Is TH p.Ser262Arg (c.786C>G) pathogenic?

TH p.Ser262Arg (c.786C>G) is classified Uncertain significance in TH (ClinVar, No assertion criteria, 1 submitter; last evaluated 2025-03-27). AlphaMissense: likely pathogenic (0.6526); Very rare (popmax 0.000341%, nfe); Associated with TH-deficient dopa-responsive dystonia.

What condition is associated with TH p.Ser262Arg (c.786C>G)?

TH p.Ser262Arg (c.786C>G) is associated with TH-deficient dopa-responsive dystonia (ClinVar).

How common is TH p.Ser262Arg (c.786C>G) in the general population?

TH p.Ser262Arg (c.786C>G) is very rare (popmax 0.000341%, nfe) (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.Ser262Arg (c.786C>G)?

AlphaMissense predicts likely pathogenic (score 0.6526) — an in-silico prediction, not a clinical call.

TH p.Ser262Arg

c.786C>G · VCV4062305

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6526 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000341%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

TH-deficient dopa-responsive dystonia

Computational evidence

Protein change
AlphaMissense	0.6526	likely pathogenic
REVEL	0.418	indeterminate
SaProt	LLR -11.97	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.4	GERP -3.5
Regional constraint	o/e 1.03	unconstrained · MANE · 7,550 bp · p 0.38 · regional, not allelic
Overall
CADD	17.31	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S293R vs ClinVar S262R) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000341% European (non-Finnish) · 4/1,173,616 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.00025% 4/1,598,520 alleles · very rare exomes 4/1,446,170 · genomes 0/152,350 · joint denominator

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.Ser262Arg
Coding: c.786C>G
MANE Select: NM_000360
Type: single nucleotide variant
Location: chr11:2166942 (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.Ser262= Likely benign ★ same residue
TH p.Ser262Gly Uncertain significance ★ ⚠ 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-ser262arg (accessed [today's date]).

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