c.2038_2040del
In-frame indelI2ConflictingLumenal · predictedI2 — Single-residue deletion in a soluble domain — variable impact
Wild-type vs Modified Structure
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
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
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Hearing loss, inheritance unstated (inheritance not specified).
- Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Monogenic hearing loss
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Remaining individuals: AF 0.0033% (2 of 60,384 alleles), 8.1x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Remaining individuals | 0.0033% | 2 / 60,384 | 0 | ~1 in 15100 |
| European (non-Finnish) | 0.00036% | 4 / 1,111,986 | 0 | ~1 in 139000 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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.
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
Inheritance and scope
Conflicting classifications of pathogenicity — for Hearing loss, inheritance unstated (inheritance not specified)
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Hearing loss, inheritance unstated (inheritance not specified).
Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes. Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
- 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.