Is GCH1 p.Arg235= (c.705G>C) pathogenic?

GCH1 p.Arg235= (c.705G>C) is classified Likely benign in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-11). Very rare (popmax 8.48e-05%, nfe); Associated with dystonia 5.

What condition is associated with GCH1 p.Arg235= (c.705G>C)?

GCH1 p.Arg235= (c.705G>C) is associated with dystonia 5, GTP cyclohydrolase I deficiency (ClinVar).

How common is GCH1 p.Arg235= (c.705G>C) in the general population?

GCH1 p.Arg235= (c.705G>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

How is Autosomal dominant dopa-responsive dystonia inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

GCH1 p.Arg235=

c.705G>C · rs2504336444 · VCV2187614

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

dystonia 5

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.44	GERP -0.33, phastCons 0.99
Overall
CADD	8.949	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 6.2e-05% 1/1,614,056 alleles · very rare exomes 1/1,461,762 · genomes 0/152,294 · 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.Arg235=
Coding: c.705G>C
MANE Select: NM_000161
dbSNP: rs2504336444
Type: single nucleotide variant
Location: chr14:54844065 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 235: an α-helix

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

Disease context

dystonia 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: GTP cyclohydrolase I deficiency

For Autosomal dominant dopa-responsive dystonia (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Europe)

Similar variants

GCH1 p.Arg235Gln Uncertain significance ★★ ⚠ same residue
GCH1 p.Arg235Trp 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

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-arg235 (accessed [today's date]).

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