Is TH p.Pro218Leu (c.653C>T) pathogenic?

TH p.Pro218Leu (c.653C>T) is classified Uncertain significance in TH (ClinVar, Multiple submitters, 5 submitters; last evaluated 2022-02-03). AlphaMissense: likely benign (0.0873); Ultra-rare (popmax 0.0834%, mid); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Pro218Leu (c.653C>T)?

TH p.Pro218Leu (c.653C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Pro218Leu (c.653C>T) in the general population?

TH p.Pro218Leu (c.653C>T) is ultra-rare (popmax 0.0834%, mid) (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.Pro218Leu (c.653C>T)?

AlphaMissense predicts likely benign (score 0.0873) — an in-silico prediction, not a clinical call.

TH p.Pro218Leu

c.653C>T · rs377729019 · VCV374731

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0873 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0834%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.0873	likely benign
REVEL	0.539	indeterminate
SaProt	LLR -10.65	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 11	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	22.8	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 P249L vs ClinVar P218L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0834% Middle Eastern · 5/5,998 alleles

Filtering AF 0.0328% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0213%

Overall 0.00269% 42/1,561,416 alleles · ultra-rare exomes 35/1,409,122 · genomes 7/152,294 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0834%	1,200
East Asian	0.0118%	8,458
African / African-American	0.00811%	12,324
Remaining individualsnot grpmax-eligible	0.00661%	15,123
Admixed American	0.00381%	26,247
European (non-Finnish)	0.00174%	57,633

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.Pro218Leu
Coding: c.653C>T
MANE Select: NM_000360
dbSNP: rs377729019
Type: single nucleotide variant
Location: chr11:2167477 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 249 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.Pro218Ser Uncertain significance ★ ⚠ same residue
TH p.Pro218= 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-pro218leu (accessed [today's date]).

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