Is TH p.Gln381Ter (c.1141C>T) pathogenic?

TH p.Gln381Ter (c.1141C>T) is classified Likely pathogenic in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-05). Very rare (popmax 0.00223%, eas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Gln381Ter (c.1141C>T)?

TH p.Gln381Ter (c.1141C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Gln381Ter (c.1141C>T) in the general population?

TH p.Gln381Ter (c.1141C>T) is very rare (popmax 0.00223%, 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.Gln381Ter

c.1141C>T · rs121917762 · VCV2679212

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 11 of 13
REVEL	0.598	indeterminate
Splicing
SpliceAI	Δ0.66	donor gain · deltas
Pangolin	Δ0.40	gain · loss 0.22 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 9.5	GERP 1.9, phastCons 1
Overall
CADD	54.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,862 alleles

Overall 6.2e-05% 1/1,612,732 alleles · very rare exomes 1/1,460,490 · genomes 0/152,242 · 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: TH
Protein: p.Gln381Ter
Coding: c.1141C>T
MANE Select: NM_000360
dbSNP: rs121917762
Type: single nucleotide variant
Location: chr11:2165727 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 381: 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.Gln381Lys Pathogenic/Likely pathogenic ★★ ⚠ same residue
TH p.Gln381His 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-gln381ter (accessed [today's date]).

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