GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Summary

GTP cyclohydrolase I deficiency with hyperphenylalaninemia (MONDO:0100186) is a disease caused by GCH1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: GCH1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 21

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		16	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	GTP cyclohydrolase I deficiency with hyperphenylalaninemia
Mondo ID	MONDO:0100186
OMIM	233910
Orphanet	2102
DOID	DOID:0112225
NCIT	C141442
SNOMED CT	23447005
GARD	0002844
Is cancer (heuristic)	no

Also known as: GTPCH deficiency · HPABH4B · hyperphenylalaninemia due to GTP cyclohydrolase deficiency · hyperphenylalaninemia, BH4-deficient, B · hyperphenylalaninemia, Bh4-deficient, type B

Data availability: 21 ClinVar variants · 4 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 › GTP cyclohydrolase I deficiency with hyperphenylalaninemia

Related subtypes (3): dihydropteridine reductase deficiency, BH4-deficient hyperphenylalaninemia A, pterin-4 alpha-carbinolamine dehydratase 1 deficiency

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

21 retrieved; paginated sample, class counts are floors:

10 uncertain significance, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3767247	NM_000161.3(GCH1):c.667A>G (p.Ser223Gly)	GCH1	Pathogenic	criteria provided, single submitter
9287	NM_000161.3(GCH1):c.633G>A (p.Met211Ile)	GCH1	Pathogenic	no assertion criteria provided
9290	NM_000161.3(GCH1):c.551G>A (p.Arg184His)	GCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
480	NM_000317.3(PTS):c.259C>T (p.Pro87Ser)	PTS	Pathogenic	criteria provided, multiple submitters, no conflicts
3069162	NM_000161.3(GCH1):c.260_261insTGAGAACCCCCA (p.Pro86_Gln87insHisGluAsnPro)	GCH1	Likely pathogenic	criteria provided, single submitter
3382216	NM_000161.3(GCH1):c.11del (p.Gly4fs)	GCH1	Likely pathogenic	criteria provided, single submitter
3061790	NM_000317.3(PTS):c.108C>A (p.Asn36Lys)	PTS	Likely pathogenic	no assertion criteria provided
161248	NM_000161.3(GCH1):c.610G>A (p.Val204Ile)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1695370	NM_000161.3(GCH1):c.644T>C (p.Met215Thr)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9281	NM_000161.3(GCH1):c.662T>C (p.Met221Thr)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
9283	NM_000161.3(GCH1):c.671A>G (p.Lys224Arg)	GCH1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1339055	NM_000161.3(GCH1):c.514G>A (p.Val172Ile)	GCH1	Uncertain significance	criteria provided, single submitter
1391073	NM_000161.3(GCH1):c.299C>T (p.Ser100Leu)	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1431041	NM_000161.3(GCH1):c.16G>T (p.Val6Leu)	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
313361	NM_000161.3(GCH1):c.*1628A>C	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
313400	NM_000161.3(GCH1):c.-56G>A	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4292450	NM_000161.3(GCH1):c.377A>T (p.His126Leu)	GCH1	Uncertain significance	criteria provided, single submitter
444330	NM_000161.3(GCH1):c.328C>G (p.Gln110Glu)	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
881769	NM_000161.3(GCH1):c.*34C>T	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
883620	NM_000161.3(GCH1):c.*1033C>T	GCH1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3061791	NM_000317.3(PTS):c.91C>A (p.Leu31Ile)	PTS	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 3 · 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
GCH1	Definitive	Autosomal dominant	GTP cyclohydrolase I deficiency	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GCH1	Orphanet:2102	GTP cyclohydrolase I deficiency
GCH1	Orphanet:98808	Autosomal dominant dopa-responsive dystonia
PTS	Orphanet:13	6-pyruvoyl-tetrahydropterin synthase deficiency

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GCH1	HGNC:4193	ENSG00000131979	P30793	GTP cyclohydrolase 1	gencc,clinvar
PTS	HGNC:9689	ENSG00000150787	Q03393	6-pyruvoyl tetrahydrobiopterin synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GCH1	GTP cyclohydrolase 1	Positively regulates nitric oxide synthesis in umbilical vein endothelial cells (HUVECs).
PTS	6-pyruvoyl tetrahydrobiopterin synthase	Involved in the biosynthesis of tetrahydrobiopterin, an essential cofactor of aromatic amino acid hydroxylases.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	2	12.0×	0.007

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GCH1	Enzyme (other)	yes	3.5.4.16	GTP_CycHdrlase_I, GTP_CycHdrlase_I_CS, GTP_CycHdrlase_I_dom
PTS	Enzyme (other)	yes	4.2.3.12	6-PTP_synth/QueD, PTPS_His_AS, PTPS_Cys_AS

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	1
secondary oocyte	1
type B pancreatic cell	1
adrenal tissue	1
left adrenal gland cortex	1
right adrenal gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GCH1	275	ubiquitous	marker	secondary oocyte, oocyte, type B pancreatic cell
PTS	298	ubiquitous	marker	adrenal tissue, right adrenal gland, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GCH1	2,123
PTS	1,897

Intra-cohort edges

A	B	Sources
GCH1	PTS	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCH1	P30793	11
PTS	Q03393	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	2	1142.0×	7e-07	GCH1, PTS

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 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	2	2407.4×	3e-06	GCH1, PTS
pteridine-containing compound biosynthetic process	1	8426.0×	0.001	GCH1
regulation of lung blood pressure	1	4213.0×	0.001	GCH1
positive regulation of nitric-oxide synthase activity	1	2808.7×	0.002	GCH1
tetrahydrofolate biosynthetic process	1	1404.3×	0.002	GCH1
regulation of removal of superoxide radicals	1	1404.3×	0.002	GCH1
dopamine biosynthetic process	1	936.2×	0.003	GCH1
neuromuscular process controlling posture	1	526.6×	0.004	GCH1
response to pain	1	443.5×	0.004	GCH1
amino acid metabolic process	1	401.2×	0.004	PTS
nitric oxide biosynthetic process	1	351.1×	0.004	GCH1
positive regulation of heart rate	1	351.1×	0.004	GCH1
response to tumor necrosis factor	1	312.1×	0.004	GCH1
response to type II interferon	1	263.3×	0.005	GCH1
regulation of blood pressure	1	110.9×	0.010	GCH1
response to lipopolysaccharide	1	62.4×	0.017	GCH1
central nervous system development	1	57.7×	0.017	PTS

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GCH1	0	0
PTS	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
PTS	1	ADMET:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCH1	3.5.4.16	GTP cyclohydrolase I
PTS	4.2.3.12	6-pyruvoyltetrahydropterin synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	GCH1, PTS
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GCH1	0	—
PTS	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.