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c.1462_1464del

In-frame indelI2Uncertain significanceTransmembrane · predicted
In-frame indel variant · indel site at position 488 · Lumenal loop 3 · WFS1 (Wolframin)

I2 — Single-residue deletion in a soluble domain — variable impact

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.1462_1464del — Cα-RMSD 2.98 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 488 (Lumenal loop 3) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 2.98 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I2
Single-residue deletion in a soluble domain — variable impact
Domain
Lumenal loop 3
Backbone Cα-RMSD
2.98 Å
vs WT · folded core (n=299)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 71) 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 · I2

A single residue removed in Lumenal loop 3 (a soluble, non-membrane region) may be tolerated or may locally distort the domain. Worth pharmacological-chaperone exploration if AlphaFold predicts a near-native fold. Predicted structure pending (ColabFold).

Clinical Evidence

ClinVar classificationUncertain significance
Review statuscriteria provided, single submitter
Associated conditions—
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.1462_1464del
ClinVar variantNM_006005.3(WFS1):c.1462_1464del (p.Phe488del)
ClinVar accessionVCV001712192
Last evaluated2022/04/11 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Classified for1★ unverified submission

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: 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)
Absent from gnomAD v4
Homozygotes
Not available

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.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the c.1462_1464del card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this I2 in-frame indel variant and its domain context.

Download c.1462_1464del PDF card ↓or markdown ↓

Full Variant Card

c.1462_1464del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 488 Domain context: Lumenal loop 3

Schema category: I2 — Single-residue deletion in a soluble domain — variable impact

A single residue removed in Lumenal loop 3 (a soluble, non-membrane region) may be tolerated or may locally distort the domain. Worth pharmacological-chaperone exploration if AlphaFold predicts a near-native fold. Predicted structure pending (ColabFold).

Structural prediction

  • Reading frame: preserved (in-frame) — no premature stop, NMD does not apply.
  • Affected domain: Lumenal loop 3
  • 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, single submitter
  • cDNA change: c.1462_1464del
  • ClinVar accession: VCV001712192
  • Last evaluated: 2022/04/11 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:15.724579Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.