Is TOR1A p.Arg223Ser (c.669G>C) pathogenic?

TOR1A p.Arg223Ser (c.669G>C) is classified Uncertain significance in TOR1A (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-26). AlphaMissense: likely pathogenic (0.581); Absent from gnomAD v4.1; Associated with dystonic disorder.

What condition is associated with TOR1A p.Arg223Ser (c.669G>C)?

TOR1A p.Arg223Ser (c.669G>C) is associated with dystonic disorder (ClinVar).

How common is TOR1A p.Arg223Ser (c.669G>C) in the general population?

TOR1A p.Arg223Ser (c.669G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about TOR1A p.Arg223Ser (c.669G>C)?

AlphaMissense predicts likely pathogenic (score 0.581) — an in-silico prediction, not a clinical call.

TOR1A p.Arg223Ser

c.669G>C · VCV4744558

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.581 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dystonic disorder

Computational evidence

Protein change
AlphaMissense	0.581	likely pathogenic
REVEL	0.159	moderately benign-leaning
SaProt	LLR -10.71	damaging
⇒ AlphaMissense and SaProt call this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -6.3	GERP -5.1
Regional constraint	o/e 0.90	unconstrained · MANE · 10 kb · p 0.042 · regional, not allelic
Overall
CADD	13.46	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: TOR1A
Protein: p.Arg223Ser
Coding: c.669G>C
MANE Select: NM_000113
Type: single nucleotide variant
Location: chr9:129818599 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 3 PDB
Residue 223: the 'interaction with snapin' region; an α-helix

Full TOR1A gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

dystonic disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

TOR1A p.Arg288Ter Pathogenic/Likely pathogenic ★★ same condition
TOR1A p.Ala239Thr Uncertain significance ★★ ⚠ same condition
TOR1A p.Ala239Val Uncertain significance ★★ ⚠ same condition
TOR1A p.Arg213Gly Uncertain significance ★★ ⚠ same condition
TOR1A p.Arg260Trp Uncertain significance ★★ ⚠ same condition
TOR1A p.Asp331Asn Uncertain significance ★★ ⚠ same condition
TOR1A p.Cys44Gly Uncertain significance ★★ ⚠ same condition
TOR1A p.Leu179Phe Uncertain significance ★★ ⚠ 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/tor1a-p-arg223ser (accessed [today's date]).

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