Is TH p.Leu205Pro (c.614T>C) pathogenic?

TH p.Leu205Pro (c.614T>C) is classified Pathogenic/Likely pathogenic in TH (ClinVar, Multiple submitters, 13 submitters; last evaluated 2025-09-19). AlphaMissense: likely pathogenic (0.8539); Very rare (popmax 0.00134%, afr); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Leu205Pro (c.614T>C)?

TH p.Leu205Pro (c.614T>C) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Leu205Pro (c.614T>C) in the general population?

TH p.Leu205Pro (c.614T>C) is very rare (popmax 0.00134%, 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.Leu205Pro (c.614T>C)?

AlphaMissense predicts likely pathogenic (score 0.8539) — an in-silico prediction, not a clinical call.

TH p.Leu205Pro

c.614T>C · rs121917763 · VCV12325

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.8539 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.8539	likely pathogenic ✓ concordant with ClinVar
REVEL	0.618	indeterminate
SaProt	LLR -13.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.17	GERP -2
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	15.5	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 L236P vs ClinVar L205P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,880 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000435% 7/1,610,598 alleles · very rare exomes 5/1,458,426 · genomes 2/152,172 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,880
European (non-Finnish)	0.000509%	196,509

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.Leu205Pro
Coding: c.614T>C
MANE Select: NM_000360
dbSNP: rs121917763
Type: single nucleotide variant
Location: chr11:2167896 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 236 UniProt numbering: a UniProt-annotated variant site (in arsegs; severe parkinsonian symptoms in early infancy; strongly reduced stability and tyrosine 3-monooxygenase activity; rare mutation); 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.Leu205= 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
TH c.90+10C>T Pathogenic/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-leu205pro (accessed [today's date]).

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