c.1385_1393del
In-frame indelI3Likely pathogenicTransmembrane · 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 3-aa in-frame deletion product — the affected region near residue 462 (Transmembrane helix 6) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 2.95 Å.
Variant Assessment
Modified-sequence structure resolved. The 3-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 Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (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★ single submitter. 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 1,111,822 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 / 1,111,822 | 0 | ~1 in 277960 |
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.1385_1393del 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.1385_1393del — WFS1 Molecular Atlas Card
Variant type: In-frame indel Change: 3 residue(s) deleted in frame at position 462 Domain context: Transmembrane helix 6
Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption
3 residues removed in frame around position 462 (Transmembrane helix 6). 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: Transmembrane helix 6
- 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
Likely pathogenic — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
This rests on a single submitter (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: Likely pathogenic
- Review status: criteria provided, single submitter
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.1385_1393del
- ClinVar accession: VCV000004514
- Last evaluated: 1/01/01 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:09.929619Z.
Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.