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c.2455_2502del

In-frame indelI3ConflictingLumenal · predicted
In-frame indel variant · indel site at position 819 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · 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.2455_2502del — Cα-RMSD 6.65 Å vs WT (folded core)
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Left: full-length wild-type wolframin (890 aa). Right: the ColabFold (AlphaFold2) prediction of the 16-aa in-frame deletion product — the affected region near residue 819 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)) is highlighted in both panes. Backbone Cα-RMSD over the folded core is 6.65 Å.

Variant Assessment

Variant type
In-frame indel
Schema
I3
Multi-residue in-frame indel — likely major structural disruption
Domain
C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Backbone Cα-RMSD
6.65 Å
vs WT · folded core (n=565)

Modified-sequence structure resolved. The 16-aa in-frame deletion was modeled with ColabFold (AlphaFold2, full-MSA; mean pLDDT 68.5) 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

16 residues removed in frame around position 819 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)). 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 classificationConflicting classifications of pathogenicity
Review statuscriteria provided, conflicting classifications
Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Cataract 41; Wolfram-like syndrome
Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%
cDNA changec.2455_2502del
ClinVar variantNM_006005.3(WFS1):c.2455_2502del (p.Gln819_Gly834del)
ClinVar accessionVCV001958301
Last evaluated2025/10/03 00:00

Observed at very low frequency in gnomAD.

Classified for1★ unverified submission

ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

  • 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
  • Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
  • Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
  • Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
  • Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
  • 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.

Population frequency
Global (all ancestries)
AF 0.00014% · 2 / 1,452,728 alleles
Homozygotes
0
Highest-frequency population
European (non-Finnish) · AF 0.00018%

Highest in European (non-Finnish): AF 0.00018% (2 of 1,106,256 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)0.00018%2 / 1,106,2560~1 in 276560

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.2455_2502del 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.2455_2502del PDF card ↓or markdown ↓

Full Variant Card

c.2455_2502del — WFS1 Molecular Atlas Card

Variant type: In-frame indel Change: 16 residue(s) deleted in frame at position 819 Domain context: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

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

16 residues removed in frame around position 819 (C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)). 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: C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
  • 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

Conflicting classifications of pathogenicity — for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296)

ClinVar classifies this variant as Conflicting classifications of pathogenicity for Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.

Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes. 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: Conflicting classifications of pathogenicity
  • Review status: criteria provided, conflicting classifications
  • Associated conditions: Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Cataract 41; Wolfram-like syndrome
  • cDNA change: c.2455_2502del
  • ClinVar accession: VCV001958301
  • Last evaluated: 2025/10/03 00:00
  • Submissions: 1

Card generated by wolfram-atlas-batch (in-frame indel pipeline) on 2026-06-08T02:41:50.637086Z. Schema: reference/card_schema_extension.md (I1–I3). WFS1: UniProt O76024, AlphaFold v6.