Is TH p.Pro64= (c.192C>T) pathogenic?

TH p.Pro64= (c.192C>T) is classified Likely benign in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-19). Ultra-rare (popmax 0.0245%, eas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Pro64= (c.192C>T)?

TH p.Pro64= (c.192C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Pro64= (c.192C>T) in the general population?

TH p.Pro64= (c.192C>T) is ultra-rare (popmax 0.0245%, eas) (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.Pro64=

c.192C>T · rs767080132 · VCV1103273

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0245%, eas)

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 -11	GERP -1.4
Overall
CADD	0.342	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0245% East Asian · 11/44,866 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0106%

Overall 0.00211% 34/1,611,664 alleles · ultra-rare exomes 27/1,459,498 · genomes 7/152,166 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0245%	4,079
African / African-American	0.0107%	9,365
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
South Asian	0.00329%	30,351
Admixed American	0.00167%	59,948
Remaining individualsnot grpmax-eligible	0.0016%	62,332
European (non-Finnish)	0.000763%	131,060

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.Pro64=
Coding: c.192C>T
MANE Select: NM_000360
dbSNP: rs767080132
Type: single nucleotide variant
Location: chr11:2169770 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 64: the 'disordered' region

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 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
TH c.90+10C>T Pathogenic/Likely pathogenic ★★ same condition
TH c.90+13G>A 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-pro64 (accessed [today's date]).

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