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S430*

NonsenseN2Pathogenic/Likely pathogenicTransmembrane · predicted
Nonsense variant · truncation point at position 430 · Lumenal loop 2 · WFS1 (Wolframin)

N2 — NMD-escape, major truncation — gene therapy track

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — truncation point at residue 430
Fullscreen ↗
Translated product
Native sequence to residue 429; everything highlighted (residues 430–890) is lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 430 marked. Right: the same model with the lost region (residues 430–890) marked — what the nonsense transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Nonsense
NMD status
NMD-escape
high confidence
Schema
N2
NMD-escape, major truncation — gene therapy track
Native protein retained
48.2%

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.

Therapeutic Implication · N2

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.

Protein Domains

Retained (aa 1–429)
  • 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
Lost / non-native (downstream)
  • 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
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)600–890

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditions—
Population frequency (gnomAD v4)Ultra-rare · AF 0.0020%
cDNA changec.1289C>A
ClinVar variantNM_006005.3(WFS1):c.1289C>A (p.Ser430Ter)
ClinVar accessionVCV002043736
Last evaluated2025/09/02 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

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Full Variant Card

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

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.

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.

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)

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

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.

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.