENES, BLALOCK_ALZHEIMERS_DISEASE_UP

GO Biological Process (6): L-phenylalanine catabolic process (GO:0006559), L-tyrosine biosynthetic process (GO:0006571), amino acid biosynthetic process (GO:0008652), catecholamine biosynthetic process (GO:0042423), aromatic amino acid metabolic process (GO:0009072), obsolete L-tyrosine biosynthetic process, by oxidation of phenylalanine (GO:0019293)

GO Molecular Function (7): phenylalanine 4-monooxygenase activity (GO:0004505), iron ion binding (GO:0005506), catalytic activity (GO:0003824), monooxygenase activity (GO:0004497), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen (GO:0016714), metal ion binding (GO:0046872)

GO Cellular Component (1): cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Diseases of metabolism	1
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
amino acid metabolic process	2
aromatic amino acid catabolic process	1
L-amino acid catabolic process	1
proteinogenic amino acid catabolic process	1
aromatic amino acid biosynthetic process	1
erythrose 4-phosphate/phosphoenolpyruvate family amino acid biosynthetic process	1
biosynthetic process	1
catecholamine metabolic process	1
catechol-containing compound biosynthetic process	1
biogenic amine biosynthetic process	1
carboxylic acid metabolic process	1
L-tyrosine biosynthetic process	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, reduced pteridine as one donor, and incorporation of one atom of oxygen	1
transition metal ion binding	1
molecular_function	1
oxidoreductase activity	1
catalytic activity	1
monooxygenase activity	1
oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen	1
cation binding	1
cytoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1929 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PAH	QDPR	P09417	845
PAH	SPR	P35270	793
PAH	DDC	P20711	781
PAH	HAL	P42357	746
PAH	DBH	P09172	709
PAH	PTS	Q03393	705
PAH	GCH1	P30793	688
PAH	PNMT	P11086	679
PAH	PCBD1	P61457	656
PAH	TYR	P14679	646
PAH	TAT	P17735	615
PAH	TBXA2R	P21731	591
PAH	DNAJC12	Q9UKB3	590
PAH	HGD	Q93099	585
PAH	FAH	P16930	542

IntAct

6 interactions, top by confidence:

A	B	Type	Score
PAH		psi-mi:“MI:0915”(physical association)	0.370
PAH	iglC2	psi-mi:“MI:0915”(physical association)	0.370
PAH	RPS24	psi-mi:“MI:0915”(physical association)	0.370
vBCL2	PAH	psi-mi:“MI:0915”(physical association)	0.370
pgm	PAH	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): PAH (Synthetic Lethality), PAH (Co-crystal Structure), PAH (Two-hybrid), QDPR (Two-hybrid), PCBD1 (Two-hybrid), CDH1 (Affinity Capture-Western), PAH (Affinity Capture-Western), PAH (Affinity Capture-Western), USP19 (Affinity Capture-Western), USP19 (Co-localization), PAH (Affinity Capture-MS), PAH (Affinity Capture-Western), USP19 (Affinity Capture-Western), USP19 (Co-localization), PAH (Affinity Capture-MS)

ESM2 similar proteins: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, G8BAW7, O17446, O42091, O80452, P00365, P00439, P04176, P04177, P07101, P09810, P11982, P15274, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P23225, P24529, P34466, P50998, P70080, P90925, P90986, Q0EAB8, Q0U2R3, Q10289, Q2HZ26, Q2KIH7, Q4W9F7, Q4WED9, Q54XS1, Q6BIV1

Diamond homologs: A0A060X6Z0, A8HQD7, A8X3V8, E5KBU3, E5KBU4, F5BFC8, O17446, O42091, P00439, P04176, P04177, P07101, P09810, P11982, P16331, P17276, P17289, P17290, P17532, P17752, P18459, P24529, P30967, P43334, P70080, P90925, P90986, Q0EAB8, Q2HZ26, Q2KIH7, Q54XS1, Q76IQ3, Q8CGU9, Q8CGV2, Q8IWU9, Q8XU39, Q92142, Q98D72, Q9A7V7, Q9KLB8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
“UVB radiation”	up-regulates	PAH
PAH	“down-regulates quantity”	phenylalanine	“chemical modification”
PAH	“up-regulates quantity”	tyrosine	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

1626 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	437
Likely pathogenic	378
Uncertain significance	308
Likely benign	338
Benign	57

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
102465	NM_000277.3(PAH):c.1006C>T (p.Gln336Ter)	Pathogenic
102468	NM_000277.3(PAH):c.1012G>T (p.Asp338Tyr)	Pathogenic
102470	NM_000277.3(PAH):c.1021A>T (p.Lys341Ter)	Pathogenic
102474	NM_000277.3(PAH):c.1024G>C (p.Ala342Pro)	Pathogenic
102475	NM_000277.3(PAH):c.1024del (p.Ala342fs)	Pathogenic
102484	NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)	Pathogenic
102487	NM_000277.3(PAH):c.1038del (p.Leu347fs)	Pathogenic
102489	NM_000277.3(PAH):c.1043_1053del (p.Leu348fs)	Pathogenic
102492	NM_000277.3(PAH):c.1046C>T (p.Ser349Leu)	Pathogenic
102497	NM_000277.3(PAH):c.1054G>T (p.Gly352Cys)	Pathogenic
102498	NM_000277.3(PAH):c.1055del (p.Gly352fs)	Pathogenic
102499	NM_000277.3(PAH):c.1056del (p.Glu353fs)	Pathogenic
102500	NM_000277.3(PAH):c.1063C>T (p.Gln355Ter)	Pathogenic
102509	NM_000277.3(PAH):c.1066-1G>A	Pathogenic
102515	NM_000277.3(PAH):c.1084C>A (p.Pro362Thr)	Pathogenic
102518	NM_000277.3(PAH):c.1089del (p.Lys363fs)	Pathogenic
102522	NM_000277.3(PAH):c.1099dup (p.Leu367fs)	Pathogenic
102524	NM_000277.3(PAH):c.1099del (p.Leu367fs)	Pathogenic
102530	NM_000277.3(PAH):c.1117_1118del (p.Ala373fs)	Pathogenic
102531	NM_000277.3(PAH):c.111dup (p.Ile38fs)	Pathogenic
102532	NM_000277.3(PAH):c.1127del (p.Asn376fs)	Pathogenic
102538	NM_000277.3(PAH):c.1157A>G (p.Tyr386Cys)	Pathogenic
102541	NM_000277.3(PAH):c.1162G>C (p.Val388Leu)	Pathogenic
102542	NM_000277.3(PAH):c.1163_1164del (p.Val388fs)	Pathogenic
102543	NM_000277.3(PAH):c.1166del (p.Ala389fs)	Pathogenic
102547	NM_000277.3(PAH):c.1183G>C (p.Ala395Pro)	Pathogenic
102549	NM_000277.3(PAH):c.1184C>G (p.Ala395Gly)	Pathogenic
102554	NM_000277.3(PAH):c.1198del (p.Arg400fs)	Pathogenic
102556	NM_000277.3(PAH):c.1199+1G>A	Pathogenic
102557	NM_000277.3(PAH):c.1199+1G>C	Pathogenic

SpliceAI

2057 predictions. Top by Δscore:

Variant	Effect	Δscore
12:102843780:C:CC	acceptor_gain	1.0000
12:102852951:C:CC	acceptor_gain	1.0000
12:102855134:A:AC	donor_gain	1.0000
12:102855135:C:CC	donor_gain	1.0000
12:102855135:CT:C	donor_gain	1.0000
12:102855135:CTCTG:C	donor_gain	1.0000
12:102866594:A:AC	donor_gain	1.0000
12:102866595:C:CC	donor_gain	1.0000
12:102866595:CTGG:C	donor_gain	1.0000
12:102894730:CTTA:C	donor_loss	1.0000
12:102894731:TTACC:T	donor_loss	1.0000
12:102894732:TA:T	donor_loss	1.0000
12:102894733:A:AC	donor_gain	1.0000
12:102894734:C:CC	donor_gain	1.0000
12:102894914:TTCTC:T	acceptor_gain	1.0000
12:102894916:CTC:C	acceptor_gain	1.0000
12:102894917:TCCTA:T	acceptor_loss	1.0000
12:102894919:C:A	acceptor_loss	1.0000
12:102894919:C:CC	acceptor_gain	1.0000
12:102894920:T:A	acceptor_loss	1.0000
12:102912786:CTGA:C	donor_loss	1.0000
12:102912787:TGA:T	donor_loss	1.0000
12:102912788:GA:G	donor_loss	1.0000
12:102912789:AC:A	donor_loss	1.0000
12:102912790:CC:C	donor_loss	1.0000
12:102839219:C:CA	acceptor_loss	0.9900
12:102840398:A:AC	donor_gain	0.9900
12:102840399:C:CC	donor_gain	0.9900
12:102843789:CCAAG:C	acceptor_gain	0.9900
12:102851757:C:CC	acceptor_gain	0.9900

AlphaMissense

2964 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:102852895:G:C	F254L	1.000
12:102852895:G:T	F254L	1.000
12:102852897:A:G	F254L	1.000
12:102844408:A:C	F331L	0.999
12:102844408:A:T	F331L	0.999
12:102844410:A:G	F331L	0.999
12:102844412:T:A	E330V	0.999
12:102846944:C:T	G307D	0.999
12:102851700:G:T	A300D	0.999
12:102844370:C:T	G344D	0.998
12:102844406:C:T	G332E	0.998
12:102844407:C:A	G332W	0.998
12:102846936:A:G	S310P	0.998
12:102846941:A:G	L308P	0.998
12:102846945:C:G	G307R	0.998
12:102852875:C:G	R261P	0.998
12:102852881:G:T	A259D	0.998
12:102852896:A:G	F254S	0.998
12:102852937:G:C	F240L	0.998
12:102852937:G:T	F240L	0.998
12:102852939:A:G	F240L	0.998
12:102844370:C:A	G344V	0.997
12:102844403:A:G	L333P	0.997
12:102846902:A:G	L321P	0.997
12:102846932:A:G	L311P	0.997
12:102846944:C:A	G307V	0.997
12:102851729:A:C	H290Q	0.997
12:102851729:A:T	H290Q	0.997
12:102851730:T:G	H290P	0.997
12:102851731:G:C	H290D	0.997

dbSNP variants (sampled 300 via entrez): RS1000018778 (12:102881550 A>T), RS1000049807 (12:102860374 A>C,G), RS1000066927 (12:102923699 G>C), RS1000099896 (12:102918557 T>C), RS1000123121 (12:102945856 C>T), RS1000124271 (12:102860139 T>C), RS1000145415 (12:102874524 C>G,T), RS1000174689 (12:102861779 A>G), RS1000189362 (12:102947231 T>C), RS1000233052 (12:102942495 C>A,T), RS1000261350 (12:102876070 G>T), RS1000262323 (12:102866347 G>A), RS1000271864 (12:102856163 A>T), RS1000278727 (12:102958174 T>TC), RS1000352363 (12:102955538 T>G)

Disease associations

OMIM: gene MIM:612349 | disease phenotypes: MIM:261600, MIM:616531, MIM:261640, MIM:178600, MIM:262600, MIM:606054

GenCC curated gene-disease

Disease	Classification	Inheritance
phenylketonuria	Definitive	Autosomal recessive
maternal phenylketonuria	Supportive	Autosomal recessive
tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria	Supportive	Autosomal recessive
mild phenylketonuria	Supportive	Autosomal recessive
classic phenylketonuria	Supportive	Autosomal recessive
mild hyperphenylalaninemia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
phenylketonuria	Definitive	AR

Mondo (14): phenylketonuria (MONDO:0009861), intellectual disability (MONDO:0001071), polymicrogyria, perisylvian, with cerebellar hypoplasia and arthrogryposis (MONDO:0014679), breast cancer (MONDO:0007254), mild hyperphenylalaninemia (MONDO:0019335), BH4-deficient hyperphenylalaninemia A (MONDO:0009863), pulmonary hypertension, primary, 1 (MONDO:0024533), pituitary hormone deficiency, combined, 2 (MONDO:0009878), RASopathy (MONDO:0021060), propionic acidemia (MONDO:0011628), maternal phenylketonuria (MONDO:0016366), tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria (MONDO:0017389), mild phenylketonuria (MONDO:0019258), classic phenylketonuria (MONDO:0019259)

Orphanet (8): Phenylketonuria (Orphanet:716), Mild hyperphenylalaninemia (Orphanet:79651), 6-pyruvoyl-tetrahydropterin synthase deficiency (Orphanet:13), Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet:238583), Idiopathic/heritable pulmonary arterial hypertension (Orphanet:422), RASopathy (Orphanet:536391), Propionic acidemia (Orphanet:35), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

58 total (30 of 58 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000286	Epicanthus
HP:0000340	Sloping forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000431	Wide nasal bridge
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000518	Cataract
HP:0000601	Hypotelorism
HP:0000635	Blue irides
HP:0000709	Psychosis
HP:0000716	Depression
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000742	Self-mutilation
HP:0000752	Hyperactivity
HP:0000958	Dry skin
HP:0000964	Eczematoid dermatitis
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001347	Hyperreflexia
HP:0001488	Bilateral ptosis
HP:0001511	Intrauterine growth retardation

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST007382_20	Plasma free amino acid levels (adjusted for twenty other PFAAs)	8.000000e-12
GCST007383_13	Plasma free amino acid levels (adjusted for one other PFAA)	4.000000e-13
GCST007383_14	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-11
GCST007383_15	Plasma free amino acid levels (adjusted for one other PFAA)	3.000000e-11
GCST007383_16	Plasma free amino acid levels (adjusted for one other PFAA)	7.000000e-11
GCST007383_17	Plasma free amino acid levels (adjusted for one other PFAA)	8.000000e-10
GCST007383_6	Plasma free amino acid levels (adjusted for one other PFAA)	2.000000e-09
GCST007383_81	Plasma free amino acid levels (adjusted for one other PFAA)	1.000000e-07
GCST007385_11	Plasma free amino acid levels	6.000000e-10
GCST008097_3	Bisphosphonate-associated atypical femoral fracture	4.000000e-07
GCST009240_390	Serum metabolite levels (CMS)	7.000000e-12
GCST009242_198	Serum metabolite levels	2.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005001	phenylalanine measurement
EFO:0005134	amino acid measurement
EFO:0009771	methionine measurement
EFO:0005058	tyrosine measurement
EFO:0009958	response to bisphosphonate
EFO:0009960	atypical femoral fracture

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D017042	Phenylketonuria, Maternal	C10.228.140.163.100.687.500; C12.050.703.575; C16.320.565.100.766.500; C16.320.565.189.687.500; C18.452.132.100.687.500; C18.452.648.100.766.500; C18.452.648.189.687.500
D010661	Phenylketonurias	C10.228.140.163.100.687; C16.320.565.100.766; C16.320.565.189.687; C18.452.132.100.687; C18.452.648.100.766; C18.452.648.189.687
D056693	Propionic Acidemia	C16.320.565.100.823; C18.452.648.100.823
C535325	6-pyruvoyl-tetrahydropterin synthase deficiency (supp.)
C563172	Pituitary Hormone Deficiency, Combined, 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3076 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

15 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs138809906	Metabolism/PK	3	l-phenylalanine
rs138809906	Metabolism/PK	3	carbocisteine
rs5030843	Metabolism/PK	3	l-phenylalanine
rs5030843	Metabolism/PK	3	carbocisteine
rs5030849	Metabolism/PK	3	l-phenylalanine
rs5030849	Metabolism/PK	3	carbocisteine
rs5030858	Metabolism/PK	3	l-phenylalanine
rs5030858	Metabolism/PK	3	carbocisteine
rs5030860	Metabolism/PK	3	carbocisteine
rs5030860	Metabolism/PK	3	l-phenylalanine
rs62516101	Metabolism/PK	3	carbocisteine
rs62516101	Metabolism/PK	3	l-phenylalanine
rs75193786	Metabolism/PK	3	carbocisteine
rs76394784	Metabolism/PK	3	carbocisteine
rs76394784	Metabolism/PK	3	l-phenylalanine

PharmGKB variants

9 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2245360	PAH		0.00	0
rs75193786	PAH	3	0.00	1	carbocisteine
rs5030843	PAH	3	0.00	2	l-phenylalanine;carbocisteine
rs138809906	PAH	3	0.00	2	l-phenylalanine;carbocisteine
rs5030849	PAH	3	0.00	2	l-phenylalanine;carbocisteine
rs5030858	PAH	3	0.00	2	l-phenylalanine;carbocisteine
rs5030860	PAH	3	0.00	2	carbocisteine;l-phenylalanine
rs76394784	PAH	3	0.00	2	carbocisteine;l-phenylalanine
rs62516101	PAH	3	0.00	2	carbocisteine;l-phenylalanine

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Amino acid hydroxylases

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
sapropterin	Activation	5.4	pKi

Binding affinities (BindingDB)

1 measured of 1 human assays (1 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
6-methyl-7,8-dihydro-5H-[1,3]dioxolo[4,5-g]isoquinolin-5-ol	KD	2990 nM	US-12257253: Triamterene or nolatrexed for use in the treatment of phenylketonuria

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.00	IC50	1000	nM	CHEMBL187878
5.16	Ki	7000	nM	CHEMBL187878

PubChem BioAssay actives

2 with measured affinity, of 5 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-amino-7-(1,2-dihydroxypropyl)-5,6,7,8-tetrahydro-3H-pteridin-4-one	241466: Inhibitory concentration against human phenylalanine hydroxylase	ic50	1.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	7
Cyclosporine	decreases expression, affects cotreatment	4
Acetaminophen	decreases expression, increases expression, affects cotreatment	3
Tetrachlorodibenzodioxin	decreases expression	3
sodium arsenite	affects methylation, decreases expression	2
entinostat	increases expression, affects cotreatment	2
Valproic Acid	decreases expression, increases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1
bisphenol A	affects expression	1
deoxynivalenol	decreases expression	1
kojic acid	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(k)fluoranthene	decreases expression	1
perfluorooctanoic acid	decreases expression	1
1,2,5,6-dibenzanthracene	decreases expression	1
periodate-oxidized adenosine	affects expression	1
benz(a)anthracene	decreases expression	1
chrysene	decreases expression	1
phenanthrene	decreases expression	1
naphthalene	decreases expression	1
indeno(1,2,3-cd)pyrene	decreases expression	1
nefazodone	affects cotreatment, decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Azathioprine	decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3636737	Binding	Inhibition of human PAH by DSF assay using L-Phe as substrate and 75 uM BH4 as cofactor	Discovery of a Specific Inhibitor of Pyomelanin Synthesis in Legionella pneumophila. — J Med Chem

Cellosaurus cell lines

18 cell lines: 7 induced pluripotent stem cell, 6 transformed cell line, 4 finite cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_9R62	GM01565	Transformed cell line	Female
CVCL_9R88	GM11110	Transformed cell line	Male
CVCL_9R90	GM11195	Transformed cell line	Male
CVCL_9R91	GM11196	Transformed cell line	Male
CVCL_D6RJ	WIMRi001-A	Induced pluripotent stem cell	Male
CVCL_D6RK	WIMRi002-A	Induced pluripotent stem cell	Female
CVCL_D6RL	WIMRi003-A	Induced pluripotent stem cell	Male
CVCL_D6RM	WIMRi004-A	Induced pluripotent stem cell	Male
CVCL_D6YU	GM28788	Transformed cell line	Male
CVCL_E1L5	HyCyte Hep-G2 KO-hPAH	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01082328	PHASE4	COMPLETED	Response to Kuvan® in Subjects With Phenylketonuria (PKU) in a 4 Weeks Testing Period
NCT01617070	PHASE4	COMPLETED	Effects of Kuvan on Melatonin Secretion
NCT01965912	PHASE4	COMPLETED	Kuvan®’s Effect on the Cognition of Children With Phenylketonuria
NCT02677870	PHASE4	COMPLETED	The Effectiveness of Kuvan in Amish PKU Patients
NCT03788343	PHASE4	COMPLETED	Phenylalanine and Its Impact on Cognition
NCT04227080	PHASE4	UNKNOWN	BH4 Responsiveness in PAH Deficiency PKU Patients
NCT06780332	PHASE4	ACTIVE_NOT_RECRUITING	Rapid Drug Desensitization Study in Adults Experiencing Hypersensitivity Reactions to Palynziq
NCT06901323	PHASE4	ACTIVE_NOT_RECRUITING	Effect of L-carnitine Supplementation on Phenylalanine and Brain-derived Neurotrophic Factor Levels in Infants and Children With Phenylketonuria
NCT07477691	PHASE4	NOT_YET_RECRUITING	Immune Modulation During Palynziq® Treatment in Adults (IMPALA)
NCT00104247	PHASE3	COMPLETED	Study to Evaluate the Safety and Efficacy of Phenoptin™ in Subjects With Phenylketonuria Who Have Elevated Phenylalanine Levels
NCT00225615	PHASE3	COMPLETED	A Phase 3, Multicenter, Open-Label Extension Study of Phenoptin in Subjects With PKU Who Have Elevated Phenylalanine Levels
NCT00272792	PHASE3	COMPLETED	Study of Phenoptin to Increase Phenylalanine Tolerance in Phenylketonuric Children on a Phenylalanine-restricted Diet
NCT00332189	PHASE3	COMPLETED	Study of Phenoptin in Subjects With Phenylketonuria Who Participated in Protocols PKU-004 or PKU-006
NCT00838435	PHASE3	COMPLETED	Effect of Kuvan on Neurocognitive Function, Blood Phenylalanine Level, Safety, and Pharmacokinetics in Children With PKU
NCT01114737	PHASE3	COMPLETED	Safety and Therapeutic Effects of Sapropterin Dihydrochloride on Neuropsychiatric Symptoms in Phenylketonuria (PKU) Patients
NCT01376908	PHASE3	COMPLETED	Kuvan® in Phenylketonuria Patients Less Than 4 Years Old
NCT01732471	PHASE3	COMPLETED	Phase 3 Open-label Study to Evaluate the Response and Safety of Kuvan® in Subjects With Phenylketonuria
NCT01819727	PHASE3	COMPLETED	An Open-Label Phase 3 Study of BMN 165 for Adults With PKU Not Previously Treated w/ BMN 165
NCT01889862	PHASE3	COMPLETED	Phase 3 Study to Evaluate the Efficacy & Safety of Self-Administered Injections of BMN165 by Adults With PKU
NCT03694353	PHASE3	COMPLETED	Safety and Efficacy of Self Administered Injections of Pegvaliase (>40mg/Day Dose) in Adults With PKU
NCT05099640	PHASE3	COMPLETED	A Study of PTC923 in Participants With Phenylketonuria
NCT05166161	PHASE3	ACTIVE_NOT_RECRUITING	A Long-Term Safety Study of PTC923 in Participants With Phenylketonuria
NCT05270837	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate the Safety and Efficacy of Pegvaliase in Adolescents (Ages 12-17) With Phenylketonuria
NCT05764239	PHASE3	TERMINATED	Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
NCT06302348	PHASE3	RECRUITING	A Study of Sepiapterin in Participants With Phenylketonuria (PKU)
NCT06628128	PHASE3	RECRUITING	A Long-Term Study of JNT-517 in Participants With Phenylketonuria
NCT06971731	PHASE3	RECRUITING	A Study of JNT-517 in Participants With Phenylketonuria (PKU)
NCT00104260	PHASE2	COMPLETED	Study to Evaluate the Response to and Safety of an 8-Day Course of Phenoptin™ Treatment in Subjects With Phenylketonuria
NCT00260000	PHASE2	COMPLETED	Study of BH4, a New and Simple Treatment of Mild PKU
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NCT01395394	PHASE2	TERMINATED	Phenylketonuria, Oxidative Stress, and BH4
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