Is GCH1 p.Pro23= (c.69C>G) pathogenic?

GCH1 p.Pro23= (c.69C>G) is classified Likely benign in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-10). Very rare (popmax 0.00278%, eas); Associated with GTP cyclohydrolase I deficiency.

What condition is associated with GCH1 p.Pro23= (c.69C>G)?

GCH1 p.Pro23= (c.69C>G) is associated with GTP cyclohydrolase I deficiency, dystonia 5 (ClinVar).

How common is GCH1 p.Pro23= (c.69C>G) in the general population?

GCH1 p.Pro23= (c.69C>G) is very rare (popmax 0.00278%, eas) (gnomAD).

GCH1 p.Pro23=

c.69C>G · rs767294964 · VCV2949734

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00278%, eas)

Conditions

GTP cyclohydrolase I deficiency

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.2	GERP -2.8
Overall
CADD	7.079	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00278% East Asian · 1/35,938 alleles

Overall 6.67e-05% 1/1,499,860 alleles · very rare exomes 1/1,347,584 · genomes 0/152,276 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GCH1
Protein: p.Pro23=
Coding: c.69C>G
MANE Select: NM_000161
dbSNP: rs767294964
Type: single nucleotide variant
Location: chr14:54902595 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 23: the 'disordered' region; a UniProt-annotated variant site (in drd)

Full GCH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

GTP cyclohydrolase I deficiency — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: dystonia 5

Similar variants

GCH1 p.Pro23Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
GCH1 c.344-1G>A Pathogenic ★★ same condition
GCH1 c.510-1G>A Pathogenic/Likely pathogenic ★★ same condition
GCH1 c.541+1G>T Pathogenic ★★ same condition
GCH1 c.541+2T>C Pathogenic ★★ same condition
GCH1 c.626+1G>A Pathogenic/Likely pathogenic ★★ same condition
GCH1 c.626+1G>T Pathogenic ★★ same condition
GCH1 c.-22C>T Pathogenic/Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/gch1-p-pro23 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown