c.2555_2560dup

In-frame indelI3ConflictingLumenal · predicted

In-frame indel variant · indel site at position 852 · 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.2555_2560dup — Cα-RMSD 5.42 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 duplication product — the affected region near residue 852 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.42 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

5.42 Å

vs WT · folded core (n=597)

Modified-sequence structure resolved. The 2-aa in-frame duplication was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.6) 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 852 (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 classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsInborn genetic diseases; Wolfram syndrome 1

Population frequency (gnomAD v4)Ultra-rare · AF 0.00048%

cDNA changec.2555_2560dup

ClinVar variantNM_006005.3(WFS1):c.2555_2560dup (p.Gln853_Leu854insProGln)

ClinVar accessionVCV000179778

Last evaluated2023/09/10 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

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Full Variant Card

c.2555_2560dup — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 2 residue(s) deleted in frame at position 852 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

Classification: Conflicting classifications of pathogenicity
Review status: criteria provided, conflicting classifications
Associated conditions: Inborn genetic diseases; Wolfram syndrome 1
cDNA change: c.2555_2560dup
ClinVar accession: VCV000179778
Last evaluated: 2023/09/10 00:00
Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:54.581002Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.