Is TH p.Arg221Cys (c.661C>T) pathogenic?

TH p.Arg221Cys (c.661C>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1052); Very rare (popmax 0.00379%, amr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Arg221Cys (c.661C>T)?

TH p.Arg221Cys (c.661C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Arg221Cys (c.661C>T) in the general population?

TH p.Arg221Cys (c.661C>T) is very rare (popmax 0.00379%, amr) (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.Arg221Cys (c.661C>T)?

AlphaMissense predicts likely benign (score 0.1052) — an in-silico prediction, not a clinical call.

TH p.Arg221Cys

c.661C>T · rs1245249248 · VCV1955471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1052 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00379%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.1052	likely benign
REVEL	0.656	pathogenic-leaning
SaProt	LLR -10.02	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP -2.5, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	28.8	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 R252C vs ClinVar R221C) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00379% Admixed American · 2/52,704 alleles

Filtering AF 0.000629% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000235%

Overall 0.000448% 7/1,563,120 alleles · very rare exomes 6/1,410,794 · genomes 1/152,326 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00379%	26,352
Remaining individualsnot grpmax-eligible	0.00165%	60,536
African / African-American	0.00135%	73,988
South Asian	0.00118%	84,972
European (non-Finnish)	0.000173%	576,848

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.Arg221Cys
Coding: c.661C>T
MANE Select: NM_000360
dbSNP: rs1245249248
Type: single nucleotide variant
Location: chr11:2167469 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 252 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.Arg221Gly Uncertain significance ★★ ⚠ same residue
TH p.Arg221Leu Uncertain significance ★ ⚠ same residue
TH p.Arg221= Likely benign ★ same residue
TH p.Arg221His 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

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-arg221cys (accessed [today's date]).

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