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c.994_996dup

In-frame indelI2Uncertain significanceTransmembrane · predicted
In-frame indel variant · indel site at position 332 · Cytoplasmic loop 1 · WFS1 (Wolframin)

I2 — Single-residue deletion in a soluble domain — variable impact

Wild-type vs Modified Structure

Wild-type · full length
Wild-type wolframin · 890 aa — AlphaFold reference
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Modified product
Modified product · c.994_996dup — Cα-RMSD 4.69 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 1-aa in-frame duplication product — the affected region near residue 332 (Cytoplasmic loop 1) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 4.69 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I2
Single-residue deletion in a soluble domain — variable impact
Domain
Cytoplasmic loop 1
Backbone Cα-RMSD
4.69 Å
vs WT · folded core (n=163)

Modified-sequence structure resolved. The 1-aa in-frame duplication was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70) 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

A single residue removed in Cytoplasmic loop 1 (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).

Clinical Evidence

ClinVar classificationUncertain significance
Review statuscriteria provided, single submitter
Associated conditions—
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.994_996dup
ClinVar variantNM_006005.3(WFS1):c.994_996dup (p.Ile332_Val333insIle)
ClinVar accessionVCV002763322
Last evaluated2024/02/02 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Therapeutic Strategy Handoff · prediction

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Full Variant Card

c.994_996dup — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 332 Domain context: Cytoplasmic loop 1

Schema category: I2 — Single-residue deletion in a soluble domain — variable impact

A single residue removed in Cytoplasmic loop 1 (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: Cytoplasmic loop 1
  • Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

  • Classification: Uncertain significance
  • Review status: criteria provided, single submitter
  • cDNA change: c.994_996dup
  • ClinVar accession: VCV002763322
  • Last evaluated: 2024/02/02 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:42:12.047853Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.