Is TH p.Arg202His (c.605G>A) pathogenic?

TH p.Arg202His (c.605G>A) is classified Pathogenic in TH (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-01-27). AlphaMissense: likely pathogenic (0.8317); Ultra-rare (popmax 0.0223%, eas); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Arg202His (c.605G>A)?

TH p.Arg202His (c.605G>A) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Arg202His (c.605G>A) in the general population?

TH p.Arg202His (c.605G>A) is ultra-rare (popmax 0.0223%, eas) (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.Arg202His (c.605G>A)?

AlphaMissense predicts likely pathogenic (score 0.8317) — an in-silico prediction, not a clinical call.

TH p.Arg202His

c.605G>A · rs80338892 · VCV12327

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.8317 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.8317	likely pathogenic ✓ concordant with ClinVar
REVEL	0.955	strongly pathogenic-leaning
SaProt	LLR -11.02	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	32.0	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 R233H vs ClinVar R202H) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0223% East Asian · 10/44,778 alleles

Filtering AF 0.0146% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0139%

Overall 0.0144% 232/1,610,938 alleles · ultra-rare exomes 211/1,458,642 · genomes 21/152,296 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0223%	4,478
European (non-Finnish)	0.0165%	6,047
Middle Eastern	0.0165%	6,056
Remaining individualsnot grpmax-eligible	0.0112%	8,911
South Asian	0.00882%	11,333
Admixed American	0.00668%	14,959
African / African-American	0.00667%	14,999
Finnishnot grpmax-eligible	0.00319%	31,321

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.Arg202His
Coding: c.605G>A
MANE Select: NM_000360
dbSNP: rs80338892
Type: single nucleotide variant
Location: chr11:2167905 (GRCh38)
Gene constraint: LOEUF 1.27 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.75 · 7 PDB
Residue 233 UniProt numbering: a UniProt-annotated variant site (in arsegs; loss of over 80% of tyrosine 3-monooxygenase activity; shifted substrate specificity from tyrosine to phenylalanine and dopa); 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.Arg202Cys 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-arg202his (accessed [today's date]).

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