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c.1495_1497del

In-frame indelI1Uncertain significanceTransmembrane · predicted
In-frame indel variant · indel site at position 499 · Transmembrane helix 7 · WFS1 (Wolframin)

I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

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.1495_1497del — Cα-RMSD 2.9 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 1-aa in-frame deletion product — the affected region near residue 499 (Transmembrane helix 7) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 2.9 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I1
Single-residue deletion in a transmembrane helix — likely catastrophic kink
Domain
Transmembrane helix 7
Backbone Cα-RMSD
2.9 Å
vs WT · folded core (n=310)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71.1) 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 · I1

A single residue removed inside Transmembrane helix 7 shifts the helical register, which typically kinks or unwinds the helix and disrupts membrane insertion — structurally similar to a severe TM missense. Gene therapy track. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationUncertain significance
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditions—
Population frequency (gnomAD v4)Ultra-rare · AF 0.00062%
cDNA changec.1495_1497del
ClinVar variantNM_006005.3(WFS1):c.1495_1497del (p.Leu499del)
ClinVar accessionVCV001519699
Last evaluated2026/01/11 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

ClinVar classifies this variant as Uncertain significance, 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: 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 0.00062% · 10 / 1,611,240 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.00085%

Highest in European (non-Finnish): AF 0.00085% (10 of 1,180,016 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)0.00085%10 / 1,180,0160~1 in 59000

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.1495_1497del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I1 in-frame indel variant and its domain context.

Download c.1495_1497del PDF card ↓or markdown ↓

Full Variant Card

c.1495_1497del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 499 Domain context: Transmembrane helix 7

Schema category: I1 — Single-residue deletion in a transmembrane helix — likely catastrophic kink

A single residue removed inside Transmembrane helix 7 shifts the helical register, which typically kinks or unwinds the helix and disrupts membrane insertion — structurally similar to a severe TM missense. Gene therapy track. Predicted structure pending (ColabFold).

Structural prediction

  • Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
  • Affected domain: Transmembrane helix 7
  • 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 — phenotype scope not stated in ClinVar

ClinVar classifies this variant as Uncertain significance, 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: Uncertain significance
  • Review status: criteria provided, multiple submitters, no conflicts
  • cDNA change: c.1495_1497del
  • ClinVar accession: VCV001519699
  • Last evaluated: 2026/01/11 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:17.652088Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.