Is TH p.Asp460Glu (c.1380C>A) pathogenic?

TH p.Asp460Glu (c.1380C>A) is classified Uncertain significance in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2021-07-19). AlphaMissense: ambiguous (0.5019); Very rare (popmax 8.74e-05%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Asp460Glu (c.1380C>A)?

TH p.Asp460Glu (c.1380C>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Asp460Glu (c.1380C>A) in the general population?

TH p.Asp460Glu (c.1380C>A) is very rare (popmax 8.74e-05%, nfe) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

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

What do computational predictors say about TH p.Asp460Glu (c.1380C>A)?

AlphaMissense predicts ambiguous (score 0.5019) — an in-silico prediction, not a clinical call.

TH p.Asp460Glu

c.1380C>A · rs748364426 · VCV989999

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5019 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.74e-05%, nfe)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.5019	ambiguous
REVEL	0.523	indeterminate
SaProt	LLR -10.18	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP -2.1, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	20.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM D491E vs ClinVar D460E) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.74e-05% European (non-Finnish) · 1/1,144,646 alleles

Overall 6.46e-05% 1/1,549,124 alleles · very rare exomes 1/1,396,806 · genomes 0/152,318 · 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.Asp460Glu
Coding: c.1380C>A
MANE Select: NM_000360
dbSNP: rs748364426
Type: single nucleotide variant
Location: chr11:2164347 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 491 UniProt numbering: a β-strand

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.Asp460Asn Uncertain significance ★★ ⚠ same residue
TH p.Asp460Tyr 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-asp460glu (accessed [today's date]).

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