c.682_684del
In-frame indelI2Pathogenic/Likely pathogenicCytoplasmic · predictedI2 — Single-residue deletion in a soluble domain — variable impact
Wild-type vs Modified Structure
Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 1-aa in-frame deletion product — the affected region near residue 228 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 0.79 Å.
Variant Assessment
Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.4) and superposed on the wild-type AlphaFold model. Kabsch-superposed Cα-RMSD over high-confidence (WT pLDDT>70) residues N-terminal to the lesion; cross-pipeline, includes ~few-Å method baseline
Therapeutic Implication · I2
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic/Likely pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: no ClinVar review status recorded. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Feed this card to Wolfram Intelligence
Download the c.682_684del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I2 in-frame indel variant and its domain context.
Full Variant Card
c.682_684del — WFS1 Molecular Atlas Card
Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 228 Domain context: N-terminal cytoplasmic (intrinsically disordered)
Schema category: I2 — Single-residue deletion in a soluble domain — variable impact
A single residue removed in N-terminal cytoplasmic (intrinsically disordered) (a soluble, non-membrane region) may be tolerated or may locally distort the domain. Worth pharmacological-chaperone exploration if AlphaFold predicts a near-native fold. Predicted structure pending (ColabFold).
Structural prediction
- Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
- Affected domain: N-terminal cytoplasmic (intrinsically disordered)
- Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).
Clinical evidence
Inheritance and scope
Pathogenic/Likely pathogenic — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Pathogenic/Likely pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Not found in the cached WFS1 ClinVar set (_reference/WFS1_clinvar_variants.csv).
Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:42:06.254545Z.
Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.