Is TH p.His330= (c.990C>T) pathogenic?

TH p.His330= (c.990C>T) is classified Likely benign in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). Ultra-rare (popmax 0.0186%, amr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.His330= (c.990C>T)?

TH p.His330= (c.990C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.His330= (c.990C>T) in the general population?

TH p.His330= (c.990C>T) is ultra-rare (popmax 0.0186%, amr) (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.His330=

c.990C>T · rs760420202 · VCV1088421

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0186%, amr)

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 -8.7	GERP -3.5
Overall
CADD	4.151	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0186% Admixed American · 11/59,200 alleles

Filtering AF 0.0103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00805%

Overall 0.000749% 12/1,602,340 alleles · ultra-rare exomes 11/1,450,082 · genomes 1/152,258 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0186%	5,382
European (non-Finnish)	8.5e-05%	1,177,072

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.His330=
Coding: c.990C>T
MANE Select: NM_000360
dbSNP: rs760420202
Type: single nucleotide variant
Location: chr11:2166537 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 330: an α-helix

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.His330fs Pathogenic ★ same residue
TH p.His330Arg Uncertain significance ★ ⚠ same residue
TH p.His330Gln 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

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-his330 (accessed [today's date]).

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