Is TH p.Thr231Ser (c.692C>G) pathogenic?

TH p.Thr231Ser (c.692C>G) is classified Likely pathogenic in TH (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-05). AlphaMissense: likely pathogenic (0.6428); Absent from gnomAD v4.1; Associated with dystonic disorder.

What condition is associated with TH p.Thr231Ser (c.692C>G)?

TH p.Thr231Ser (c.692C>G) is associated with dystonic disorder, TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Thr231Ser (c.692C>G) in the general population?

TH p.Thr231Ser (c.692C>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TH p.Thr231Ser (c.692C>G)?

AlphaMissense predicts likely pathogenic (score 0.6428) — an in-silico prediction, not a clinical call.

TH p.Thr231Ser

c.692C>G · rs1590168246 · VCV691996

Likely pathogenic Multiple submitters

Classification

Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6428 · 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	0.6428	likely pathogenic ✓ concordant with ClinVar
REVEL	0.839	moderately pathogenic-leaning
SaProt	LLR -10.94	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 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	25.0	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 T262S vs ClinVar T231S) — 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.Thr231Ser
Coding: c.692C>G
MANE Select: NM_000360
dbSNP: rs1590168246
Type: single nucleotide variant
Location: chr11:2167438 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 262 UniProt numbering: an α-helix

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

Also linked: TH-deficient dopa-responsive dystonia

Similar variants

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
TH c.90+13G>A 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-thr231ser (accessed [today's date]).

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