# 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)

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## 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).

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## 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.

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## 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)_

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## 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

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## 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.

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_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._