Is TH p.Ser195= (c.585G>C) pathogenic?

TH p.Ser195= (c.585G>C) is classified Conflicting classifications of pathogenicity in TH (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-23). Very rare (popmax 0.0011%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ser195= (c.585G>C)?

TH p.Ser195= (c.585G>C) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ser195= (c.585G>C) in the general population?

TH p.Ser195= (c.585G>C) is very rare (popmax 0.0011%, 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.Ser195=

c.585G>C · rs376615793 · VCV424969

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.022	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -2.5
Overall
CADD	2.513	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/90,754 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00031% 5/1,611,498 alleles · very rare exomes 5/1,459,216 · genomes 0/152,282 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	90,754
European (non-Finnish)	0.000339%	294,854

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.Ser195=
Coding: c.585G>C
MANE Select: NM_000360
dbSNP: rs376615793
Type: single nucleotide variant
Location: chr11:2167925 (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

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.Ser195Ter Pathogenic ★ same residue
TH p.Ser195Leu Uncertain significance ★ ⚠ same residue
TH p.Ser195fs 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

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-ser195 (accessed [today's date]).

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