Pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Summary

Pterin-4 alpha-carbinolamine dehydratase 1 deficiency (MONDO:0009908) is a disease caused by PCBD1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Causal gene: PCBD1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 119
• Phenotypes (HPO): 13

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0004923	Hyperphenylalaninemia	Very frequent (80-99%)
HP:0040210	Abnormal circulating biopterin concentration	Very frequent (80-99%)
HP:0010553	Oculogyric crisis	Frequent (30-79%)
HP:0040206	Abnormal circulating neopterin concentration	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0002917	Hypomagnesemia	Occasional (5-29%)
HP:0008936	Axial hypotonia	Occasional (5-29%)
HP:0012758	Neurodevelopmental delay	Occasional (5-29%)
HP:0001300	Parkinsonism	Very rare (<1-4%)
HP:0004904	Maturity-onset diabetes of the young	Very rare (<1-4%)
HP:0100021	Cerebral palsy	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	pterin-4 alpha-carbinolamine dehydratase 1 deficiency
Mondo ID	MONDO:0009908
MeSH	C538382
OMIM	264070
Orphanet	1578
DOID	DOID:0081131
SNOMED CT	124646004
UMLS	C1849700
MedGen	337890
GARD	0002843
Is cancer (heuristic)	no

Also known as: CADH deficiency · dehydratase deficiency · HPABH4D · hyperphenylalaninemia due to dehydratase deficiency · hyperphenylalaninemia due to pterin-4-alpha-carbinolamine dehydratase deficiency · hyperphenylalaninemia with primapterinuria · hyperphenylalaninemia, BH4-deficient, D · hyperphenylalaninemia, Bh4-deficient, type D · PCBD deficiency · PCBD1 deficiency · PCD deficiency · pterin-4 alpha-carbinolamine dehydratase 1 deficiency · tetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) due to pterin-4-alpha-carbinolamine dehydratase deficiency

Data availability: 119 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn disorder of amino acid and other organic acid metabolism › inborn disorder of amino acid metabolism › hyperphenylalaninemia due to tetrahydrobiopterin deficiency › pterin-4 alpha-carbinolamine dehydratase 1 deficiency

Related subtypes (3): dihydropteridine reductase deficiency, BH4-deficient hyperphenylalaninemia A, GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

119 retrieved; paginated sample, class counts are floors:

65 likely benign, 25 uncertain significance, 9 likely pathogenic, 8 pathogenic, 4 conflicting classifications of pathogenicity, 3 pathogenic/likely pathogenic, 3 benign, 1 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
180130	NM_000281.3(PCBD1):c.[79G>T;263G>A]		Pathogenic	no assertion criteria provided
16795	NM_000281.4(PCBD1):c.259G>T (p.Glu87Ter)	PCBD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16799	NM_000281.4(PCBD1):c.292C>T (p.Gln98Ter)	PCBD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1996775	NM_000281.4(PCBD1):c.108_118del (p.Lys36fs)	PCBD1	Pathogenic	criteria provided, single submitter
2697933	NM_000281.4(PCBD1):c.201dup (p.Asn68Ter)	PCBD1	Pathogenic	criteria provided, single submitter
2912706	NM_000281.4(PCBD1):c.111del (p.Gln37fs)	PCBD1	Pathogenic	criteria provided, single submitter
3244842	NC_000010.10:g.(?72643707)(72648290_?)del	PCBD1	Pathogenic	criteria provided, single submitter
3244843	NC_000010.10:g.(?72643707)(72645009_?)del	PCBD1	Pathogenic	criteria provided, single submitter
802585	NM_000281.4(PCBD1):c.272del (p.Asn91fs)	PCBD1	Pathogenic	criteria provided, single submitter
91905	NM_000281.4(PCBD1):c.46del (p.Leu16fs)	PCBD1	Pathogenic	criteria provided, single submitter
91907	NM_000281.4(PCBD1):c.289G>A (p.Glu97Lys)	PCBD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3003037	NM_000281.4(PCBD1):c.3+1G>T	LOC130004020	Likely pathogenic	criteria provided, single submitter
16796	NM_000281.4(PCBD1):c.244T>C (p.Cys82Arg)	PCBD1	Likely pathogenic	criteria provided, single submitter
2432444	NM_000281.4(PCBD1):c.117_121del (p.His39fs)	PCBD1	Likely pathogenic	criteria provided, single submitter
2640562	NM_000281.4(PCBD1):c.252_254delinsGTGCTCACCATGGGTG (p.Leu85fs)	PCBD1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3596650	NM_000281.4(PCBD1):c.166C>T (p.Gln56Ter)	PCBD1	Likely pathogenic	criteria provided, single submitter
3596659	NM_000281.4(PCBD1):c.152_155dup (p.Arg52fs)	PCBD1	Likely pathogenic	criteria provided, single submitter
3596685	NM_000281.4(PCBD1):c.61_62dup (p.Ala22fs)	PCBD1	Likely pathogenic	criteria provided, single submitter
3596703	NM_000281.4(PCBD1):c.4-2A>C	PCBD1	Likely pathogenic	criteria provided, single submitter
3596716	NM_000281.4(PCBD1):c.1A>G (p.Met1Val)	PCBD1	Likely pathogenic	criteria provided, single submitter
2194208	NM_000281.4(PCBD1):c.3+18C>T	LOC130004020	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1508980	NM_000281.4(PCBD1):c.294A>G (p.Gln98=)	PCBD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
428616	NM_000281.4(PCBD1):c.313T>C (p.Ter105Gln)	PCBD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
722191	NM_000281.4(PCBD1):c.204C>T (p.Asn68=)	PCBD1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
300349	NM_000281.4(PCBD1):c.-27C>G	LOC130004020	Uncertain significance	criteria provided, single submitter
1046659	NM_000281.4(PCBD1):c.91C>T (p.Arg31Cys)	PCBD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1372630	NM_000281.4(PCBD1):c.5C>T (p.Ala2Val)	PCBD1	Uncertain significance	criteria provided, single submitter
1384033	NM_000281.4(PCBD1):c.262C>T (p.Arg88Trp)	PCBD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
16797	NM_000281.4(PCBD1):c.236C>T (p.Thr79Ile)	PCBD1	Uncertain significance	criteria provided, single submitter
1971225	NM_000281.4(PCBD1):c.37A>T (p.Arg13Trp)	PCBD1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
PCBD1	Definitive	Autosomal recessive	pterin-4 alpha-carbinolamine dehydratase 1 deficiency	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PCBD1	Orphanet:1578	Pterin-4 alpha-carbinolamine dehydratase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PCBD1	HGNC:8646	ENSG00000166228	P61457	Pterin-4-alpha-carbinolamine dehydratase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PCBD1	Pterin-4-alpha-carbinolamine dehydratase	Involved in tetrahydrobiopterin biosynthesis.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PCBD1	Other/Unknown	no		Pterin_deHydtase, PCD_sf

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
right adrenal gland cortex	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PCBD1	280	ubiquitous	marker	right lobe of liver, body of pancreas, right adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PCBD1	1,496

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PCBD1	P61457	96.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Phenylalanine metabolism	1	1903.3×	5e-04	PCBD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tetrahydrobiopterin biosynthetic process	1	2407.4×	4e-04	PCBD1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PCBD1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	PCBD1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PCBD1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.