Is TH p.Ser456= (c.1368C>T) pathogenic?

TH p.Ser456= (c.1368C>T) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-22). Ultra-rare (popmax 0.0762%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ser456= (c.1368C>T)?

TH p.Ser456= (c.1368C>T) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ser456= (c.1368C>T) in the general population?

TH p.Ser456= (c.1368C>T) is ultra-rare (popmax 0.0762%, sas) (gnomAD).

How is Autosomal recessive dopa-responsive dystonia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

TH p.Ser456=

c.1368C>T · rs45538536 · VCV304068

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0762%, sas)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -9.4	GERP -3.4
Overall
CADD	0.343	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0762% South Asian · 64/83,986 alleles

Filtering AF 0.0612% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0557%

Overall 0.0307% 476/1,552,314 alleles · ultra-rare exomes 440/1,400,112 · genomes 36/152,202 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0762%	1,312
European (non-Finnish)	0.0326%	3,066
Finnishnot grpmax-eligible	0.026%	3,840
Remaining individualsnot grpmax-eligible	0.0201%	4,977
Middle Eastern	0.0171%	5,860
African / African-American	0.00832%	12,020
Admixed American	0.00379%	26,373
East Asian	0.00238%	41,930

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.Ser456=
Coding: c.1368C>T
MANE Select: NM_000360
dbSNP: rs45538536
Type: single nucleotide variant
Location: chr11:2164359 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 456: a β-strand

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.Ser456Cys Uncertain significance ★ ⚠ same residue
TH p.Ser456_Val457insTer 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-ser456 (accessed [today's date]).

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