Is TH p.Arg221Leu (c.662G>T) pathogenic?

TH p.Arg221Leu (c.662G>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2021-09-01). AlphaMissense: likely benign (0.1466); No allele count reported in gnomAD v4.1 (AN 1,562,876); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Arg221Leu (c.662G>T)?

TH p.Arg221Leu (c.662G>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Arg221Leu (c.662G>T) in the general population?

TH p.Arg221Leu (c.662G>T) is no allele count reported in gnomAD v4.1 (AN 1,562,876) (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.Arg221Leu (c.662G>T)?

AlphaMissense predicts likely benign (score 0.1466) — an in-silico prediction, not a clinical call.

TH p.Arg221Leu

c.662G>T · rs150559011 · VCV412033

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1466 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,562,876)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.1466	likely benign
REVEL	0.427	indeterminate
SaProt	LLR -9.17	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.87	GERP -0.067, phastCons 0.46
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R252L vs ClinVar R221L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,562,876). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: TH
Protein: p.Arg221Leu
Coding: c.662G>T
MANE Select: NM_000360
dbSNP: rs150559011
Type: single nucleotide variant
Location: chr11:2167468 (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.Arg221Cys 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-arg221leu (accessed [today's date]).

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