Is TOR1A p.Arg288Ter (c.862C>T) pathogenic?

TOR1A p.Arg288Ter (c.862C>T) is classified Pathogenic/Likely pathogenic in TOR1A (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-02-10). Very rare (popmax 0.00333%, amr); Associated with TOR1A-related disorder.

What condition is associated with TOR1A p.Arg288Ter (c.862C>T)?

TOR1A p.Arg288Ter (c.862C>T) is associated with TOR1A-related disorder, dystonic disorder, early-onset generalized limb-onset dystonia (ClinVar).

How common is TOR1A p.Arg288Ter (c.862C>T) in the general population?

TOR1A p.Arg288Ter (c.862C>T) is very rare (popmax 0.00333%, amr) (gnomAD).

TOR1A p.Arg288Ter

c.862C>T · rs760768475 · VCV559927

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Conditions

TOR1A-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (5 of 5) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.7	GERP 2.6, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00333% Admixed American · 2/59,990 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00167% 27/1,613,964 alleles · very rare exomes 25/1,461,894 · genomes 2/152,070 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,995
European (non-Finnish)	0.00203%	49,168
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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: TOR1A
Protein: p.Arg288Ter
Coding: c.862C>T
MANE Select: NM_000113
dbSNP: rs760768475
Type: single nucleotide variant
Location: chr9:129814109 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 3 PDB
Residue 288: a UniProt-annotated variant site (in amc5); a UniProt-annotated variant site (in dyt1; increased identical protein binding; decreased atp-dependent chaperone mediated protein folding; changed nuclear membrane organization); the 'interaction with klc1' region

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

Disease context

TOR1A-related disorder

Also linked: dystonic disorder early-onset generalized limb-onset dystonia arthrogryposis multiplex congenita 5

Similar variants

TOR1A p.Arg288Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
TOR1A p.Arg288Leu Uncertain significance ⚠ same residue
TOR1A p.Arg282Ter Likely pathogenic ★★ same condition
TOR1A c.-4G>C Uncertain significance ★★ 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

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-arg288ter (accessed [today's date]).

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