RareResearch.AI
← Back to atlas

c.1401_1403del

In-frame indelI1Pathogenic/Likely pathogenicTransmembrane · predicted
In-frame indel variant · indel site at position 467 · Transmembrane helix 6 · 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
Fullscreen ↗
Modified product
Modified product · c.1401_1403del — Cα-RMSD 3.26 Å vs WT (folded core)
Fullscreen ↗

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 467 (Transmembrane helix 6) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 3.26 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I1
Single-residue deletion in a transmembrane helix — likely catastrophic kink
Domain
Transmembrane helix 6
Backbone Cα-RMSD
3.26 Å
vs WT · folded core (n=290)

Modified-sequence structure resolved. The 1-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 70.7) 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 6 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 classificationPathogenic/Likely pathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.00048%
cDNA changec.1401_1403del
ClinVar variantNM_006005.3(WFS1):c.1401_1403del (p.Leu468del)
ClinVar accessionVCV001070757
Last evaluated2025/01/26 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

ClinVar classifies this variant as Pathogenic/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 0.00048% · 7 / 1,459,888 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.00063%

Highest in European (non-Finnish): AF 0.00063% (7 of 1,111,852 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)0.00063%7 / 1,111,8520~1 in 79420

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.1401_1403del 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.1401_1403del PDF card ↓or markdown ↓

Full Variant Card

c.1401_1403del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 467 Domain context: Transmembrane helix 6

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

A single residue removed inside Transmembrane helix 6 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 6
  • 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/Likely pathogenic — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)

ClinVar classifies this variant as Pathogenic/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: Pathogenic/Likely pathogenic
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.1401_1403del
  • ClinVar accession: VCV001070757
  • Last evaluated: 2025/01/26 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:11.860074Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.