GTP cyclohydrolase I deficiency

Summary

GTP cyclohydrolase I deficiency (MONDO:0100184) is a disease caused by GCH1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: GCH1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 490
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	GTP cyclohydrolase I deficiency
Mondo ID	MONDO:0100184
UMLS	C0268467
MedGen	75683
GARD	0026074
Is cancer (heuristic)	no

Also known as: GTP cyclohydrolase I deficiency · GTP-cyclohydrolase I deficiency

Data availability: 490 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: 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 › inborn disorder of phenylalanine and tyrosine metabolism › disorder of phenylalanine metabolism › tetrahydrobiopterin metabolic process disease › GTP cyclohydrolase I deficiency

Related subtypes (2): dihydropteridine reductase deficiency, dopa-responsive dystonia due to sepiapterin reductase deficiency

Subtypes (3): dystonia 5, dystonia, dopa-responsive, with or without hyperphenylalaninemia, autosomal recessive, 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

490 retrieved; paginated sample, class counts are floors:

184 uncertain significance, 168 likely benign, 58 pathogenic, 35 conflicting classifications of pathogenicity, 13 likely pathogenic, 13 benign, 10 pathogenic/likely pathogenic, 9 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2422501	NC_000014.8:g.(?54410919)(55369403_?)del	BMP4	Pathogenic	criteria provided, single submitter
1070262	NC_000014.8:g.(?55313807)(55313858_?)del	GCH1	Pathogenic	criteria provided, single submitter
1070263	NC_000014.8:g.(?55332039)(55369387_?)del	GCH1	Pathogenic	criteria provided, single submitter
1070688	NM_000161.3(GCH1):c.158G>A (p.Trp53Ter)	GCH1	Pathogenic	criteria provided, single submitter
1199011	NM_000161.3(GCH1):c.578_583del (p.Ile193_Glu195delinsLys)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1354621	NM_000161.3(GCH1):c.109G>T (p.Glu37Ter)	GCH1	Pathogenic	criteria provided, single submitter
1419261	NM_000161.3(GCH1):c.212del (p.Leu71fs)	GCH1	Pathogenic	criteria provided, single submitter
1432028	NM_000161.3(GCH1):c.724G>T (p.Glu242Ter)	GCH1	Pathogenic	criteria provided, single submitter
1452723	NM_000161.3(GCH1):c.1A>C (p.Met1Leu)	GCH1	Pathogenic	criteria provided, single submitter
1454629	NC_000014.8:g.(?55312466)(55313868_?)del	GCH1	Pathogenic	criteria provided, single submitter
1454630	NC_000014.8:g.(?55310735)(55313868_?)del	GCH1	Pathogenic	criteria provided, single submitter
1455907	NM_000161.3(GCH1):c.453+2T>G	GCH1	Pathogenic	criteria provided, single submitter
1457490	NM_000161.3(GCH1):c.395_396del (p.Val132fs)	GCH1	Pathogenic	criteria provided, single submitter
1460271	NC_000014.8:g.(?55369019)(55369381_?)del	GCH1	Pathogenic	criteria provided, single submitter
2135414	NM_000161.3(GCH1):c.185del (p.Glu62fs)	GCH1	Pathogenic	criteria provided, single submitter
2135615	NM_000161.3(GCH1):c.49del (p.Arg17fs)	GCH1	Pathogenic	criteria provided, single submitter
2135851	NM_000161.3(GCH1):c.626+2T>C	GCH1	Pathogenic	criteria provided, single submitter
2137592	NM_000161.3(GCH1):c.233del (p.Ile78fs)	GCH1	Pathogenic	criteria provided, single submitter
2422499	NC_000014.8:g.(?55310735)(55326474_?)del	GCH1	Pathogenic	criteria provided, single submitter
265173	NM_000161.3(GCH1):c.631_632del (p.Met211fs)	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2925514	NM_000161.3(GCH1):c.751T>C (p.Ter251Arg)	GCH1	Pathogenic	criteria provided, single submitter
2925519	NM_000161.3(GCH1):c.453+1G>A	GCH1	Pathogenic	criteria provided, single submitter
2925520	NM_000161.3(GCH1):c.-22C>T	GCH1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2947428	NM_000161.3(GCH1):c.307C>T (p.Gln103Ter)	GCH1	Pathogenic	criteria provided, single submitter
2953555	NM_000161.3(GCH1):c.601G>C (p.Gly201Arg)	GCH1	Pathogenic	criteria provided, single submitter
3243958	NC_000014.8:g.(?55310735)(55369403_?)del	GCH1	Pathogenic	criteria provided, single submitter
3759244	NM_000161.3(GCH1):c.309del (p.Gln103fs)	GCH1	Pathogenic	criteria provided, single submitter
3759245	NM_000161.3(GCH1):c.242C>A (p.Ser81Ter)	GCH1	Pathogenic	criteria provided, single submitter
381665	NM_000161.3(GCH1):c.607G>A (p.Gly203Arg)	GCH1	Pathogenic	criteria provided, multiple submitters, no conflicts
447375	NM_000161.3(GCH1):c.510-1G>A	GCH1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
BMP4	Orphanet:139471	Microphthalmia with brain and digit anomalies
BMP4	Orphanet:199306	Cleft lip/palate
BMP4	Orphanet:828	Stickler syndrome
BMP4	Orphanet:93100	Renal agenesis, unilateral

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
BMP4	HGNC:1071	ENSG00000125378	P12644	Bone morphogenetic protein 4	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).
BMP4	Bone morphogenetic protein 4	Growth factor of the TGF-beta superfamily that plays essential roles in many developmental processes, including neurogenesis, vascular development, angiogenesis and osteogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

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
BMP4	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGF-beta-like

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
pigmented layer of retina	1
rectum	1
retina	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
BMP4	189	ubiquitous	marker	pigmented layer of retina, retina, rectum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BMP4	4,425
GCH1	2,123

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GCH1	P30793	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BMP4	P12644	79.12

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. 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
Formation of lateral plate mesoderm	1	1142.0×	0.008	BMP4
Formation of intermediate mesoderm	1	713.8×	0.008	BMP4
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	571.0×	0.008	GCH1
Specification of primordial germ cells	1	439.2×	0.008	BMP4
Kidney development	1	407.9×	0.008	BMP4
Germ layer formation at gastrulation	1	335.9×	0.008	BMP4
Formation of the nephric duct	1	317.2×	0.008	BMP4
Specification of the neural plate border	1	317.2×	0.008	BMP4
Formation of the ureteric bud	1	248.3×	0.009	BMP4
Formation of paraxial mesoderm	1	203.9×	0.010	BMP4
Elastic fibre formation	1	167.9×	0.011	BMP4
Molecules associated with elastic fibres	1	154.3×	0.011	BMP4
Gastrulation	1	129.8×	0.012	BMP4
Reproduction	1	95.2×	0.015	BMP4
Post-translational protein phosphorylation	1	50.1×	0.026	BMP4
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	43.3×	0.029	BMP4
Extracellular matrix organization	1	31.6×	0.037	BMP4
Post-translational protein modification	1	9.6×	0.113	BMP4
Developmental Biology	1	7.2×	0.141	BMP4
Metabolism of proteins	1	6.2×	0.155	BMP4

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
pteridine-containing compound biosynthetic process	1	8426.0×	0.002	GCH1
intermediate mesodermal cell differentiation	1	8426.0×	0.002	BMP4
positive regulation of cardiac muscle fiber development	1	8426.0×	0.002	BMP4
bronchus development	1	8426.0×	0.002	BMP4
bud dilation involved in lung branching	1	8426.0×	0.002	BMP4
mammary gland formation	1	8426.0×	0.002	BMP4
negative regulation of mesenchymal cell proliferation involved in ureter development	1	8426.0×	0.002	BMP4
negative regulation of glomerulus development	1	8426.0×	0.002	BMP4
regulation of mesodermal cell differentiation	1	8426.0×	0.002	BMP4
negative regulation of metanephric S-shaped body morphogenesis	1	8426.0×	0.002	BMP4
negative regulation of metanephric comma-shaped body morphogenesis	1	8426.0×	0.002	BMP4
regulation of lung blood pressure	1	4213.0×	0.002	GCH1
tendon cell differentiation	1	4213.0×	0.002	BMP4
positive regulation of branching involved in lung morphogenesis	1	4213.0×	0.002	BMP4
negative regulation of glomerular mesangial cell proliferation	1	4213.0×	0.002	BMP4
negative regulation of branching involved in ureteric bud morphogenesis	1	4213.0×	0.002	BMP4
positive regulation of primary miRNA processing	1	4213.0×	0.002	BMP4
mesodermal cell fate determination	1	2808.7×	0.002	BMP4
specification of animal organ position	1	2808.7×	0.002	BMP4
regulation of cell fate commitment	1	2808.7×	0.002	BMP4
deltoid tuberosity development	1	2808.7×	0.002	BMP4
positive regulation of nitric-oxide synthase activity	1	2808.7×	0.002	GCH1
trachea development	1	2808.7×	0.002	BMP4
glomerular capillary formation	1	2808.7×	0.002	BMP4
nephric duct formation	1	2808.7×	0.002	BMP4
positive regulation of cardiac neural crest cell migration involved in outflow tract morphogenesis	1	2808.7×	0.002	BMP4
lens induction in camera-type eye	1	2106.5×	0.002	BMP4
prostatic bud formation	1	2106.5×	0.002	BMP4
epithelial-mesenchymal cell signaling	1	2106.5×	0.002	BMP4
negative regulation of prostatic bud formation	1	2106.5×	0.002	BMP4

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
BMP4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
BMP4	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GCH1	3.5.4.16	GTP cyclohydrolase I

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	1	GCH1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	BMP4

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	—
BMP4	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns