E752*
NonsenseN4Pathogenic/Likely pathogenicLumenal · 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 752 marked. Right: the same model with the lost region (residues 752–890) marked — what the nonsense transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 752 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/Likely 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 0.0072% (85 of 1,180,010 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) | 0.0072% | 85 / 1,180,010 | 0 | ~1 in 6940 |
| Remaining individuals | 0.0048% | 3 / 62,470 | 0 | ~1 in 10410 |
| Admixed American · under-sampled | 0.0017% | 1 / 59,988 | 0 | — |
| African / African American · under-sampled | 0.0013% | 1 / 74,950 | 0 | — |
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
E752* — WFS1 Molecular Atlas Card
Variant type: Nonsense (premature stop codon) Position: 752 Wild-type residue: Glutamic acid (E) 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 752 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 – 751 (84.4% of full-length protein)
- Residues lost: 752 – 890 (15.6% 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 600–751 retained, aa 752–890 lost
Lost domains
(no full domains lost — only distal C-terminus)
Clinical evidence
Inheritance and scope
Pathogenic/Likely 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/Likely 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/Likely 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.2254G>T
- ClinVar accession: VCV000215399
- Last evaluated: 2025/03/26 00:00
- Submissions: 1
Population frequency
- Frequency: Ultra-rare · AF 0.0056%
- Allele count: 90 of 1,612,754 alleles (~806,377 individuals)
- gnomAD variant ID:
4-6302049-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
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 2026-07-31T21:00:09.303036Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
WFS1 reference: UniProt O76024, AlphaFold model v6.