c.2385_2390del

In-frame indelI3Pathogenic/Likely pathogenicLumenal · predicted

In-frame indel variant · indel site at position 795 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · 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.2385_2390del — Cα-RMSD 5.82 Å vs WT (folded core)

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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 2-aa in-frame deletion product — the affected region near residue 795 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.82 Å.

Variant Assessment

Variant type

In-frame indel

Schema

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

Domain

C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

Backbone Cα-RMSD

5.82 Å

vs WT · folded core (n=546)

Modified-sequence structure resolved. The 2-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.1) 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

2 residues removed in frame around position 795 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)). 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 classificationPathogenic/Likely pathogenic

Review status—

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2385_2390del

ClinVar variantc.2385_2390del

ClinVar accession—

Last evaluated—

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

Therapeutic Strategy Handoff · prediction

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Download the c.2385_2390del 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.2385_2390del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 2 residue(s) deleted in frame at position 795 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

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

Structural prediction

Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
Affected domain: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Predicted modified structure: pending — AlphaFold/ColabFold prediction of the modified sequence and backbone-RMSD vs wild-type backfill here (Wave 2).

Clinical evidence

Not found in the cached WFS1 ClinVar set (_reference/WFS1_clinvar_variants.csv).

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:44.754666Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.