GCH1

Chr 14ADAR

GTP cyclohydrolase 1

Also known as: DYT14, DYT5, DYT5a, GCH, GTP-CH-1, GTPCH1, HPABH4B

NCBI Gene: 2643ENSG00000131979UniProt: P30793

This gene encodes a member of the GTP cyclohydrolase family. The encoded protein is the first and rate-limiting enzyme in tetrahydrobiopterin (BH4) biosynthesis, catalyzing the conversion of GTP into 7,8-dihydroneopterin triphosphate. BH4 is an essential cofactor required by aromatic amino acid hydroxylases as well as nitric oxide synthases. Mutations in this gene are associated with malignant hyperphenylalaninemia and dopa-responsive dystonia. Several alternatively spliced transcript variants encoding different isoforms have been described; however, not all variants give rise to a functional enzyme. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Dystonia, DOPA-responsiveMIM #128230
ADAR
Hyperphenylalaninemia, BH4-deficient, BMIM #233910
AR
649
ClinVar variants
146
Pathogenic / LP
0.90
pLI score· haploinsufficient
3
Active trials
Clinical Summary— GCH1
🧬
Gene-Disease Validity (ClinGen)
GTP cyclohydrolase I deficiency · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.90). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
146 Pathogenic / Likely Pathogenic· 246 VUS of 649 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.40LOEUF
pLI 0.903
Z-score 2.93
OE 0.08 (0.03–0.40)
Highly constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.52Z-score
OE missense 0.63 (0.53–0.76)
86 obs / 135.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.08 (0.03–0.40)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.53–0.76)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.16
0≤1.21.6
LoF obs/exp: 1 / 11.9Missense obs/exp: 86 / 135.8Syn Z: -0.90

ClinVar Variant Classifications

649 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic104
Likely Pathogenic42
VUS246
Likely Benign189
Benign30
Conflicting38
104
Pathogenic
42
Likely Pathogenic
246
VUS
189
Likely Benign
30
Benign
38
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
40
18
46
0
104
Likely Pathogenic
13
19
10
0
42
VUS
3
184
57
2
246
Likely Benign
1
1
79
108
189
Benign
0
0
30
0
30
Conflicting
—38
Total57222222110649

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

GCH1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GCH1-related dystonia

definitive
ADUndeterminedUncertain
Dev. Disorders
G2P ↗

GCH1-related GTP cyclohydrolase 1 deficiency

definitive
ARUndeterminedUncertain
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Dystonia, DOPA-responsive

MIM #128230

Molecular basis of disorder known

Autosomal dominantAutosomal recessive

Hyperphenylalaninemia, BH4-deficient, B

MIM #233910

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — GCH1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dystonia.
Balint B et al.·Nat Rev Dis Primers
2018Review
Effects of oral sepiapterin on blood Phe concentration in a broad range of patients with phenylketonuria (APHENITY): results of an international, phase 3, randomised, double-blind, placebo-controlled trial.
Muntau AC et al.·Lancet
2024Clinical trial
The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.
Chen YP et al.·Eur J Neurol
2022
Targeting ferroptosis: a new therapeutic opportunity for kidney diseases.
Long Z et al.·Front Immunol
2024Review
The Genetic Landscape of Complex Childhood-Onset Hyperkinetic Movement Disorders.
Pérez-Dueñas B et al.·Mov Disord
2022
Dystonia-plus syndromes.
Asmus F et al.·Eur J Neurol
2010Review
Genetics in dystonia.
Klein C·Parkinsonism Relat Disord
2014Review
Relationship of Genotype, Phenotype, and Treatment in Dopa-Responsive Dystonia: MDSGene Review.
Weissbach A et al.·Mov Disord
2022Review
Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk.
Doehring A et al.·Mutat Res
2008Review
The metabolite BH4 controls T cell proliferation in autoimmunity and cancer.
Cronin SJF et al.·Nature
2018
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RRM2/GCH1 signaling decreased cisplatin sensitivity in cervical cancer by modulating the ferroptosis process.
Zhao J et al.·Histol Histopathol
2026
Dysregulation of Serpinb6a-Gch1 axis contributes to DFNB91 deafness that is amendable to gene therapies.
Cheng C et al.·Mol Ther
2026
A rare GCH1 p.Arg170Gly variant shows impaired enzymatic activity and co-occurs with a novel NEXMIF p.Asp155GlnfsTer2 leading to a complex neurological phenotype: functional studies and clinical aspects.
Ślusarczyk K et al.·Mol Genet Metab
2026Functional
HOXC8 derived from cancer-associated fibroblasts regulates lung cancer cell malignant metastasis and ferroptosis by mediating the transcription of GCH1.
Qin C et al.·Pathol Res Pract
2026
Novel Pathogenic GCH1 Variant in Familial DOPA-Responsive Dystonia.
Engel J et al.·Neuropediatrics
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
DystoniaMovement DisordersCombined Dystonia

Long-read Genome Sequencing for the Molecular Diagnosis of Dystonia

NOT YET RECRUITING
NCT06999096Phase NAUniversity Hospital, Strasbourg, FranceStarted 2025-08
Long-read whole genome sequencing
AnalgesiaCardiac Surgery

Precision Analgesia for Cardiac Surgery

NOT YET RECRUITING
NCT05612399Kathirvel SubramaniamStarted 2026-04-01
PPAPSpine Fusion

Personalized Perioperative Analgesia Platform (PPAP) for Pediatric Spine Fusion Surgery (sIRB)

RECRUITING
NCT05367609Phase NASenthil SadhasivamStarted 2022-09-20
Preoperative Genotyping

External Resources

Links to major genomics databases and tools