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c.1024_1032dup

In-frame indelI3Likely pathogenicTransmembrane · predicted
In-frame indel variant · indel site at position 342 · Transmembrane helix 2 · WFS1 (Wolframin)

I3 — Multi-residue in-frame indel — likely major structural disruption

Wild-type vs Modified Structure

Wild-type · full length
Wild-type wolframin · 890 aa — AlphaFold reference
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Modified product
Modified product · c.1024_1032dup — Cα-RMSD 4.59 Å vs WT (folded core)
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 3-aa in-frame duplication product — the affected region near residue 342 (Transmembrane helix 2) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 4.59 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I3
Multi-residue in-frame indel — likely major structural disruption
Domain
Transmembrane helix 2
Backbone Cα-RMSD
4.59 Å
vs WT · folded core (n=166)

Modified-sequence structure resolved. The 3-aa in-frame duplication was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.5) 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

3 residues removed in frame around position 342 (Transmembrane helix 2). 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).

Clinical Evidence

ClinVar classificationLikely pathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.00027%
cDNA changec.1024_1032dup
ClinVar variantNM_006005.3(WFS1):c.1024_1032dup (p.Phe344_Ile345insAlaPhePhe)
ClinVar accessionVCV001709484
Last evaluated2023/08/15 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

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
  • 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.

Population frequency
Global (all ancestries)
AF 0.00027% · 4 / 1,461,810 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.00036%

Highest in European (non-Finnish): AF 0.00036% (4 of 1,111,936 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 groupAllele freq.AC / ANHom.Carrier est.
European (non-Finnish)0.00036%4 / 1,111,9360~1 in 138990

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.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.1024_1032dup 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.

Download c.1024_1032dup PDF card ↓or markdown ↓

Full Variant Card

c.1024_1032dup — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 3 residue(s) deleted in frame at position 342 Domain context: Transmembrane helix 2

Schema category: I3 — Multi-residue in-frame indel — likely major structural disruption

3 residues removed in frame around position 342 (Transmembrane helix 2). 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 2
  • 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.

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, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.1024_1032dup
  • ClinVar accession: VCV001709484
  • Last evaluated: 2023/08/15 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:40:58.283235Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.