Is TH p.Pro4= (c.12C>T) pathogenic?

TH p.Pro4= (c.12C>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-27). Rare (popmax 0.455%, mid); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Pro4= (c.12C>T)?

TH p.Pro4= (c.12C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Pro4= (c.12C>T) in the general population?

TH p.Pro4= (c.12C>T) is rare (popmax 0.455%, mid) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TH p.Pro4=

c.12C>T · rs147131010 · VCV374422

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

rare (popmax 0.455%, mid)

Conditions

TH-deficient dopa-responsive dystonia

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 -0.12	GERP -1.8
Overall
CADD	13.55	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.455% Middle Eastern · 27/5,928 alleles

Filtering AF 0.321% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.277%

Overall 0.0229% 369/1,611,860 alleles · rare exomes 341/1,459,596 · genomes 28/152,264 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.455%	220
European (non-Finnish)	0.0253%	3,946
Admixed American	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.016%	6,245
African / African-American	0.0133%	7,502
South Asian	0.00879%	11,380
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,558
Finnishnot grpmax-eligible	0.0016%	62,374

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: TH
Protein: p.Pro4=
Coding: c.12C>T
MANE Select: NM_000360
dbSNP: rs147131010
Type: single nucleotide variant
Location: chr11:2171775 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB

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

Disease context

TH-deficient dopa-responsive dystonia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Autosomal recessive dopa-responsive dystonia (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

TH p.Pro4Leu Uncertain significance ★ ⚠ same residue
TH p.Pro4Thr Uncertain significance ⚠ same residue
TH c.1200+2T>C Likely pathogenic ★★ same condition
TH c.1334+1G>A Likely pathogenic ★★ same condition
TH c.312+1G>A Likely pathogenic ★★ same condition
TH c.488-1G>A Pathogenic ★★ same condition
TH c.644+1G>A Likely pathogenic ★★ same condition
TH c.695+1G>C 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/th-p-pro4 (accessed [today's date]).

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