Is GCH1 p.Pro40= (c.120G>C) pathogenic?

GCH1 p.Pro40= (c.120G>C) is classified Likely benign in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-18). Absent from gnomAD v4.1; Associated with GTP cyclohydrolase I deficiency.

What condition is associated with GCH1 p.Pro40= (c.120G>C)?

GCH1 p.Pro40= (c.120G>C) is associated with GTP cyclohydrolase I deficiency, dystonia 5 (ClinVar).

How common is GCH1 p.Pro40= (c.120G>C) in the general population?

GCH1 p.Pro40= (c.120G>C) is absent from gnomAD v4.1 (gnomAD).

GCH1 p.Pro40=

c.120G>C · rs2504540843 · VCV2945435

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 0.088	GERP -0.41, phastCons 0.009
Overall
CADD	9.441	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GCH1
Protein: p.Pro40=
Coding: c.120G>C
MANE Select: NM_000161
dbSNP: rs2504540843
Type: single nucleotide variant
Location: chr14:54902544 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 40: the 'disordered' region

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.Pro40Arg Uncertain significance ★★ ⚠ 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-pro40 (accessed [today's date]).

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