Is GCH1 p.Pro49Ser (c.145C>T) pathogenic?

GCH1 p.Pro49Ser (c.145C>T) is classified Uncertain significance in GCH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-06). AlphaMissense: likely benign (0.0777); Very rare (popmax 0.000682%, nfe); Associated with dystonia 5.

What condition is associated with GCH1 p.Pro49Ser (c.145C>T)?

GCH1 p.Pro49Ser (c.145C>T) is associated with dystonia 5, GTP cyclohydrolase I deficiency (ClinVar).

How common is GCH1 p.Pro49Ser (c.145C>T) in the general population?

GCH1 p.Pro49Ser (c.145C>T) is very rare (popmax 0.000682%, 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.

What do computational predictors say about GCH1 p.Pro49Ser (c.145C>T)?

AlphaMissense predicts likely benign (score 0.0777) — an in-silico prediction, not a clinical call.

GCH1 p.Pro49Ser

c.145C>T · rs573085618 · VCV2925684

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0777 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000682%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

dystonia 5

Computational evidence

Protein change
AlphaMissense	0.0777	likely benign
REVEL	0.336	indeterminate
SaProt	LLR -6.56	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP 0.72, phastCons 0.99
Regional constraint	o/e 0.97	unconstrained · MANE · 264 bp · p 0.74 · regional, not allelic
Overall
CADD	14.69	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.000682% European (non-Finnish) · 8/1,172,948 alleles

Filtering AF 0.000293% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.000501% 8/1,596,374 alleles · very rare exomes 7/1,444,074 · genomes 1/152,300 · 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.Pro49Ser
Coding: c.145C>T
MANE Select: NM_000161
dbSNP: rs573085618
Type: single nucleotide variant
Location: chr14:54902519 (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

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.Pro49His Uncertain significance ★ ⚠ same residue
GCH1 p.Pro49= Likely benign ★ 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-pro49ser (accessed [today's date]).

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