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W867*

NonsenseN4Pathogenic/Likely pathogenicLumenal · predicted
Nonsense variant · truncation point at position 867 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

N4 — NMD-escape, minor truncation — highest druggability

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — truncation point at residue 867
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Translated product
Native sequence to residue 866; everything highlighted (residues 867–890) is lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 867 marked. Right: the same model with the lost region (residues 867–890) marked — what the nonsense transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Nonsense
NMD status
NMD-escape
high confidence
Schema
N4
NMD-escape, minor truncation — highest druggability
Native protein retained
97.3%

Stop codon at position 867 is in the last exon (exon 8, starts ~aa 413). NMD does not target stop codons in the last exon — a truncated protein is produced.

Therapeutic Implication · N4

Most domains preserved; only the distal C-terminus is truncated. Highest druggability category among nonsense variants. Candidates: pharmacological chaperones for the partially-folded protein, small-molecule mimetics for the lost C-terminal sequence, and high-content screening (Initiative 8).

Protein Domains

Retained (aa 1–866)
  • N-terminal cytoplasmic (intrinsically disordered)1–310
  • Transmembrane helix 1311–331
  • Cytoplasmic loop 1332–340
  • Transmembrane helix 2341–361
  • Lumenal loop 1362–370
  • Transmembrane helix 3371–391
  • Cytoplasmic loop 2392–400
  • Transmembrane helix 4401–421
  • Lumenal loop 2422–431
  • Transmembrane helix 5432–452
  • Cytoplasmic loop 3453–461
  • Transmembrane helix 6462–482
  • Lumenal loop 3483–496
  • Transmembrane helix 7497–517
  • Cytoplasmic loop 4518–532
  • Transmembrane helix 8533–553
  • Lumenal loop 4554–573
  • Transmembrane helix 9574–594
  • Cytoplasmic loop 5 / pre-lumenal595–599
Lost / non-native (downstream)
—

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1
Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%
cDNA changec.2600G>A
ClinVar variantNM_006005.3(WFS1):c.2600G>A (p.Trp867Ter)
ClinVar accessionVCV000452384
Last evaluated2017/09/29 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

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Download the W867* card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this N4 nonsense variant and its domain context.

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Full Variant Card

W867* — WFS1 Molecular Atlas Card

Variant type: Nonsense (premature stop codon) Position: 867 Wild-type residue: Tryptophan (W) Domain context (where the stop falls): C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)

Schema category: N4 — NMD-escape, minor truncation — highest druggability

Most domains preserved; only the distal C-terminus is truncated. Highest druggability category among nonsense variants. Candidates: pharmacological chaperones for the partially-folded protein, small-molecule mimetics for the lost C-terminal sequence, and high-content screening (Initiative 8).

NMD prediction

  • Status: NMD-escape
  • Confidence: high
  • Reasoning: Stop codon at position 867 is in the last exon (exon 8, starts ~aa 413). NMD does not target stop codons in the last exon — a truncated protein is produced.

Truncation analysis

  • Residues retained: 1 – 866 (97.3% of full-length protein)
  • Residues lost: 867 – 890 (2.7% of full-length protein)

Retained domains

  • N-terminal cytoplasmic (intrinsically disordered) (aa 1–310)
  • Transmembrane helix 1 (aa 311–331)
  • Cytoplasmic loop 1 (aa 332–340)
  • Transmembrane helix 2 (aa 341–361)
  • Lumenal loop 1 (aa 362–370)
  • Transmembrane helix 3 (aa 371–391)
  • Cytoplasmic loop 2 (aa 392–400)
  • Transmembrane helix 4 (aa 401–421)
  • Lumenal loop 2 (aa 422–431)
  • Transmembrane helix 5 (aa 432–452)
  • Cytoplasmic loop 3 (aa 453–461)
  • Transmembrane helix 6 (aa 462–482)
  • Lumenal loop 3 (aa 483–496)
  • Transmembrane helix 7 (aa 497–517)
  • Cytoplasmic loop 4 (aa 518–532)
  • Transmembrane helix 8 (aa 533–553)
  • Lumenal loop 4 (aa 554–573)
  • Transmembrane helix 9 (aa 574–594)
  • Cytoplasmic loop 5 / pre-lumenal (aa 595–599)

Partially retained at truncation point

  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) — partial: aa 600–866 retained, aa 867–890 lost

Lost domains

(no full domains lost — only distal C-terminus)

Clinical evidence

  • Classification: Pathogenic/Likely pathogenic
  • Review status: criteria provided, multiple submitters, no conflicts
  • Associated conditions: Wolfram syndrome 1
  • cDNA change: c.2600G>A
  • ClinVar accession: VCV000452384
  • Last evaluated: 2017/09/29 00:00
  • Submissions: 1

Why this variant matters

Late-truncation variants in the distal C-terminus are the most druggable nonsense category in WFS1. The atlas card surfaces both the small-molecule mimetic angle (rescuing the lost C-terminal sequence) and the chaperone angle (stabilizing the mostly-intact protein). High-content screening (Initiative 8) is a strong fit.

Card generated by wolfram-atlas-batch skill (v1) on 2026-06-08T02:19:03.062769Z. NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md. WFS1 reference: UniProt O76024, AlphaFold model v6.