Is TH p.Arg476Trp (c.1426C>T) pathogenic?

TH p.Arg476Trp (c.1426C>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-29). AlphaMissense: likely benign (0.1038); Very rare (popmax 0.00483%, eas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Arg476Trp (c.1426C>T)?

TH p.Arg476Trp (c.1426C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Arg476Trp (c.1426C>T) in the general population?

TH p.Arg476Trp (c.1426C>T) is very rare (popmax 0.00483%, eas) (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.Arg476Trp (c.1426C>T)?

AlphaMissense predicts likely benign (score 0.1038) — an in-silico prediction, not a clinical call.

TH p.Arg476Trp

c.1426C>T · rs201616746 · VCV1403964

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00483%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.1038	likely benign
REVEL	0.318	indeterminate
SaProt	LLR -10.87	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	GERP -1.4, phastCons 0.9
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	22.0	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 R507W vs ClinVar R476W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00483% East Asian · 2/41,420 alleles

Filtering AF 0.0008% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000326%

Overall 0.00105% 16/1,517,760 alleles · very rare exomes 13/1,365,442 · genomes 3/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00483%	20,710
African / African-American	0.00281%	35,532
Remaining individualsnot grpmax-eligible	0.00172%	58,274
South Asian	0.00128%	78,068
European (non-Finnish)	0.000885%	112,984

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.Arg476Trp
Coding: c.1426C>T
MANE Select: NM_000360
dbSNP: rs201616746
Type: single nucleotide variant
Location: chr11:2164301 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 507 UniProt numbering: 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.Arg476Gln Uncertain significance ★★ ⚠ same residue
TH p.Arg476= Likely benign ★ 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-arg476trp (accessed [today's date]).

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