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c.1243_1245del

In-frame indelI1PathogenicTransmembrane · predicted
In-frame indel variant · indel site at position 415 · Transmembrane helix 4 · 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.1243_1245del — Cα-RMSD 3.56 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 415 (Transmembrane helix 4) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 3.56 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I1
Single-residue deletion in a transmembrane helix — likely catastrophic kink
Domain
Transmembrane helix 4
Backbone Cα-RMSD
3.56 Å
vs WT · folded core (n=239)

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 4 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
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWFS1-Related Spectrum Disorders; Early-onset non-syndromic cataract; Rare genetic deafness; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
Population frequency (gnomAD v4)Ultra-rare · AF 0.0064%
cDNA changec.1243_1245del
ClinVar variantNM_006005.3(WFS1):c.1243_1245del (p.Val415del)
ClinVar accessionVCV000215406
Last evaluated2026/01/25 00:00

Observed at very low frequency in gnomAD.

Classified for2★ documented assertion

ClinVar classifies this variant as Pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Hearing loss, inheritance unstated (inheritance not specified); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.

  • WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-Related Spectrum Disorders
  • Cataract 41autosomal dominant · OMIM 116400submitted as: Early-onset non-syndromic cataract; Cataract 41
  • Hearing loss, inheritance unstatedinheritance not specifiedsubmitted as: Rare genetic deafness
  • Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
  • Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
  • Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
  • WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
  • 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 0.0064% · 103 / 1,614,026 alleles
Homozygotes
0
Highest-frequency population
Admixed American · AF 0.033%

Highest in Admixed American: AF 0.033% (20 of 60,000 alleles), 5.2x the global figure. The global AF describes the general population, not the at-risk group.

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.
Admixed American0.033%20 / 60,0000~1 in 1500
European (non-Finnish)0.0065%77 / 1,180,0300~1 in 7660
Remaining individuals0.0064%4 / 62,4840~1 in 7810
African / African American0.0027%2 / 74,9020~1 in 18730

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.1243_1245del 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.1243_1245del PDF card ↓or markdown ↓

Full Variant Card

c.1243_1245del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 1 residue(s) deleted in frame at position 415 Domain context: Transmembrane helix 4

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

A single residue removed inside Transmembrane helix 4 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 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 — for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Hearing loss, inheritance unstated (inheritance not specified); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant)

ClinVar classifies this variant as Pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Cataract 41 (autosomal dominant, OMIM 116400); Hearing loss, inheritance unstated (inheritance not specified); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.

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, multiple submitters, no conflicts
  • Associated conditions: WFS1-Related Spectrum Disorders; Early-onset non-syndromic cataract; Rare genetic deafness; Wolfram-like syndrome; Cataract 41; Wolfram syndrome 1; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
  • cDNA change: c.1243_1245del
  • ClinVar accession: VCV000215406
  • Last evaluated: 2026/01/25 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:02.167061Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.