# S430* — WFS1 Molecular Atlas Card

**Variant type:** Nonsense (premature stop codon)
**Position:** 430
**Wild-type residue:** Serine (S)
**Domain context (where the stop falls):** Lumenal loop 2

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## Schema category: **N2 — NMD-escape, major truncation — gene therapy track**

Truncated protein produced but missing the transmembrane bundle and/or the entire C-terminal ER-lumenal domain. Too compromised for chaperone-based rescue. Gene therapy via allele replacement is the primary path.

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## NMD prediction

- **Status:** NMD-escape
- **Confidence:** high
- **Reasoning:** Stop codon at position 430 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 – 429 (48.2% of full-length protein)
- **Residues lost:** 430 – 890 (51.8% 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)

### Partially retained at truncation point
- **Lumenal loop 2** — partial: aa 422–429 retained, aa 430–431 lost

### Lost domains
- 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)
- C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) (aa 600–890)

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## Clinical evidence

- **Classification:** Pathogenic/Likely pathogenic
- **Review status:** criteria provided, multiple submitters, no conflicts
- **cDNA change:** c.1289C>A
- **ClinVar accession:** VCV002043736
- **Last evaluated:** 2025/09/02 00:00
- **Submissions:** 1

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## Why this variant matters

A truncated protein is made but stripped of the transmembrane bundle and/or C-terminal ER-lumenal domain — the regions wolframin needs for membrane anchoring and calcium-handling function. Chaperone strategies that work for missense variants don't apply here. The card surfaces gene therapy as the primary path and quantifies the structural loss to support that decision.

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_Card generated by `wolfram-atlas-batch` skill (v1) on 2026-06-08T02:18:06.503676Z._
_NMD rule and schema definitions: `reference/nmd_rules.md`, `reference/card_schema_extension.md`._
_WFS1 reference: UniProt O76024, AlphaFold model v6._