Phenylketonuria

Summary

Phenylketonuria (MONDO:0009861) is a disease (an umbrella term covering 5 Mondo subtypes) caused by PAH (GenCC Definitive), with 8 cohort genes and 167 clinical trials. Top therapeutic interventions include sapropterin, pegvaliase, and amino acids.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: PAH (GenCC Definitive)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 8
• ClinVar variants: 1,569
• Phenotypes (HPO): 25
• Clinical trials: 167

Clinical features

Epidemiology

Prevalence records

103 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	4.1366	Worldwide	Validated
Prevalence at birth	1-9 / 100 000	6.4	Worldwide	Validated
Point prevalence	1-5 / 10 000	11.5079	Europe	Validated
Prevalence at birth	1-5 / 10 000	11.4	Europe	Validated
Point prevalence	1-5 / 10 000	10.99	France	Validated
Point prevalence	1-5 / 10 000	10	United Kingdom	Validated
Point prevalence	1-5 / 10 000	22	Ireland	Validated
Point prevalence	1-9 / 1 000 000	0.8928	Finland	Validated
Point prevalence	1-9 / 100 000	4	United States	Validated
Point prevalence	1-9 / 100 000	3.5999	Latin America	Validated
Point prevalence	1-9 / 100 000	4	Brazil	Validated
Point prevalence	1-9 / 100 000	8.89	Australia	Validated
Point prevalence	1-5 / 10 000	11.9	Iceland	Validated
Point prevalence	1-9 / 1 000 000	0.8	Japan	Validated
Point prevalence	1-9 / 100 000	6.2798	China	Validated
Point prevalence	1-9 / 1 000 000	0.4399	Thailand	Validated
Point prevalence	1-5 / 10 000	14.99	Turkey	Validated
Point prevalence	1-9 / 100 000	6.89	United Arab Emirates	Validated
Point prevalence	1-5 / 10 000	20	Jordan	Validated
Point prevalence	1-9 / 100 000	5.4644	India	Validated

Signs & symptoms

Clinical features (HPO)

25 HPO clinical features (Orphanet curated; top 25 by frequency):

HPO ID	Term	Frequency
HP:0032351	Phenylalaninuria	Very frequent (80-99%)
HP:0000252	Microcephaly	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000938	Osteopenia	Frequent (30-79%)
HP:0000964	Eczematoid dermatitis	Frequent (30-79%)
HP:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001328	Specific learning disability	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002353	EEG abnormality	Frequent (30-79%)
HP:0002500	Abnormal cerebral white matter morphology	Frequent (30-79%)
HP:0004923	Hyperphenylalaninemia	Frequent (30-79%)
HP:0010864	Intellectual disability, severe	Frequent (30-79%)
HP:0410021	Musty odor	Frequent (30-79%)
HP:0000716	Depression	Occasional (5-29%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000736	Short attention span	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001298	Encephalopathy	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002061	Lower limb spasticity	Occasional (5-29%)
HP:0030680	Abnormal cardiovascular system morphology	Occasional (5-29%)
HP:0100704	Cerebral visual impairment	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	phenylketonuria
Mondo ID	MONDO:0009861
MeSH	D010661
OMIM	261600
Orphanet	716
DOID	DOID:9281
ICD-11	444122923
NCIT	C81315
SNOMED CT	7573000
UMLS	C0031485
MedGen	19244
GARD	0007383
MedDRA	10034872
NORD	1574
Is cancer (heuristic)	no

Also known as: hyperphenylalaninemia, non-PKU mild · PAH deficiency · phenylalanine hydroxylase deficiency · phenylketonuria · PKU

Data availability: 1,569 ClinVar variants · 813 ClinGen variant curations · 4 GenCC gene-disease records · 31 cell lines.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › phenylketonuria

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

Subtypes (5): maternal phenylketonuria, tetrahydrobiopterin-responsive hyperphenylalaninemia/phenylketonuria, mild phenylketonuria, classic phenylketonuria, mild 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

600 retrieved; paginated sample, class counts are floors:

200 pathogenic, 180 likely pathogenic, 97 likely benign, 87 uncertain significance, 19 pathogenic/likely pathogenic, 12 benign, 4 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
102873	NM_000277.3(PAH):c.843-2A>T	LOC126861615	Pathogenic	reviewed by expert panel
102874	NM_000277.3(PAH):c.844G>A (p.Asp282Asn)	LOC126861615	Pathogenic	criteria provided, multiple submitters, no conflicts
102875	NM_000277.3(PAH):c.845A>G (p.Asp282Gly)	LOC126861615	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102876	NM_000277.3(PAH):c.847A>T (p.Ile283Phe)	LOC126861615	Pathogenic	criteria provided, multiple submitters, no conflicts
102877	NM_000277.3(PAH):c.848T>A (p.Ile283Asn)	LOC126861615	Pathogenic	reviewed by expert panel
102880	NM_000277.3(PAH):c.856G>A (p.Glu286Lys)	LOC126861615	Pathogenic	reviewed by expert panel
102882	NM_000277.3(PAH):c.865G>C (p.Gly289Arg)	LOC126861615	Pathogenic	reviewed by expert panel
102884	NM_000277.3(PAH):c.884C>G (p.Ser295Ter)	LOC126861615	Pathogenic	reviewed by expert panel
102888	NM_000277.3(PAH):c.907del (p.Ser303fs)	LOC126861615	Pathogenic	reviewed by expert panel
1065376	NM_000277.3(PAH):c.843-1G>A	LOC126861615	Pathogenic	reviewed by expert panel
1065384	NM_000277.3(PAH):c.510-735_912+434del	LOC126861615	Pathogenic	reviewed by expert panel
120292	NM_000277.3(PAH):c.912+2T>C	LOC126861615	Pathogenic	reviewed by expert panel
102465	NM_000277.3(PAH):c.1006C>T (p.Gln336Ter)	PAH	Pathogenic	reviewed by expert panel
102468	NM_000277.3(PAH):c.1012G>T (p.Asp338Tyr)	PAH	Pathogenic	reviewed by expert panel
102470	NM_000277.3(PAH):c.1021A>T (p.Lys341Ter)	PAH	Pathogenic	reviewed by expert panel
102473	NM_000277.3(PAH):c.1024G>A (p.Ala342Thr)	PAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102474	NM_000277.3(PAH):c.1024G>C (p.Ala342Pro)	PAH	Pathogenic	criteria provided, multiple submitters, no conflicts
102475	NM_000277.3(PAH):c.1024del (p.Ala342fs)	PAH	Pathogenic	reviewed by expert panel
102477	NM_000277.3(PAH):c.1028A>G (p.Tyr343Cys)	PAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102484	NM_000277.3(PAH):c.1033G>T (p.Ala345Ser)	PAH	Pathogenic	reviewed by expert panel
102487	NM_000277.3(PAH):c.1038del (p.Leu347fs)	PAH	Pathogenic	reviewed by expert panel
102489	NM_000277.3(PAH):c.1043_1053del (p.Leu348fs)	PAH	Pathogenic	reviewed by expert panel
102490	NM_000277.3(PAH):c.1045T>G (p.Ser349Ala)	PAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102492	NM_000277.3(PAH):c.1046C>T (p.Ser349Leu)	PAH	Pathogenic	criteria provided, multiple submitters, no conflicts
102495	NM_000277.3(PAH):c.1049C>A (p.Ser350Tyr)	PAH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
102497	NM_000277.3(PAH):c.1054G>T (p.Gly352Cys)	PAH	Pathogenic	reviewed by expert panel
102498	NM_000277.3(PAH):c.1055del (p.Gly352fs)	PAH	Pathogenic	reviewed by expert panel
102499	NM_000277.3(PAH):c.1056del (p.Glu353fs)	PAH	Pathogenic	reviewed by expert panel
102500	NM_000277.3(PAH):c.1063C>T (p.Gln355Ter)	PAH	Pathogenic	reviewed by expert panel
102509	NM_000277.3(PAH):c.1066-1G>A	PAH	Pathogenic	reviewed by expert panel

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 21 · 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
PAH	Definitive	Autosomal recessive	phenylketonuria	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PAH	Orphanet:2209	Maternal phenylketonuria syndrome
PAH	Orphanet:293284	Tetrahydrobiopterin-responsive phenylketonuria
PAH	Orphanet:708895	Tetrahydrobiopterin-unresponsive phenylketonuria
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta
NSUN2	Orphanet:235	Dubowitz syndrome
NSUN2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
FDXR	Orphanet:542585	Auditory neuropathy-optic atrophy syndrome
FDXR	Orphanet:543470	Optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome
ASCL1	Orphanet:99803	Haddad syndrome
PI4KA	Orphanet:436252	Combined immunodeficiency-multiple intestinal atresia
PI4KA	Orphanet:631079	Autosomal recessive spastic paraplegia type 84
PI4KA	Orphanet:98889	Bilateral perisylvian polymicrogyria

Cohort genes → proteins

8 cohort genes, 8 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PAH	HGNC:8582	ENSG00000171759	P00439	Phenylalanine-4-hydroxylase	gencc,clinvar
SLC7A5	HGNC:11063	ENSG00000103257	Q01650	Large neutral amino acids transporter small subunit 1	clinvar
TSPAN1	HGNC:20657	ENSG00000117472	O60635	Tetraspanin-1	clinvar
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	clinvar
NSUN2	HGNC:25994	ENSG00000037474	Q08J23	RNA cytosine C(5)-methyltransferase NSUN2	clinvar
FDXR	HGNC:3642	ENSG00000161513	P22570	NADPH:adrenodoxin oxidoreductase, mitochondrial	clinvar
ASCL1	HGNC:738	ENSG00000139352	P50553	Achaete-scute homolog 1	clinvar
PI4KA	HGNC:8983	ENSG00000241973	P42356	Phosphatidylinositol 4-kinase alpha	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PAH	Phenylalanine-4-hydroxylase	Catalyzes the hydroxylation of L-phenylalanine to L-tyrosine.
SLC7A5	Large neutral amino acids transporter small subunit 1	The heterodimer with SLC3A2 functions as a sodium-independent, high-affinity transporter that mediates uptake of large neutral amino acids such as phenylalanine, tyrosine, leucine, histidine, methionine, tryptophan, valine, isoleucine and…
TSPAN1	Tetraspanin-1	Structural component of specialized membrane microdomains known as tetraspanin-enriched microdomains (TERMs), which act as platforms for receptor clustering and signaling.
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
NSUN2	RNA cytosine C(5)-methyltransferase NSUN2	RNA cytosine C(5)-methyltransferase that methylates cytosine to 5-methylcytosine (m5C) in various RNAs, such as tRNAs, mRNAs and some long non-coding RNAs (lncRNAs).
FDXR	NADPH:adrenodoxin oxidoreductase, mitochondrial	Serves as the first electron transfer protein in all the mitochondrial P450 systems including cholesterol side chain cleavage in all steroidogenic tissues, steroid 11-beta hydroxylation in the adrenal cortex, 25-OH-vitamin D3-24 hydroxylat…
ASCL1	Achaete-scute homolog 1	Transcription factor that plays a key role in neuronal differentiation: acts as a pioneer transcription factor, accessing closed chromatin to allow other factors to bind and activate neural pathways.
PI4KA	Phosphatidylinositol 4-kinase alpha	Acts on phosphatidylinositol (PtdIns) in the first committed step in the production of the second messenger inositol-1,4,5,-trisphosphate.

Protein-family classification

Druggable: 4 · Difficult: 1 · Unknown: 3 · Druggable fraction: 0.5

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
Transporter	1	9.7×	0.348
Enzyme (other)	2	3.0×	0.348
Kinase	1	3.5×	0.424
Transcription factor	1	1.0×	0.805
Other/Unknown	3	0.7×	0.919

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PAH	Enzyme (other)	yes	1.14.16.1	ArAA_hydroxylase, ACT_dom, Phe-4-hydroxylase_tetra
SLC7A5	Transporter	yes		AA/rel_permease1, L_AA_transporter, AminoAcid_Transporter
TSPAN1	Other/Unknown	no		Tetraspanin_animals, Tetraspanin_EC2_sf, Tetraspanin/Peripherin
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
NSUN2	Enzyme (other)	yes	2.1.1.202	MeTrfase_RsmB-F_NOP2_dom, RCMT, RCMT_NCL1
FDXR	Other/Unknown	no		Ferredox_Rdtase_adrenod, FAD/NAD-bd_sf, Ferredox_Rdtase
ASCL1	Transcription factor	no		bHLH_dom, MASH1/Ascl1a-like, HLH_DNA-bd_sf
PI4KA	Kinase	yes		PI3/4_kinase_cat_dom, PI3K_accessory_dom, Kinase-like_dom_sf

Expression context

Cohort genes with no expression data: 0.

8 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)	8
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gall bladder	1
liver	1
right lobe of liver	1
pigmented layer of retina	1
retina	1
type B pancreatic cell	1
bronchial epithelial cell	1
epithelium of bronchus	1
mucosa of transverse colon	1
periodontal ligament	1
skin of hip	1
stromal cell of endometrium	1
right uterine tube	1
secondary oocyte	1
upper arm skin	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1
CA1 field of hippocampus	1
ganglionic eminence	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PAH	175	broad	marker	right lobe of liver, liver, gall bladder
SLC7A5	275	ubiquitous	marker	pigmented layer of retina, retina, type B pancreatic cell
TSPAN1	206	broad	marker	bronchial epithelial cell, epithelium of bronchus, mucosa of transverse colon
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
NSUN2	260	ubiquitous	marker	upper arm skin, right uterine tube, secondary oocyte
FDXR	208	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland cortex
ASCL1	143	broad	marker	ganglionic eminence, ventricular zone, CA1 field of hippocampus
PI4KA	143	ubiquitous	marker	superior frontal gyrus, right frontal lobe, Brodmann (1909) area 9

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COL1A1	5,341
NSUN2	3,213
SLC7A5	2,685
ASCL1	2,422
FDXR	2,373
PAH	1,953
PI4KA	1,755
TSPAN1	949

Structural data

PDB: 5 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC7A5	Q01650	21
PAH	P00439	20
COL1A1	P02452	14
NSUN2	Q08J23	9
PI4KA	P42356	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FDXR	P22570	91.66
TSPAN1	O60635	88.31
ASCL1	P50553	68.22

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 60. Enrichment computed across 8 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
Phenylketonuria	1	1631.4×	0.023	PAH
Defective VWF binding to collagen type I	1	543.8×	0.023	COL1A1
Electron transport from NADPH to Ferredoxin	1	407.9×	0.023	FDXR
Enhanced cleavage of VWF variant by ADAMTS13	1	407.9×	0.023	COL1A1
Defective VWF cleavage by ADAMTS13 variant	1	407.9×	0.023	COL1A1
Synthesis of PIPs at the ER membrane	1	326.3×	0.023	PI4KA
Defective CYP11A1 causes AICSR	1	326.3×	0.023	FDXR
Cell surface interactions at the vascular wall	2	27.2×	0.023	SLC7A5, COL1A1
Phenylalanine metabolism	1	271.9×	0.023	PAH
Enhanced binding of GP1BA variant to VWF multimer:collagen	1	233.1×	0.023	COL1A1
Defective binding of VWF variant to GPIb:IX:V	1	233.1×	0.023	COL1A1
GP1b-IX-V activation signalling	1	135.9×	0.032	COL1A1
Metabolic disorders of biological oxidation enzymes	1	125.5×	0.032	FDXR
Mitochondrial iron-sulfur cluster biogenesis	1	116.5×	0.032	FDXR
Pregnenolone biosynthesis	1	116.5×	0.032	FDXR
Anchoring fibril formation	1	108.8×	0.032	COL1A1
Tryptophan catabolism	1	108.8×	0.032	SLC7A5
Cytochrome P450 - arranged by substrate type	1	102.0×	0.032	FDXR
Platelet Adhesion to exposed collagen	1	96.0×	0.032	COL1A1
Synthesis of PIPs at the Golgi membrane	1	90.6×	0.032	PI4KA
Scavenging by Class A Receptors	1	85.9×	0.032	COL1A1
Fibronectin matrix formation	1	81.6×	0.032	COL1A1
Crosslinking of collagen fibrils	1	81.6×	0.032	COL1A1
Metabolism of steroid hormones	1	74.2×	0.034	FDXR
RUNX2 regulates osteoblast differentiation	1	65.3×	0.035	COL1A1
Basigin interactions	1	62.8×	0.035	SLC7A5
Platelet Aggregation (Plug Formation)	1	62.8×	0.035	COL1A1
Syndecan interactions	1	60.4×	0.035	COL1A1
Endogenous sterols	1	56.3×	0.036	FDXR
MET activates PTK2 signaling	1	54.4×	0.036	COL1A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to hyperoxia	2	280.9×	0.003	SLC7A5, COL1A1
noradrenergic neuron fate commitment	1	2106.5×	0.006	ASCL1
L-tyrosine biosynthetic process	1	2106.5×	0.006	PAH
neuroblast fate determination	1	2106.5×	0.006	ASCL1
amino acid biosynthetic process	1	2106.5×	0.006	PAH
meiotic cell cycle checkpoint signaling	1	2106.5×	0.006	NSUN2
regulation of timing of subpallium neuron differentiation	1	2106.5×	0.006	ASCL1
lung neuroendocrine cell differentiation	1	2106.5×	0.006	ASCL1
carotid body glomus cell differentiation	1	2106.5×	0.006	ASCL1
cellular response to magnetism	1	2106.5×	0.006	ASCL1
cellular response to vitamin E	1	2106.5×	0.006	COL1A1
reorganization of cellular membranes to establish viral sites of replication	1	2106.5×	0.006	PI4KA
positive regulation of L-leucine import across plasma membrane	1	2106.5×	0.006	SLC7A5
vestibular nucleus development	1	1053.2×	0.007	ASCL1
musculoskeletal movement, spinal reflex action	1	1053.2×	0.007	ASCL1
subpallium neuron fate commitment	1	1053.2×	0.007	ASCL1
adrenal chromaffin cell differentiation	1	1053.2×	0.007	ASCL1
cellular response to fluoride	1	1053.2×	0.007	COL1A1
L-tryptophan transmembrane transport	1	1053.2×	0.007	SLC7A5
methionine transport	1	702.2×	0.007	SLC7A5
tyrosine transport	1	702.2×	0.007	SLC7A5
spinal cord oligodendrocyte cell fate specification	1	702.2×	0.007	ASCL1
cerebral cortex GABAergic interneuron differentiation	1	702.2×	0.007	ASCL1
tooth mineralization	1	702.2×	0.007	COL1A1
catecholamine biosynthetic process	1	702.2×	0.007	PAH
olfactory pit development	1	702.2×	0.007	ASCL1
ventral spinal cord interneuron fate commitment	1	702.2×	0.007	ASCL1
stomach neuroendocrine cell differentiation	1	702.2×	0.007	ASCL1
L-histidine transport	1	702.2×	0.007	SLC7A5
cellular response to L-arginine	1	702.2×	0.007	SLC7A5

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Pegvaliase	Approved (phase 4)
Sepiapterin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Sapropterin.

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 5

Druggability breadth: 5 of 8 evidence-associated genes (62%) 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
SLC7A5	LEVODOPA
PI4KA	ADENOSINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC7A5	6	4
NSUN2	1	2
PI4KA	1	4
PAH	0	0
TSPAN1	0	0
COL1A1	0	0
FDXR	0	0
ASCL1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LEVODOPA	4	SLC7A5
TYROSINE	4	SLC7A5
ADENOSINE	4	PI4KA
LEUCINE	3	SLC7A5
PHENYLALANINE	3	SLC7A5
HISTIDINE	2	SLC7A5
VALINE	2	SLC7A5
MOLIBRESIB	2	NSUN2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PI4KA	86	Binding:83, Functional:2, ADMET:1
SLC7A5	80	Binding:71, ADMET:9
NSUN2	11	Binding:11
COL1A1	8	Binding:8
PAH	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PAH	1.14.16.1	phenylalanine 4-monooxygenase
NSUN2	2.1.1.202, 2.1.1.203	multisite-specific tRNA:(cytosine-C5)-methyltransferase, tRNA (cytosine34-C5)-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

7 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)
LEVODOPA	4	SLC7A5
TYROSINE	4	SLC7A5
ADENOSINE	4	PI4KA
LEUCINE	3	SLC7A5
HISTIDINE	2	SLC7A5
VALINE	2	SLC7A5
MOLIBRESIB	2	NSUN2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC7A5, PI4KA
B	Phased (≥1) drug, not yet approved	1	NSUN2
C	Druggable family + PDB, no drug	1	PAH
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TSPAN1, COL1A1, FDXR, ASCL1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PAH	4	—
TSPAN1	0	—
COL1A1	8	—
FDXR	0	—
ASCL1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 167.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	106
PHASE3	18
PHASE2	12
PHASE4	9
PHASE1/PHASE2	9
PHASE1	9
EARLY_PHASE1	3
PHASE2/PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
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)
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
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
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)
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
NCT00432822	PHASE2/PHASE3	TERMINATED	Long-Term Tetrahydrobiopterin Treatment in PKU Patients of 0-18 Years - Study on Phenylalanine Tolerance and Safety
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
NCT05764239	PHASE3	TERMINATED	Efficacy and Safety of SYNB1934 in Patients With PKU (SYNPHENY-3)
NCT04480567	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	AAV Gene Therapy Study for Subjects with PKU
NCT05972629	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Phase 1/Phase 2 Open-label Study to Evaluate the Safety, Tolerability, and Efficacy of a Single Intravenous Administration of SAR444836 in Adult Participants With Phenylketonuria
NCT06332807	PHASE1/PHASE2	RECRUITING	AAV Gene Therapy Clinical Study in Adult Classic PKU (PHEdom)
NCT06687733	PHASE1/PHASE2	RECRUITING	Safety and Efficacy Study of NGGT002 in cPKU Adult Subjects
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
NCT00841100	PHASE2	COMPLETED	Kuvan Therapy in Phenylketonuria (PKU): The Effect of Blood Phenylalanine Concentration on Kuvan Response
NCT00924703	PHASE2	COMPLETED	Long-Term Extension of Previous rAvPAL-PEG Protocols in Subjects With PKU (PAL-003)
NCT00925054	PHASE2	COMPLETED	Dose-Finding Study to Evaluate the Safety, Efficacy, & Tolerability of Multiple Doses of rAvPAL-PEG in Subjects With PKU
NCT01212744	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy Study of rAvPAL-PEG Administered Daily in Subjects With Phenylketonuria (PKU)
NCT01395394	PHASE2	TERMINATED	Phenylketonuria, Oxidative Stress, and BH4
NCT01465100	PHASE1/PHASE2	TERMINATED	Liver Cell Transplant for Phenylketonuria

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
SAPROPTERIN	4	42
PEGVALIASE	4	9
AMINO ACIDS	4	1
LEVOCARNITINE	4	1
SEPIAPTERIN	3	3
DOCONEXENT	3	1
PHENYLALANINE	3	1
LABAFENOGENE MARSELECOBAC	2	1
BEVUFENOGENE NOFEPARVOVEC	1	2
CHEMBL4063304	0	3
CHEMBL4439413	0	1
CYCLIC ADENOSINE MONOPHOSPHATE	0	1