W478*
NonsenseN3Pathogenic/Likely pathogenicTransmembrane · predictedN3 — NMD-escape, moderate truncation — chaperone exploration
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 478 marked. Right: the same model with the lost region (residues 478–890) marked — what the nonsense transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 478 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 · N3
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
- 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Optic atrophy / optic neuropathyautosomal dominantsubmitted as: Optic neuropathy
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0048% (57 of 1,180,030 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0048% | 57 / 1,180,030 | 0 | ~1 in 10350 |
| African / African American | 0.0040% | 3 / 74,914 | 0 | ~1 in 12490 |
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
W478* — WFS1 Molecular Atlas Card
Variant type: Nonsense (premature stop codon) Position: 478 Wild-type residue: Tryptophan (W) Domain context (where the stop falls): Transmembrane helix 6
Schema category: N3 — NMD-escape, moderate truncation — chaperone exploration
Truncated protein retains substantial structure but loses C-terminal domains. Worth screening generic ER chaperones (4-PBA, TUDCA) and sigma-1 receptor agonists. Lower confidence than for missense variants, but a candidate for the high-content drug screen (Initiative 8).
NMD prediction
- Status: NMD-escape
- Confidence: high
- Reasoning: Stop codon at position 478 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 – 477 (53.6% of full-length protein)
- Residues lost: 478 – 890 (46.4% 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)
Partially retained at truncation point
- Transmembrane helix 6 — partial: aa 462–477 retained, aa 478–482 lost
Lost domains
- 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
Inheritance and scope
Pathogenic/Likely pathogenic — for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Optic atrophy / optic neuropathy (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
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: Pathogenic/Likely pathogenic
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: Optic neuropathy; Wolfram syndrome 1
- cDNA change: c.1433G>A
- ClinVar accession: VCV001526050
- Last evaluated: 2025/10/07 00:00
- Submissions: 1
Population frequency
- Frequency: Ultra-rare · AF 0.0037%
- Allele count: 60 of 1,611,630 alleles (~805,815 individuals)
- gnomAD variant ID:
4-6301228-G-A - Interpretation: Observed at very low frequency in gnomAD.
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
Moderate truncation leaves some of the protein intact, including portions of the transmembrane bundle. Whether the partial protein can be coaxed into function with chaperones is an open question — the atlas surfaces it as a candidate for the Initiative 8 drug screen, with the explicit structural data needed to design that screen.
Card generated by wolfram-atlas-batch skill (v1) on 2026-07-31T21:00:59.227742Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
WFS1 reference: UniProt O76024, AlphaFold model v6.