Is GCH1 p.Pro49= (c.147C>G) pathogenic?

GCH1 p.Pro49= (c.147C>G) is classified Likely benign in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-18). Ultra-rare (popmax 0.0297%, afr); Associated with GTP cyclohydrolase I deficiency.

What condition is associated with GCH1 p.Pro49= (c.147C>G)?

GCH1 p.Pro49= (c.147C>G) is associated with GTP cyclohydrolase I deficiency, dystonia 5 (ClinVar).

How common is GCH1 p.Pro49= (c.147C>G) in the general population?

GCH1 p.Pro49= (c.147C>G) is ultra-rare (popmax 0.0297%, afr) (gnomAD).

GCH1 p.Pro49=

c.147C>G · rs377631489 · VCV1611694

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0297%, afr)

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 -3.3	GERP -3.3
Overall
CADD	4.654	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0297% African / African-American · 22/74,160 alleles

Filtering AF 0.0201% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.00144% 23/1,597,274 alleles · ultra-rare exomes 12/1,445,096 · genomes 11/152,178 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0297%	3,371
European (non-Finnish)	8.52e-05%	1,173,405

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.Pro49=
Coding: c.147C>G
MANE Select: NM_000161
dbSNP: rs377631489
Type: single nucleotide variant
Location: chr14:54902517 (GRCh38)
Gene constraint: LOEUF 0.899 · pLI 0.36 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 86.89 · 11 PDB
Residue 49: 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.Pro49His Uncertain significance ★ ⚠ same residue
GCH1 p.Pro49Ser Uncertain significance ★ ⚠ same residue
GCH1 p.Pro49Ala Likely benign ★ same residue
GCH1 p.Pro49Leu 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

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-pro49 (accessed [today's date]).

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