RareResearch.AI
← Back to atlas

c.2038_2040del

In-frame indelI2ConflictingLumenal · predicted
In-frame indel variant · indel site at position 680 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · 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
Fullscreen ↗
Modified product
Modified product · c.2038_2040del — Cα-RMSD 5.49 Å vs WT (folded core)
Fullscreen ↗

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 680 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.49 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I2
Single-residue deletion in a soluble domain — variable impact
Domain
C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Backbone Cα-RMSD
5.49 Å
vs WT · folded core (n=448)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.4) 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 C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (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 classificationConflicting classifications of pathogenicity
Review statuscriteria provided, conflicting classifications
Associated conditionsMonogenic hearing loss
Population frequency (gnomAD v4)Ultra-rare · AF 0.00041%
cDNA changec.2038_2040del
ClinVar variantNM_006005.3(WFS1):c.2038_2040del (p.Glu680del)
ClinVar accessionVCV001965830
Last evaluated2025/07/29 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.2038_2040del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I2 in-frame indel variant and its domain context.

Download c.2038_2040del PDF card ↓or markdown ↓

Full Variant Card

c.2038_2040del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 680 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

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

A single residue removed in C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (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).

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: Monogenic hearing loss
  • cDNA change: c.2038_2040del
  • ClinVar accession: VCV001965830
  • Last evaluated: 2025/07/29 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:37.032389Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.