S888*
NonsenseN4ConflictingTransmembrane · predictedN4 — NMD-escape, minor truncation — highest druggability
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 888 marked. Right: the same model with the lost region (residues 888–890) marked — what the nonsense transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 888 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
Protein Domains
- 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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Full Variant Card
S888* — WFS1 Molecular Atlas Card
Variant type: Nonsense (premature stop codon) Position: 888 Wild-type residue: Serine (S) 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 888 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 – 887 (99.7% of full-length protein)
- Residues lost: 888 – 890 (0.3% 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 600–887 retained, aa 888–890 lost
Lost domains
(no full domains lost — only distal C-terminus)
Clinical evidence
Inheritance and scope
Conflicting classifications of pathogenicity — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes. Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
- Classification: Conflicting classifications of pathogenicity
- Review status: criteria provided, conflicting classifications
- Associated conditions: Wolfram syndrome 1; Inborn genetic diseases
- cDNA change: c.2663C>A
- ClinVar accession: VCV001299577
- Last evaluated: 2022/09/27 00:00
- Submissions: 1
Population frequency
- Frequency: Absent from gnomAD v4
- Alleles screened: 1,460,448 (~730,224 individuals)
- gnomAD variant ID:
4-6302458-C-A - Interpretation: Not observed in ~730,224 individuals — consistent with a rare allele (ACMG PM2_supporting).
Source: gnomAD v4 joint exome + genome callset, cached locally. Frequency is population evidence only — it does not by itself establish or exclude pathogenicity.
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 2026-07-31T21:00:53.260238Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
WFS1 reference: UniProt O76024, AlphaFold model v6.