c.2529_2546del
In-frame indelI3Likely pathogenicLumenal · 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 6-aa in-frame deletion product — the affected region near residue 843 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 5.48 Å.
Variant Assessment
Modified-sequence structure resolved. The 6-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.6) 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. The only conditions submitted (Neurodevelopmental abnormality) fall outside the established WFS1 phenotype families. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Also submitted under Neurodevelopmental abnormality — outside the established WFS1 phenotype families; recorded here as a submission, not presented as a WFS1 phenotype.
- 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.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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.2529_2546del 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.2529_2546del — WFS1 Molecular Atlas Card
Variant type: In-frame indel Change: 6 residue(s) deleted in frame at position 843 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption
6 residues removed in frame around position 843 (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
Likely pathogenic — phenotype scope not stated in ClinVar
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. The only conditions submitted (Neurodevelopmental abnormality) fall outside the established WFS1 phenotype families. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
Also submitted under Neurodevelopmental abnormality — outside the established WFS1 phenotype families; recorded here as a submission, not presented as a WFS1 phenotype. 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: Neurodevelopmental abnormality
- cDNA change: c.2529_2546del
- ClinVar accession: VCV003767240
- Last evaluated: 2024/05/30 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:52.635548Z.
Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.