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c.1385_1393del

In-frame indelI3Likely pathogenicTransmembrane · predicted
In-frame indel variant · indel site at position 462 · Transmembrane helix 6 · WFS1 (Wolframin)

I3 — Multi-residue in-frame indel — likely major structural disruption

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.1385_1393del — Cα-RMSD 2.95 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 3-aa in-frame deletion product — the affected region near residue 462 (Transmembrane helix 6) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 2.95 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I3
Multi-residue in-frame indel — likely major structural disruption
Domain
Transmembrane helix 6
Backbone Cα-RMSD
2.95 Å
vs WT · folded core (n=285)

Modified-sequence structure resolved. The 3-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 · I3

3 residues removed in frame around position 462 (Transmembrane helix 6). A change this size usually perturbs local packing and can propagate to the fold. Gene therapy is the primary path unless an AlphaFold prediction of the modified sequence shows a surprisingly intact fold. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationLikely pathogenic
Review statuscriteria provided, single submitter
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%
cDNA changec.1385_1393del
ClinVar variantNM_006005.3(WFS1):c.1385_1393del (p.Glu462_Thr464del)
ClinVar accessionVCV000004514
Last evaluated1/01/01 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.1385_1393del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I3 in-frame indel variant and its domain context.

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Full Variant Card

c.1385_1393del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 3 residue(s) deleted in frame at position 462 Domain context: Transmembrane helix 6

Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption

3 residues removed in frame around position 462 (Transmembrane helix 6). A change this size usually perturbs local packing and can propagate to the fold. Gene therapy is the primary path unless an AlphaFold prediction of the modified sequence shows a surprisingly intact fold. Predicted structure pending (ColabFold).

Structural prediction

  • Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
  • Affected domain: Transmembrane helix 6
  • Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

  • Classification: Likely pathogenic
  • Review status: criteria provided, single submitter
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.1385_1393del
  • ClinVar accession: VCV000004514
  • Last evaluated: 1/01/01 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:09.929619Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.