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K762*

NonsenseN4PathogenicLumenal · predicted
Nonsense variant · truncation point at position 762 · 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 762
Fullscreen ↗
Translated product
Native sequence to residue 761; everything highlighted (residues 762–890) is lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 762 marked. Right: the same model with the lost region (residues 762–890) 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
85.5%

Stop codon at position 762 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 1–761)
  • 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
Review statuscriteria provided, single submitter
Associated conditions—
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.2284A>T
ClinVar variantNM_006005.3(WFS1):c.2284A>T (p.Lys762Ter)
ClinVar accessionVCV003714958
Last evaluated2024/08/17 00:00

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

Therapeutic Strategy Handoff · prediction

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Full Variant Card

K762* — WFS1 Molecular Atlas Card

Variant type: Nonsense (premature stop codon) Position: 762 Wild-type residue: Lysine (K) 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 762 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 – 761 (85.5% of full-length protein)
  • Residues lost: 762 – 890 (14.5% 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 600–761 retained, aa 762–890 lost

Lost domains

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

Clinical evidence

  • Classification: Pathogenic
  • Review status: criteria provided, single submitter
  • cDNA change: c.2284A>T
  • ClinVar accession: VCV003714958
  • Last evaluated: 2024/08/17 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 2026-06-08T02:18:57.181821Z. NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md. WFS1 reference: UniProt O76024, AlphaFold model v6.