E273*
NonsenseN1PathogenicCytoplasmic · predictedN1 — NMD-targeted — null allele
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the truncation point at residue 273 marked. Right: the same model with the lost region (residues 273–890) marked — what the nonsense transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 273 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
Protein Domains
- 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic for Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- 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 0.0053% (59 of 1,111,996 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) | 0.0053% | 59 / 1,111,996 | 0 | ~1 in 9420 |
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.
Feed this card to Wolfram Intelligence
Download the E273* card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this N1 nonsense variant and its domain context.
Full Variant Card
E273* — WFS1 Molecular Atlas Card
Variant type: Nonsense (premature stop codon) Position: 273 Wild-type residue: Glutamic acid (E) 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 273 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 – 272 (30.6% of full-length protein)
- Residues lost: 273 – 890 (69.4% of full-length protein)
Retained domains
(no domains fully retained)
Partially retained at truncation point
- N-terminal cytoplasmic (intrinsically disordered) — partial: aa 1–272 retained, aa 273–310 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
Inheritance and scope
Pathogenic — for Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296)
ClinVar classifies this variant as Pathogenic for Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296). 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
- Review status: criteria provided, multiple submitters, no conflicts
- Associated conditions: Cataract 41; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Wolfram syndrome 1; Wolfram-like syndrome
- cDNA change: c.817G>T
- ClinVar accession: VCV000918066
- Last evaluated: 2026/02/01 00:00
- Submissions: 1
Population frequency
- Frequency: Ultra-rare · AF 0.0040%
- Allele count: 59 of 1,460,432 alleles (~730,216 individuals)
- gnomAD variant ID:
4-6295145-G-T - 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
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 2026-07-31T21:00:03.282140Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
WFS1 reference: UniProt O76024, AlphaFold model v6.