PCBD1

Summary

PCBD1 (pterin-4 alpha-carbinolamine dehydratase 1, HGNC:8646) is a protein-coding gene on chromosome 10q22.1, encoding Pterin-4-alpha-carbinolamine dehydratase (P61457). Involved in tetrahydrobiopterin biosynthesis.

This gene encodes a member of the pterin-4-alpha-carbinolamine dehydratase family. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. The encoded protein functions as both a dehydratase involved in tetrahydrobiopterin biosynthesis, and as a cofactor for HNF1A-dependent transcription. A deficiency of this enzyme leads to hyperphenylalaninemia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5092 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pterin-4 alpha-carbinolamine dehydratase 1 deficiency (Definitive, ClinGen)
• GWAS associations: 7
• Clinical variants (ClinVar): 130 total — 7 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 18
• MANE Select transcript: NM_000281

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8646
Approved symbol	PCBD1
Name	pterin-4 alpha-carbinolamine dehydratase 1
Location	10q22.1
Locus type	gene with protein product
Status	Approved
Aliases	PCD
Ensembl gene	ENSG00000166228
Ensembl biotype	protein_coding
OMIM	126090
Entrez	5092

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000299299, ENST00000493228, ENST00000493961, ENST00000875521, ENST00000875522, ENST00000931187, ENST00000947467

RefSeq mRNA: 2 — MANE Select: NM_000281 NM_000281, NM_001289797

CCDS: CCDS31217

Canonical transcript exons

ENST00000299299 — 4 exons

Exon	Start	End
ENSE00001254988	70883510	70884048
ENSE00001304698	70888531	70888565
ENSE00003613239	70885798	70885929
ENSE00003688621	70885152	70885232

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.1208 / max 302.2024, expressed in 1808 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
109868	44.5793	1808
109865	0.2765	112
109867	0.2434	107
109866	0.0215	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.18	gold quality
body of pancreas	UBERON:0001150	98.62	gold quality
right adrenal gland cortex	UBERON:0035827	98.47	gold quality
right adrenal gland	UBERON:0001233	98.40	gold quality
left adrenal gland	UBERON:0001234	98.18	gold quality
left adrenal gland cortex	UBERON:0035825	98.16	gold quality
apex of heart	UBERON:0002098	98.02	gold quality
mucosa of transverse colon	UBERON:0004991	97.94	gold quality
body of stomach	UBERON:0001161	97.93	gold quality
right atrium auricular region	UBERON:0006631	97.92	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.76	gold quality
adrenal cortex	UBERON:0001235	97.68	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.65	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.65	gold quality
lower esophagus	UBERON:0013473	97.64	gold quality
liver	UBERON:0002107	97.59	gold quality
islet of Langerhans	UBERON:0000006	97.50	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.48	gold quality
adrenal gland	UBERON:0002369	97.42	gold quality
right coronary artery	UBERON:0001625	97.41	gold quality
adult mammalian kidney	UBERON:0000082	97.34	gold quality
heart left ventricle	UBERON:0002084	97.33	gold quality
rectum	UBERON:0001052	97.28	gold quality
left coronary artery	UBERON:0001626	97.17	gold quality
transverse colon	UBERON:0001157	97.13	gold quality
pancreas	UBERON:0001264	97.13	gold quality
cardiac ventricle	UBERON:0002082	97.05	gold quality
metanephros cortex	UBERON:0010533	96.99	gold quality
right uterine tube	UBERON:0001302	96.97	gold quality
adenohypophysis	UBERON:0002196	96.88	gold quality

Single-cell (SCXA)

Detected in 9 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	84.53
E-MTAB-8410	yes	46.61
E-HCAD-10	yes	41.23
E-MTAB-6701	yes	20.23
E-MTAB-9388	yes	12.15
E-MTAB-8271	yes	8.19
E-HCAD-13	yes	7.67
E-CURD-10	no	335.87
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
FXYD2	Repression

miRNA regulators (miRDB)

29 targeting PCBD1, 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-4482-3P	99.98	72.50	3147
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-4263	99.18	69.25	2236
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-3689A-5P	98.35	70.12	1049
HSA-MIR-3689B-5P	98.35	70.12	1049
HSA-MIR-3689E	98.35	70.12	1049
HSA-MIR-3689F	98.35	70.08	1052
HSA-MIR-4684-3P	98.24	69.91	1075
HSA-MIR-10526-3P	97.86	64.97	1342
HSA-MIR-204-3P	97.80	66.84	1656
HSA-MIR-4646-5P	97.70	66.84	1692
HSA-MIR-495-5P	97.62	68.28	682
HSA-MIR-6742-5P	96.32	64.01	869
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-6796-5P	95.37	66.08	1120
HSA-MIR-6840-5P	88.69	60.91	68

Literature-anchored findings (GeneRIF, showing 40)

• the Tsc1-Tsc2 complex antagonizes the TOR-mediated response to amino acid availability (PMID:12172555)
• Rheb functions in the insulin signaling pathway upstream of TOR. (PMID:12766776)
• Loss of Tsc1 and Tsc2 or ectopic activation of Rheb results in constitutive activation of TOR and renders S6K activity resistant to amino acid starvation. (PMID:12771962)
• S6 kinase (dS6K) and a single 4E-BP (d4E-BP) are phosphorylated via the insulin and target of rapamycin (TOR) signaling pathways. (PMID:14645523)
• results suggest that dTOR and dRictor have a shared positive role in the phosphorylation of the hydrophobic motif site of dAkt/dPKB (PMID:15718470)
• tap42 functions independently of target of rapamycin to regulate cell division and survival in Drosophila (PMID:15802506)
• TOR-mediated cell-cycle activation causes neurodegeneration in a Drosophila tauopathy model, identifying TOR and the cell cycle as potential therapeutic targets in tauopathies and Alzheimer Disease. (PMID:16461276)
• Endocytosis acts both as an effector function downstream of TOR and as a physiologically relevant regulator of TOR signaling. (PMID:16785324)
• Here, they show that reducing the function of Drosophila TOR results in decreased lipid stores and glucose levels. (PMID:16890541)
• Results show that mildly increasing systemic Rheb-TOR-S6K signaling sensitizes the whole organism to oxidative stress and promotes senescence of locomotor activity with age. (PMID:17038544)
• Rheb-TOR signaling controls S2 cell growth by promoting ribosome production and protein synthesis, not by direct effects on the import of amino acids or glucose. The effect of insulin signaling upon TOR activity varies by cellular type and context. (PMID:17371599)
• Results show that the effects of TOR on growth and metabolism was mediated by Myc. (PMID:18177722)
• Vps34 is regulated by TOR-dependent nutrient signals directly at sites of autophagosome formation. (PMID:18474623)
• InR/TOR signaling regulates the timing of differentiation through modulation of EGFR target genes in developing photoreceptors. (PMID:18505882)
• a function of Rag GTPases in TORC1 activation in response to amino acid signals (PMID:18604198)
• Ptp61F is a novel modulator of TOR activity (PMID:18653470)
• The Tor pathway couples nutrition and developmental timing in Drosophila. (PMID:18854141)
• Knockout of Atg1 or Atg13 results in a similar, selective defect in autophagy in response to TOR inactivation. (PMID:19225150)
• Studies show the increasingly prominent links between TOR signaling and aging in invertebrates. (PMID:19539012)
• up-regulation of dEif4e is sufficient to recapitulate the effects of high dTOR or insulin signaling in cardiac aging in Drosophila. (PMID:19594484)
• Data indicate that TOR induces cell death by suppressing autophagy and provide direct genetic evidence that autophagy alleviates cell death in several common types of neurodegenerative disease. (PMID:19720874)
• Sin1, Rictor, Trc and target of rapamycin (TOR), components of the TOR complex 2 (TORC2), are required for dendritic tiling of class IV da neurons (PMID:19875983)
• analysis of Dendritic tiling through TOR signalling (PMID:20010972)
• sestrin appears to be a negative feedback regulator of TOR that integrates metabolic & stress inputs & prevents pathologies caused by chronic TOR activation (PMID:20203043)
• Data show that mating status modulates food choice in females, that it relies on the action of the sex peptide receptor in sensory neurons, and that neuronal TOR/S6K function affects this decision, possibly signaling the fly’s current nutritional status. (PMID:20471268)
• These results uncover specific TOR functions in the control of stem cells versus their differentiating progeny, and reveal parallels between Drosophila and mammalian follicle growth. (PMID:20504961)
• TSC1/2 prevents precocious GSC differentiation by inhibiting TORC1 activity and subsequently differentiation-promoting programs (PMID:20573703)
• dAkt activation under wild-type conditions is defined by feedback inhibition that depends on TOR Complex 1 (PMID:20585550)
• Cellular detoxification pathways, increased autophagy and altered protein synthesis have all been implicated in increased lifespan from reduced IIS/TOR activity, with the role of defence against oxidative stress unresolved (PMID:20849947)
• we review the contribution of the model organism Drosophila in the understanding of TOR signaling and the various biological processes it modulates that may impact on aging (PMID:21130151)
• Drosophila FoxA ortholog Fork head regulates growth and gene expression downstream of Target of rapamycin (PMID:21217822)
• TORC1-S6K-RPS6 (as a fusion protein)signaling axis is regulated by many subcellular components, including the Class I vesicle coat (COPI), the spliceosome, the proteasome, the nuclear pore, and the translation initiation machinery. (PMID:21239477)
• These results highlight an unexpected crosstalk whereby the normally growth-promoting, nutrient-sensing PI3K/TOR pathway suppresses tumour formation in neural stem cells with compromised cell polarity. (PMID:22173033)
• Target of rapamycin (Tor) mutants did show a phenotype that mimicked WT starvation-induced PCD, indicating an insulin independent regulation of PCD via Tor signaling. (PMID:22240900)
• PI3K-Akt-TOR pathway is an important regulator of sindbis virus replication in mosquito cells and Drosophila. (PMID:22258238)
• Thus, stimulation of Pol III is a key downstream effector of TOR in the control of cellular and systemic growth. (PMID:22367393)
• Loss of postsynaptic TOR disrupts a retrograde compensatory enhancement in neurotransmitter release that is normally triggered by a reduction in postsynaptic glutamate receptor activity. (PMID:22500638)
• The buffy null mutant reacted to starvation with the expected responses such as inhibition of target of rapamycin (Tor) signaling, autophagy initiation and mobilization of stored lipids. (PMID:22824239)
• DREF is required for growth downstream of TOR, but not insulin/PI3K signaling. (PMID:22960233)
• p53-related protein kinase is required for PI3K/TOR pathway-dependent growth. (PMID:23444356)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcbd1	ENSDARG00000031981
mus_musculus	Pcbd1	ENSMUSG00000020098
rattus_norvegicus	Pcbd1	ENSRNOG00000000566
drosophila_melanogaster	Pcd	FBGN0024841
caenorhabditis_elegans	pcbd-1	WBGENE00020397

Paralogs (1): PCBD2 (ENSG00000132570)

Protein

Protein identifiers

Pterin-4-alpha-carbinolamine dehydratase — P61457 (reviewed: P61457)

Alternative names: 4-alpha-hydroxy-tetrahydropterin dehydratase, Dimerization cofactor of hepatocyte nuclear factor 1-alpha, Phenylalanine hydroxylase-stimulating protein, Pterin carbinolamine dehydratase

All UniProt accessions (1): P61457

UniProt curated annotations — full annotation on UniProt →

Function. Involved in tetrahydrobiopterin biosynthesis. Seems to both prevent the formation of 7-pterins and accelerate the formation of quinonoid-BH2. Coactivator for HNF1A-dependent transcription. Regulates the dimerization of homeodomain protein HNF1A and enhances its transcriptional activity. Also acts as a coactivator for HNF1B-dependent transcription.

Subunit / interactions. Homotetramer and homodimer. Heterotetramer with HNF1A; formed by a dimer of dimers. Interacts with HNF1B (via HNF-p1 domain); the interaction increases HNF1B transactivation activity.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. Hyperphenylalaninemia, BH4-deficient, D (HPABH4D) [MIM:264070] An autosomal recessive disease characterized by primapterinuria, a variant form of hyperphenylalaninemia defined by increased excretion of 7-substituted pterins in the urine. Patients with primapterinuria show an increased ratio of neopterin to biopterin in the urine, excretion of subnormal levels of biopterins, and normal levels of biogenic amines in cerebrospinal fluid. Neurologic signs are mild, present in the neonatal period only, and include hypotonia, delayed motor development and tremor. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the pterin-4-alpha-carbinolamine dehydratase family.

RefSeq proteins (2): NP_000272, NP_001276726 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001533	Pterin_deHydtase	Family
IPR036428	PCD_sf	Homologous_superfamily

Pfam: PF01329

Catalyzed reactions (Rhea), 1 shown:

• (4aS,6R)-4a-hydroxy-L-erythro-5,6,7,8-tetrahydrobiopterin = (6R)-L-erythro-6,7-dihydrobiopterin + H2O (RHEA:11920)

UniProt features (12 total): sequence variant 7, binding site 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61457-F1	96.55	0.95

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 (2): 61–63; 78–81

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8964208	Phenylalanine metabolism

MSigDB gene sets: 217 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GRUETZMANN_PANCREATIC_CANCER_DN, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_POLYOL_METABOLIC_PROCESS, GOBP_AMINO_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_PTERIDINE_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_AROMATIC_AMINO_ACID_METABOLIC_PROCESS, ZHAN_V2_LATE_DIFFERENTIATION_GENES, HSIAO_LIVER_SPECIFIC_GENES

GO Biological Process (3): tetrahydrobiopterin biosynthetic process (GO:0006729), obsolete L-tyrosine biosynthetic process, by oxidation of phenylalanine (GO:0019293), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (6): transcription coactivator activity (GO:0003713), phenylalanine 4-monooxygenase activity (GO:0004505), 4-alpha-hydroxytetrahydrobiopterin dehydratase activity (GO:0008124), identical protein binding (GO:0042802), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (5): nucleoplasm (GO:0005654), cytosol (GO:0005829), extracellular exosome (GO:0070062), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Phenylalanine and tyrosine metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
diol biosynthetic process	1
pteridine-containing compound biosynthetic process	1
tetrahydrobiopterin metabolic process	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	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
hydro-lyase activity	1
protein binding	1
binding	1
catalytic activity	1
nuclear lumen	1
cytoplasm	1
extracellular vesicle	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCBD1	QDPR	P09417	945
PCBD1	HNF1A	P20823	843
PCBD1	GCH1	P30793	841
PCBD1	SPR	P35270	765
PCBD1	PTS	Q03393	764
PCBD1	DYRK1B	Q9Y463	706
PCBD1	PAH	P00439	656
PCBD1	GCHFR	P30047	603
PCBD1	GATA5	Q9BWX5	596
PCBD1	TPH1	P17752	581
PCBD1	TH	P07101	575
PCBD1	LCT	P09848	548
PCBD1	HNF1B	P35680	545
PCBD1	MCEE	Q96PE7	496
PCBD1	SLC41A3	Q96GZ6	451

IntAct

154 interactions, top by confidence:

A	B	Type	Score
PCBD1	PCBD1	psi-mi:“MI:0915”(physical association)	0.860
HNF1B	PCBD1	psi-mi:“MI:0915”(physical association)	0.810
PCBD1	HNF1B	psi-mi:“MI:0915”(physical association)	0.810
PCBD1	FXR2	psi-mi:“MI:0915”(physical association)	0.800
FXR2	PCBD1	psi-mi:“MI:0915”(physical association)	0.800
PCBD1	GORASP2	psi-mi:“MI:0915”(physical association)	0.800
PCBD1	LNX1	psi-mi:“MI:0915”(physical association)	0.780
LNX1	PCBD1	psi-mi:“MI:0915”(physical association)	0.780
TFF3	PCBD1	psi-mi:“MI:0915”(physical association)	0.720
PCBD1	TFF3	psi-mi:“MI:0915”(physical association)	0.720
PCBD1	HNF1A	psi-mi:“MI:0915”(physical association)	0.710
PCBD1	NTAQ1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (118): PCBD1 (Two-hybrid), TFF3 (Two-hybrid), FXR2 (Two-hybrid), LNX1 (Two-hybrid), NUDT18 (Two-hybrid), PCBD1 (Two-hybrid), PCBD1 (Two-hybrid), FXR2 (Two-hybrid), LNX1 (Two-hybrid), GORASP2 (Two-hybrid), NIF3L1 (Two-hybrid), WDYHV1 (Two-hybrid), PCBD1 (Affinity Capture-Western), PCBD1 (Co-fractionation), PCBD1 (Co-fractionation)

ESM2 similar proteins: A0K2V4, A4JA07, A4YJY8, A5VN26, A9AJD5, A9M6T4, B0CIJ4, B1K1I7, B1YQ64, B2S7X9, B2UGY6, B3Q9E4, B4E566, B4RBN1, B6JAT9, B9JCJ2, B9JUA0, C0RGE2, C3MAI8, O73930, P61457, P61458, P61459, P61734, P65722, P65723, P73790, Q07N39, Q0BJP4, Q13D98, Q13SM2, Q1GDR0, Q1QHE0, Q214W1, Q2J3Z9, Q2RNC0, Q2YNV0, Q39L06, Q3JXT0, Q3SNS9

Diamond homologs: A0K2V4, A0M1H4, A1SSU3, A2BVF3, A2C7K4, A4JA07, A4YJY8, A5E8P9, A5FWK8, A5GMR6, A5V667, A5VN26, A6UE17, A6VSD2, A6WV21, A7HSX5, A8LKP0, A9AJD5, A9M6T4, B0CIJ4, B0T207, B1K1I7, B1YQ64, B1ZY08, B2S7X9, B2T7M8, B2UGY6, B3Q9E4, B4E566, B4RBN1, B4RXT2, B5ZTF5, B6JAT9, B8GYB5, B9JCJ2, B9JUA0, C0RGE2, C3MAI8, O42658, O73930

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PCBD1	“up-regulates quantity by expression”	FXYD2	“transcriptional regulation”
PCBD1	“up-regulates activity”	HNF1B	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 111 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
intrinsic apoptotic signaling pathway	5	17.6×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	8
Uncertain significance	27
Likely benign	66
Benign	11

Top pathogenic / likely-pathogenic (15)

Variant ID	HGVS	Classification
1996775	NM_000281.4(PCBD1):c.108_118del (p.Lys36fs)	Pathogenic
2697933	NM_000281.4(PCBD1):c.201dup (p.Asn68Ter)	Pathogenic
2912706	NM_000281.4(PCBD1):c.111del (p.Gln37fs)	Pathogenic
3244842	NC_000010.10:g.(?72643707)(72648290_?)del	Pathogenic
3244843	NC_000010.10:g.(?72643707)(72645009_?)del	Pathogenic
802585	NM_000281.4(PCBD1):c.272del (p.Asn91fs)	Pathogenic
91905	NM_000281.4(PCBD1):c.46del (p.Leu16fs)	Pathogenic
16796	NM_000281.4(PCBD1):c.244T>C (p.Cys82Arg)	Likely pathogenic
2432444	NM_000281.4(PCBD1):c.117_121del (p.His39fs)	Likely pathogenic
2640562	NM_000281.4(PCBD1):c.252_254delinsGTGCTCACCATGGGTG (p.Leu85fs)	Likely pathogenic
3596650	NM_000281.4(PCBD1):c.166C>T (p.Gln56Ter)	Likely pathogenic
3596659	NM_000281.4(PCBD1):c.152_155dup (p.Arg52fs)	Likely pathogenic
3596685	NM_000281.4(PCBD1):c.61_62dup (p.Ala22fs)	Likely pathogenic
3596703	NM_000281.4(PCBD1):c.4-2A>C	Likely pathogenic
3596716	NM_000281.4(PCBD1):c.1A>G (p.Met1Val)	Likely pathogenic

SpliceAI

570 predictions. Top by Δscore:

Variant	Effect	Δscore
10:70885147:CTCA:C	donor_loss	1.0000
10:70885148:TCAC:T	donor_loss	1.0000
10:70885149:CA:C	donor_loss	1.0000
10:70885150:ACCT:A	donor_loss	1.0000
10:70885151:C:CG	donor_loss	1.0000
10:70885229:AGGCC:A	acceptor_loss	1.0000
10:70885230:GGCC:G	acceptor_loss	1.0000
10:70885231:GCC:G	acceptor_loss	1.0000
10:70885232:CCT:C	acceptor_loss	1.0000
10:70885233:CT:C	acceptor_loss	1.0000
10:70885234:T:C	acceptor_loss	1.0000
10:70885796:AC:A	donor_gain	1.0000
10:70885797:CC:C	donor_gain	1.0000
10:70888526:CTCA:C	donor_loss	1.0000
10:70888527:TCA:T	donor_loss	1.0000
10:70888528:CA:C	donor_loss	1.0000
10:70888529:A:AT	donor_loss	1.0000
10:70888530:C:A	donor_loss	1.0000
10:70884046:GACCT:G	acceptor_loss	0.9900
10:70884047:ACCT:A	acceptor_loss	0.9900
10:70884048:CCTG:C	acceptor_loss	0.9900
10:70884049:C:A	acceptor_loss	0.9900
10:70884049:C:CC	acceptor_gain	0.9900
10:70884050:T:A	acceptor_loss	0.9900
10:70885150:A:AC	donor_gain	0.9900
10:70885151:C:CC	donor_gain	0.9900
10:70885230:GGC:G	acceptor_gain	0.9900
10:70885231:GC:G	acceptor_gain	0.9900
10:70885232:CC:C	acceptor_gain	0.9900
10:70885233:C:CC	acceptor_gain	0.9900

AlphaMissense

697 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:70885199:C:G	A57P	0.997
10:70885860:A:G	W25R	0.997
10:70885860:A:T	W25R	0.997
10:70885172:A:G	W66R	0.996
10:70885172:A:T	W66R	0.996
10:70885198:G:T	A57D	0.996
10:70885804:G:C	F43L	0.996
10:70885804:G:T	F43L	0.996
10:70885806:A:G	F43L	0.996
10:70885207:G:T	A54D	0.995
10:70885858:C:A	W25C	0.995
10:70885858:C:G	W25C	0.995
10:70883987:G:T	A93D	0.993
10:70884000:C:G	D89H	0.993
10:70884041:A:T	I75N	0.993
10:70885181:G:C	H63D	0.993
10:70885227:A:C	F47L	0.993
10:70885227:A:T	F47L	0.993
10:70885229:A:G	F47L	0.993
10:70885177:G:T	P64H	0.992
10:70885184:G:C	H62D	0.992
10:70885222:A:G	F49S	0.992
10:70883999:T:A	D89V	0.991
10:70883999:T:G	D89A	0.991
10:70885221:G:C	F49L	0.991
10:70885221:G:T	F49L	0.991
10:70885223:A:G	F49L	0.991
10:70885164:G:C	N68K	0.990
10:70885164:G:T	N68K	0.990
10:70885859:C:G	W25S	0.990

dbSNP variants (sampled 300 via entrez): RS1000165736 (10:70886020 A>C), RS1000350616 (10:70888200 G>C), RS1000551440 (10:70883012 A>C), RS1002061003 (10:70885022 G>A,T), RS1002525371 (10:70890236 T>C), RS1002556582 (10:70889941 G>A), RS1002650132 (10:70883105 A>C), RS1002819357 (10:70890026 T>C), RS1002855238 (10:70889628 T>C), RS1003468162 (10:70883516 G>A), RS1003532310 (10:70888741 A>C), RS1003702886 (10:70885261 G>A), RS1003827426 (10:70888576 G>A,C,T), RS1003858762 (10:70888256 C>T), RS1004358032 (10:70889494 T>G)

Disease associations

OMIM: gene MIM:126090 | disease phenotypes: MIM:264070

GenCC curated gene-disease

Disease	Classification	Inheritance
pterin-4 alpha-carbinolamine dehydratase 1 deficiency	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
pterin-4 alpha-carbinolamine dehydratase 1 deficiency	Definitive	AR

Mondo (1): pterin-4 alpha-carbinolamine dehydratase 1 deficiency (MONDO:0009908)

Orphanet (2): Pterin-4 alpha-carbinolamine dehydratase deficiency (Orphanet:1578), Hyperphenylalaninemia due to tetrahydrobiopterin deficiency (Orphanet:238583)

HPO phenotypes

18 total (18 of 18 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000737	Irritability
HP:0001270	Motor delay
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001300	Parkinsonism
HP:0001337	Tremor
HP:0002917	Hypomagnesemia
HP:0004904	Maturity-onset diabetes of the young
HP:0004923	Hyperphenylalaninemia
HP:0008297	Transient hyperphenylalaninemia
HP:0008936	Axial hypotonia
HP:0010553	Oculogyric crisis
HP:0012758	Neurodevelopmental delay
HP:0033594	Elevated urinary 7-biopterin level
HP:0040206	Abnormal circulating neopterin concentration
HP:0040210	Abnormal circulating biopterin concentration
HP:0100021	Cerebral palsy

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001762_286	Obesity-related traits	8.000000e-06
GCST001762_593	Obesity-related traits	3.000000e-06
GCST001762_646	Obesity-related traits	2.000000e-06
GCST003253_5	Microalbuminuria	4.000000e-06
GCST004628_41	Immature fraction of reticulocytes	3.000000e-10
GCST006585_1505	Blood protein levels	8.000000e-11
GCST007576_436	Chronotype	1.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005119	antioxidant measurement
EFO:0004501	HOMA-IR
EFO:0007986	reticulocyte count
EFO:0008328	chronotype measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C538382	Hyperphenylalaninemia with primapterinuria (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, affects cotreatment, increases expression, decreases expression	6
trichostatin A	decreases expression, affects cotreatment	3
bisphenol A	decreases expression, affects cotreatment, decreases methylation	2
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	2
bisphenol F	increases expression	1
glycidyl methacrylate	increases expression	1
methylselenic acid	decreases expression	1
arsenite	affects binding, increases reaction	1
zinc chloride	increases expression	1
cobaltous chloride	decreases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
ochratoxin A	increases expression	1
monomethylarsonous acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol S	increases expression	1
3-(2-hydroxy-4-(2-methylnonan-2-yl)phenyl)cyclohexan-1-ol	increases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Carmustine	decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3DI	Abcam HEK293T PCBD1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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