Is TH p.Thr368Ser (c.1102A>T) pathogenic?

TH p.Thr368Ser (c.1102A>T) is classified Uncertain significance in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2021-08-28). AlphaMissense: ambiguous (0.4856); Very rare (popmax 0.00199%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Thr368Ser (c.1102A>T)?

TH p.Thr368Ser (c.1102A>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Thr368Ser (c.1102A>T) in the general population?

TH p.Thr368Ser (c.1102A>T) is very rare (popmax 0.00199%, nfe) (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.Thr368Ser (c.1102A>T)?

AlphaMissense predicts ambiguous (score 0.4856) — an in-silico prediction, not a clinical call.

TH p.Thr368Ser

c.1102A>T · rs537643329 · VCV965479

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4856 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00199%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.4856	ambiguous
REVEL	0.887	moderately pathogenic-leaning
SaProt	LLR -8.26	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.6, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	29.3	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 T399S vs ClinVar T368S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00199% European (non-Finnish) · 23/1,153,046 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00111%

Overall 0.00147% 23/1,561,100 alleles · very rare exomes 19/1,409,484 · genomes 4/151,616 · joint denominator

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.Thr368Ser
Coding: c.1102A>T
MANE Select: NM_000360
dbSNP: rs537643329
Type: single nucleotide variant
Location: chr11:2166004 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 399 UniProt numbering: a UniProt-annotated variant site (in arsegs; loss of over 80% of tyrosine 3-monooxygenase activity); 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.Thr368Met Pathogenic/Likely 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
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-thr368ser (accessed [today's date]).

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