Is TH p.Ala95= (c.285G>A) pathogenic?

TH p.Ala95= (c.285G>A) is classified Likely benign in TH (ClinVar, Single submitter, 2 submitters; last evaluated 2025-04-02). Ultra-rare (popmax 0.011%, sas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ala95= (c.285G>A)?

TH p.Ala95= (c.285G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ala95= (c.285G>A) in the general population?

TH p.Ala95= (c.285G>A) is ultra-rare (popmax 0.011%, 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.Ala95=

c.285G>A · rs749856378 · VCV1098938

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.011%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.3	GERP -1.4
Overall
CADD	3.201	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.011% South Asian · 10/91,080 alleles

Filtering AF 0.00594% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00453%

Overall 0.00112% 18/1,613,358 alleles · ultra-rare exomes 17/1,461,336 · genomes 1/152,022 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.011%	9,108
East Asian	0.00223%	44,860
African / African-American	0.00134%	74,866
European (non-Finnish)	0.000508%	196,661

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.Ala95=
Coding: c.285G>A
MANE Select: NM_000360
dbSNP: rs749856378
Type: single nucleotide variant
Location: chr11:2169677 (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.Ala95Glu Uncertain significance ★★ ⚠ same residue
TH p.Ala95Gly Uncertain significance ★★ ⚠ same residue
TH p.Ala95Val Uncertain significance ★★ ⚠ same residue
TH p.Ala95fs 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

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-ala95 (accessed [today's date]).

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