p.Lys178fs
FrameshiftF1Uncertain significanceCytoplasmic · predictedF1 — Frameshift, NMD-targeted — null allele
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 178 marked. Right: the same model with the non-native (scrambled) and lost region (residues 178–890) marked — what the frameshift transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 247 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 · F1
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Uncertain significance 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
- This rests on a single submitter (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★ single submitter. 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
c.528_531dup — WFS1 Molecular Atlas Card
Variant type: Frameshift Frameshift point: residue 178 Predicted premature stop (PTC): residue 247 Domain context (where the frame breaks): N-terminal cytoplasmic (intrinsically disordered)
Schema category: F1 — Frameshift, NMD-targeted — null allele
The frameshift creates a premature termination codon well upstream of the last exon-exon junction; the 50-nt rule predicts the transcript is degraded by nonsense-mediated decay. No frameshifted protein is produced — functionally a null allele. Therapeutic options: (a) translational readthrough drugs (Ataluren/PTC124, aminoglycosides) — notably LESS effective for frameshifts than for nonsense variants, because reading through the PTC still yields out-of-frame protein; (b) gene therapy via allele replacement is the higher-yield path.
Premature-stop prediction
- Frameshift point: aa 178
- Predicted PTC: aa 247 (69 codons downstream of the frame break)
- Method: deterministic translation of edited NM_006005.3 CDS (frameshift position = first changed residue, HGVS convention)
- Confidence: high
NMD prediction
- Status: NMD-targeted
- Confidence: high
- Reasoning: Stop codon at position 247 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.
Protein consequence
- Native (wild-type) sequence retained: aa 1 – 177 (19.9% of full-length protein)
- Non-native scrambled stretch: aa 178 – 246 (69 residues of out-of-frame sequence)
- Lost beyond the PTC: aa 247 – 890 (644 residues)
Native domains retained (upstream of the frameshift)
(no domains fully retained)
Domain interrupted at the frameshift point
- N-terminal cytoplasmic (intrinsically disordered) — native aa 1–177 retained; aa 178–310 replaced by non-native sequence
Native domains downstream of the frameshift (lost or non-native)
- 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
Uncertain significance — for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Uncertain significance 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.
This rests on a single submitter (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: Uncertain significance
- Review status: criteria provided, single submitter
- Associated conditions: Wolfram syndrome 1
- cDNA change: c.528_531dup
- ClinVar accession: VCV001264334
- Last evaluated: 1/01/01 00:00
- Submissions: 1
Why this variant matters
The frame breaks early enough that the premature stop is caught by nonsense-mediated decay — the transcript is degraded before any out-of-frame protein accumulates. That makes this, in effect, a clean null allele: the atlas points the therapeutic conversation at gene replacement, and notes that readthrough drugs are a weaker fit here than for true nonsense variants because reading through the stop still yields scrambled protein.
Card generated by wolfram-atlas-batch skill (v2 — frameshift pipeline) on 2026-06-08T02:16:58.315886Z.
NMD rule and schema definitions: reference/nmd_rules.md, reference/card_schema_extension.md.
CDS reference: NM_006005.3 (171..2843). WFS1 reference: UniProt O76024, AlphaFold model v6.