Is GCH1 p.Ser166= (c.498C>T) pathogenic?

GCH1 p.Ser166= (c.498C>T) is classified Likely benign in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-02). Very rare (popmax 0.00331%, sas); Associated with dystonia 5.

What condition is associated with GCH1 p.Ser166= (c.498C>T)?

GCH1 p.Ser166= (c.498C>T) is associated with dystonia 5, GTP cyclohydrolase I deficiency (ClinVar).

How common is GCH1 p.Ser166= (c.498C>T) in the general population?

GCH1 p.Ser166= (c.498C>T) is very rare (popmax 0.00331%, sas) (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.Ser166=

c.498C>T · rs2039865915 · VCV2925087

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00331%, sas)

Conditions

dystonia 5

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 7.3	GERP 0.23, phastCons 1
Overall
CADD	12.08	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00331% South Asian · 3/90,650 alleles

Filtering AF 0.000879% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000444%

Overall 0.000188% 3/1,592,030 alleles · very rare exomes 2/1,439,846 · genomes 1/152,184 · 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.Ser166=
Coding: c.498C>T
MANE Select: NM_000161
dbSNP: rs2039865915
Type: single nucleotide variant
Location: chr14:54859692 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 166: 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 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
GCH1 p.Arg184Cys 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-ser166 (accessed [today's date]).

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