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c.1661_1687del

In-frame indelI3PathogenicCytoplasmic · predicted
In-frame indel variant · indel site at position 554 · Lumenal loop 4 · 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.1661_1687del — Cα-RMSD 3.49 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 9-aa in-frame deletion product — the affected region near residue 554 (Lumenal loop 4) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 3.49 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I3
Multi-residue in-frame indel — likely major structural disruption
Domain
Lumenal loop 4
Backbone Cα-RMSD
3.49 Å
vs WT · folded core (n=365)

Modified-sequence structure resolved. The 9-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.3) 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

9 residues removed in frame around position 554 (Lumenal loop 4). 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 classificationPathogenic
Review statuscriteria provided, single submitter
Associated conditions—
Population frequency (gnomAD v4)Ultra-rare · AF 0.00012%
cDNA changec.1661_1687del
ClinVar variantNM_006005.3(WFS1):c.1661_1687del (p.Leu554_Tyr563delinsHis)
ClinVar accessionVCV002418917
Last evaluated2025/04/13 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.

  • 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.

Population frequency
Global (all ancestries)
AF 0.00012% · 2 / 1,612,542 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.00017%

Highest in European (non-Finnish): AF 0.00017% (2 of 1,180,046 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)0.00017%2 / 1,180,0460~1 in 295010

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.1661_1687del 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.1661_1687del PDF card ↓or markdown ↓

Full Variant Card

c.1661_1687del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 9 residue(s) deleted in frame at position 554 Domain context: Lumenal loop 4

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

9 residues removed in frame around position 554 (Lumenal loop 4). 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: Lumenal loop 4
  • 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

Pathogenic — phenotype scope not stated in ClinVar

ClinVar classifies this variant as Pathogenic, but does not state what it is classified for. ClinVar records no condition for this variant. A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.

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: Pathogenic
  • Review status: criteria provided, single submitter
  • cDNA change: c.1661_1687del
  • ClinVar accession: VCV002418917
  • Last evaluated: 2025/04/13 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:29.302001Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.