c.1619_1642dup
In-frame indelI3Uncertain significanceTransmembrane · 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 8-aa in-frame duplication product — the affected region near residue 540 (Transmembrane helix 8) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 2.8 Å.
Variant Assessment
Modified-sequence structure resolved. The 8-aa in-frame duplication was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 69.4) 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Uncertain significance 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.
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
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Full Variant Card
c.1619_1642dup — WFS1 Molecular Atlas Card
Variant type: In-frame indel Change: 8 residue(s) deleted in frame at position 540 Domain context: Transmembrane helix 8
Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption
8 residues removed in frame around position 540 (Transmembrane helix 8). 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 8
- 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
Uncertain significance — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Uncertain significance 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: Uncertain significance
- Review status: criteria provided, single submitter
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.1619_1642dup
- ClinVar accession: VCV004293404
- Last evaluated: 2024/10/17 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:27.373077Z.
Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.