Is TH p.Asp5fs (c.12dup) pathogenic?

TH p.Asp5fs (c.12dup) is classified Pathogenic in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2021-12-14). Very rare (popmax 0.0011%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Asp5fs (c.12dup)?

TH p.Asp5fs (c.12dup) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Asp5fs (c.12dup) in the general population?

TH p.Asp5fs (c.12dup) is very rare (popmax 0.0011%, sas) (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.Asp5fs

c.12dup · rs1057516716 · VCV370720

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 1 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.24	GERP -1.8

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,042 alleles

Overall 6.2e-05% 1/1,612,004 alleles · very rare exomes 1/1,459,754 · genomes 0/152,250 · 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.Asp5fs
Coding: c.12dup
MANE Select: NM_000360
dbSNP: rs1057516716
Type: Duplication
Location: chr11:2171774 (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.Asp5Asn Uncertain significance ★★ ⚠ same residue
TH p.Asp5= Likely benign ★ same residue
TH c.90+7dup Pathogenic/Likely pathogenic ★★ same condition
TH p.Glu266fs Pathogenic/Likely pathogenic ★★ same condition
TH p.Leu356fs Likely pathogenic ★★ same condition
TH c.91-833dup Pathogenic ★ same condition
TH c.91-883dup Pathogenic ★ same condition
TH p.Ala418fs 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-asp5fs (accessed [today's date]).

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