Is TOR1A p.Phe205Ile (c.613T>A) pathogenic?

TOR1A p.Phe205Ile (c.613T>A) is classified Conflicting classifications of pathogenicity in TOR1A (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-09-02). AlphaMissense: likely pathogenic (0.956); Ultra-rare (popmax 0.0298%, nfe); Associated with dystonic disorder.

What condition is associated with TOR1A p.Phe205Ile (c.613T>A)?

TOR1A p.Phe205Ile (c.613T>A) is associated with dystonic disorder, early-onset generalized limb-onset dystonia (ClinVar).

How common is TOR1A p.Phe205Ile (c.613T>A) in the general population?

TOR1A p.Phe205Ile (c.613T>A) is ultra-rare (popmax 0.0298%, nfe) (gnomAD).

What do computational predictors say about TOR1A p.Phe205Ile (c.613T>A)?

AlphaMissense predicts likely pathogenic (score 0.956) — an in-silico prediction, not a clinical call.

TOR1A p.Phe205Ile

c.613T>A · rs267607134 · VCV18438

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

likely pathogenic

0.956 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0298%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

dystonic disorder

Computational evidence

Protein change
AlphaMissense	0.956	likely pathogenic
REVEL	0.763	pathogenic-leaning
SaProt	LLR -12.60	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 11	GERP 2.4, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 10 kb · p 0.042 · regional, not allelic
Overall
CADD	29.4	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

Grpmax group 0.0298% European (non-Finnish) · 352/1,180,040 alleles

Filtering AF 0.0272% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0262%

Overall 0.0227% 367/1,613,346 alleles · ultra-rare exomes 348/1,461,154 · genomes 19/152,192 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0298%	3,352
Remaining individualsnot grpmax-eligible	0.0096%	10,414
African / African-American	0.00801%	12,488
Finnishnot grpmax-eligible	0.00474%	21,105

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.Phe205Ile
Coding: c.613T>A
MANE Select: NM_000113
dbSNP: rs267607134
Type: single nucleotide variant
Location: chr9:129818752 (GRCh38)
Gene constraint: LOEUF 0.84 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 85.82 · 3 PDB
Residue 205: the 'interaction with snapin' region; a β-strand; a UniProt-annotated variant site (in dyt1; increased identical protein binding; decreased atp-dependent chaperone mediated protein folding; changed nuclear membrane organization; decreased neuron projection development)

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

Also linked: early-onset generalized limb-onset dystonia

Similar variants

TOR1A p.Phe205Leu Uncertain significance ★ ⚠ same residue
TOR1A p.Arg288Ter Pathogenic/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
TOR1A p.Asp331Asn 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-phe205ile (accessed [today's date]).

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