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R42*

NonsenseN1Pathogenic/Likely pathogenicCytoplasmic · predicted
Nonsense variant · truncation point at position 42 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

N1 — NMD-targeted — null allele

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — truncation point at residue 42
Fullscreen ↗
Translated product
Native sequence to residue 41; everything highlighted (residues 42–890) is lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 42 marked. Right: the same model with the lost region (residues 42–890) marked — what the nonsense transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Nonsense
NMD status
NMD-targeted
high confidence
Schema
N1
NMD-targeted — null allele
Native protein retained
4.6%

Stop codon at position 42 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.

Therapeutic Implication · N1

Transcript degraded by NMD; no truncated protein produced. Therapeutic options: (a) translational readthrough drugs — Ataluren/PTC124, gentamicin-class aminoglycosides — may rescue partial readthrough; (b) gene therapy — allele replacement is the higher-yield long-term path. Pharmacological chaperones do not apply since no protein is made.

Protein Domains

Retained (aa 1–41)
—
Lost / non-native (downstream)
  • 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
  • C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)600–890

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic
Review statuscriteria provided, multiple submitters, no conflicts
Associated conditionsWolfram syndrome 1; Wolfram-like syndrome; WFS1-related disorder; Inborn genetic diseases; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
Population frequency (gnomAD v4)Ultra-rare · AF 0.0068%
cDNA changec.124C>T
ClinVar variantNM_006005.3(WFS1):c.124C>T (p.Arg42Ter)
ClinVar accessionVCV000189251
Last evaluated2025/10/14 00:00

Observed at very low frequency in gnomAD.

Therapeutic Strategy Handoff · prediction

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Full Variant Card

R42* — WFS1 Molecular Atlas Card

Variant type: Nonsense (premature stop codon) Position: 42 Wild-type residue: Arginine (R) Domain context (where the stop falls): N-terminal cytoplasmic (intrinsically disordered)

Schema category: N1 — NMD-targeted — null allele

Transcript degraded by NMD; no truncated protein produced. Therapeutic options: (a) translational readthrough drugs — Ataluren/PTC124, gentamicin-class aminoglycosides — may rescue partial readthrough; (b) gene therapy — allele replacement is the higher-yield long-term path. Pharmacological chaperones do not apply since no protein is made.

NMD prediction

  • Status: NMD-targeted
  • Confidence: high
  • Reasoning: Stop codon at position 42 is more than 50 nt upstream of the last exon-exon junction (~aa 413). The 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No truncated protein is produced; functionally a null allele.

Truncation analysis

  • Residues retained: 1 – 41 (4.6% of full-length protein)
  • Residues lost: 42 – 890 (95.4% of full-length protein)

Retained domains

(no domains fully retained)

Partially retained at truncation point

  • N-terminal cytoplasmic (intrinsically disordered) — partial: aa 1–41 retained, aa 42–310 lost

Lost domains

  • 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)
  • 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
  • Associated conditions: Wolfram syndrome 1; Wolfram-like syndrome; WFS1-related disorder; Inborn genetic diseases; Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus
  • cDNA change: c.124C>T
  • ClinVar accession: VCV000189251
  • Last evaluated: 2025/10/14 00:00
  • Submissions: 1

Why this variant matters

This variant is biologically silent — the transcript is degraded before any truncated protein can be made. From a therapeutic standpoint, that simplifies the problem (one null allele) and points toward two specific paths: readthrough compounds that exploit the ribosome's natural ability to bypass premature stops, or gene-level replacement therapy. The atlas surfaces this clarity directly.

Card generated by wolfram-atlas-batch skill (v1) on 2026-06-08T02:17:31.343174Z. NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md. WFS1 reference: UniProt O76024, AlphaFold model v6.