Is TH p.Pro88Leu (c.263C>T) pathogenic?

TH p.Pro88Leu (c.263C>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-24). AlphaMissense: likely benign (0.0653); Ultra-rare (popmax 0.0253%, afr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Pro88Leu (c.263C>T)?

TH p.Pro88Leu (c.263C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Pro88Leu (c.263C>T) in the general population?

TH p.Pro88Leu (c.263C>T) is ultra-rare (popmax 0.0253%, afr) (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.Pro88Leu (c.263C>T)?

AlphaMissense predicts likely benign (score 0.0653) — an in-silico prediction, not a clinical call.

TH p.Pro88Leu

c.263C>T · rs150260759 · VCV304083

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0653 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0253%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.0653	likely benign
REVEL	0.278	benign-leaning
SaProt	LLR -8.51	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.24, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	12.97	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 P119L vs ClinVar P88L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0253% African / African-American · 19/75,046 alleles

Filtering AF 0.0165% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0137%

Overall 0.00353% 57/1,613,370 alleles · ultra-rare exomes 46/1,461,104 · genomes 11/152,266 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0253%	3,950
South Asian	0.0209%	4,792
Admixed American	0.00666%	15,006
Remaining individualsnot grpmax-eligible	0.0064%	15,626
East Asian	0.00223%	44,864
European (non-Finnish)	0.000848%	117,990

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.Pro88Leu
Coding: c.263C>T
MANE Select: NM_000360
dbSNP: rs150260759
Type: single nucleotide variant
Location: chr11:2169699 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB

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.Pro88= Benign ★ same residue
TH p.Pro88fs Pathogenic ★ 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-pro88leu (accessed [today's date]).

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