c.682_684del

In-frame indelI2Pathogenic/Likely pathogenicCytoplasmic · predicted

In-frame indel variant · indel site at position 228 · N-terminal cytoplasmic (intrinsically disordered) · 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.682_684del — Cα-RMSD 0.79 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 228 (N-terminal cytoplasmic (intrinsically disordered)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 0.79 Å.

Variant Assessment

Variant type

In-frame indel

Schema

Single-residue deletion in a soluble domain — variable impact

Domain

N-terminal cytoplasmic (intrinsically disordered)

Backbone Cα-RMSD

0.79 Å

vs WT · folded core (n=122)

Modified-sequence structure resolved. The 1-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 · I2

A single residue removed in N-terminal cytoplasmic (intrinsically disordered) (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 classificationPathogenic/Likely pathogenic

Review status—

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.682_684del

ClinVar variantc.682_684del

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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Full Variant Card

c.682_684del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 228 Domain context: N-terminal cytoplasmic (intrinsically disordered)

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

Structural prediction

Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
Affected domain: N-terminal cytoplasmic (intrinsically disordered)
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 2026-06-08T02:42:06.254545Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.