Is GCH1 p.Pro86Arg (c.257C>G) pathogenic?

GCH1 p.Pro86Arg (c.257C>G) is classified Uncertain significance in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2017-10-24). AlphaMissense: likely pathogenic (0.5699); Absent from gnomAD v4.1; Associated with GTP cyclohydrolase I deficiency.

What condition is associated with GCH1 p.Pro86Arg (c.257C>G)?

GCH1 p.Pro86Arg (c.257C>G) is associated with GTP cyclohydrolase I deficiency, dystonia 5 (ClinVar).

How common is GCH1 p.Pro86Arg (c.257C>G) in the general population?

GCH1 p.Pro86Arg (c.257C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GCH1 p.Pro86Arg (c.257C>G)?

AlphaMissense predicts likely pathogenic (score 0.5699) — an in-silico prediction, not a clinical call.

GCH1 p.Pro86Arg

c.257C>G · rs1555362836 · VCV529412

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5699 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

GTP cyclohydrolase I deficiency

Computational evidence

Protein change
AlphaMissense	0.5699	likely pathogenic
REVEL	0.861	moderately pathogenic-leaning
SaProt	LLR -13.24	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 264 bp · p 0.74 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

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.Pro86Arg
Coding: c.257C>G
MANE Select: NM_000161
dbSNP: rs1555362836
Type: single nucleotide variant
Location: chr14:54902407 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 86: a β-strand

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.Pro86= Likely benign ★ 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-pro86arg (accessed [today's date]).

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