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c.1243_1245del

In-frame indelI1PathogenicTransmembrane · predicted
In-frame indel variant · indel site at position 415 · Transmembrane helix 4 · WFS1 (Wolframin)

I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

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.1243_1245del — Cα-RMSD 3.56 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 deletion product — the affected region near residue 415 (Transmembrane helix 4) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 3.56 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I1
Single-residue deletion in a transmembrane helix — likely catastrophic kink
Domain
Transmembrane helix 4
Backbone Cα-RMSD
3.56 Å
vs WT · folded core (n=239)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.7) 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 · I1

A single residue removed inside Transmembrane helix 4 shifts the helical register, which typically kinks or unwinds the helix and disrupts membrane insertion — structurally similar to a severe TM missense. Gene therapy track. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationPathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWFS1-Related Spectrum Disorders; Early-onset non-syndromic cataract; Rare genetic deafness; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
Population frequency (gnomAD v4)Ultra-rare · AF 0.0064%
cDNA changec.1243_1245del
ClinVar variantNM_006005.3(WFS1):c.1243_1245del (p.Val415del)
ClinVar accessionVCV000215406
Last evaluated2026/01/25 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.1243_1245del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I1 in-frame indel variant and its domain context.

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Full Variant Card

c.1243_1245del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 415 Domain context: Transmembrane helix 4

Schema category: I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

A single residue removed inside Transmembrane helix 4 shifts the helical register, which typically kinks or unwinds the helix and disrupts membrane insertion — structurally similar to a severe TM missense. Gene therapy track. Predicted structure pending (ColabFold).

Structural prediction

  • Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
  • Affected domain: Transmembrane helix 4
  • Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

  • Classification: Pathogenic
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: WFS1-Related Spectrum Disorders; Early-onset non-syndromic cataract; Rare genetic deafness; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
  • cDNA change: c.1243_1245del
  • ClinVar accession: VCV000215406
  • Last evaluated: 2026/01/25 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:02.167061Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.