Is TH p.Leu113Pro (c.338T>C) pathogenic?

TH p.Leu113Pro (c.338T>C) is classified Uncertain significance in TH (ClinVar, Single submitter, 1 submitter; last evaluated 2019-12-13). AlphaMissense: likely pathogenic (0.9902); Absent from gnomAD v4.1; Associated with dystonic disorder.

What condition is associated with TH p.Leu113Pro (c.338T>C)?

TH p.Leu113Pro (c.338T>C) is associated with dystonic disorder (ClinVar).

How common is TH p.Leu113Pro (c.338T>C) in the general population?

TH p.Leu113Pro (c.338T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TH p.Leu113Pro (c.338T>C)?

AlphaMissense predicts likely pathogenic (score 0.9902) — an in-silico prediction, not a clinical call.

TH p.Leu113Pro

c.338T>C · rs1846169144 · VCV836034

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9902 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dystonic disorder

Computational evidence

Protein change
AlphaMissense	0.9902	likely pathogenic · top 7% in TH
REVEL	0.853	moderately pathogenic-leaning
SaProt	LLR -16.49	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 0.8, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	27.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 L144P vs ClinVar L113P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TH
Protein: p.Leu113Pro
Coding: c.338T>C
MANE Select: NM_000360
dbSNP: rs1846169144
Type: single nucleotide variant
Location: chr11:2168640 (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

dystonic disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TH p.Leu113Val Uncertain significance ★ ⚠ same residue
TH p.Leu113= Likely benign ★ same residue
TH p.Gln150Ter Pathogenic ★★ same condition
TH p.Thr231Ser Likely pathogenic ★★ same condition
TH c.1200+2T>C Likely pathogenic ★★ same type
TH c.1334+1G>A Likely pathogenic ★★ same type
TH c.312+1G>A Likely pathogenic ★★ same type
TH c.488-1G>A Pathogenic ★★ same type

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-leu113pro (accessed [today's date]).

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