Is TH p.Arg89= (c.267G>A) pathogenic?

TH p.Arg89= (c.267G>A) is classified Benign/Likely benign in TH (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-03). Common (popmax 6.07%, mid) — too common for a highly-penetrant pathogenic allele; Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Arg89= (c.267G>A)?

TH p.Arg89= (c.267G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How is Autosomal recessive dopa-responsive dystonia inherited?

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

TH p.Arg89=

Q: How common is TH p.Arg89= (c.267G>A) in the general population?

TH p.Arg89= (c.267G>A) is common (popmax 6.07%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.267G>A · rs76240471 · VCV263254

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

gnomAD v4.1

Common

common (popmax 6.07%, mid) — too common for a highly-penetrant pathogenic allele

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 0.32	GERP -1.4
Overall
CADD	9.383	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 6.07% Middle Eastern · 368/6,058 alleles

Filtering AF 5.56% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.36%

Overall 0.644% 10,383/1,613,418 alleles · common exomes 9,580/1,461,148 · genomes 803/152,270 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	6.07%	16
South Asian	4.37%	23
Ashkenazi Jewishnot grpmax-eligible	2%	50
Remaining individualsnot grpmax-eligible	1.01%	99
Admixed American	0.645%	155
European (non-Finnish)	0.367%	272
African / African-American	0.111%	904
Amishnot grpmax-eligible	0.11%	910
Finnishnot grpmax-eligible	0.0142%	7,051
East Asian	0.00446%	22,435

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.Arg89=
Coding: c.267G>A
MANE Select: NM_000360
dbSNP: rs76240471
Type: single nucleotide variant
Location: chr11:2169695 (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 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-arg89 (accessed [today's date]).

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