c.2614_2625del
In-frame indelI3ConflictingTransmembrane · predictedI3 — Multi-residue in-frame indel — likely major structural disruption
Wild-type vs Modified Structure
Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 4-aa in-frame deletion product — the affected region near residue 872 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.21 Å.
Variant Assessment
Modified-sequence structure resolved. The 4-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 · I3
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder
- 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 European (non-Finnish): AF 0.00018% (2 of 1,111,998 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00018% | 2 / 1,111,998 | 0 | ~1 in 278000 |
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.2614_2625del 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.
Full Variant Card
c.2614_2625del — WFS1 Molecular Atlas Card
Variant type: In-frame indel Change: 4 residue(s) deleted in frame at position 872 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption
4 residues removed in frame around position 872 (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).
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 WFS1-related spectrum (unresolved mode) (dominant or recessive)
ClinVar classifies this variant as Conflicting classifications of pathogenicity for WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
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: WFS1-related disorder
- cDNA change: c.2614_2625del
- ClinVar accession: VCV002632570
- Last evaluated: 2024/11/25 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:42:02.381933Z.
Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.