c.409_424dup — WFS1 Molecular Atlas Card

Variant type: Frameshift Frameshift point: residue 142 Predicted premature stop (PTC): residue 251 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 142
• Predicted PTC: aa 251 (109 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 251 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 – 141 (15.8% of full-length protein)
• Non-native scrambled stretch: aa 142 – 250 (109 residues of out-of-frame sequence)
• Lost beyond the PTC: aa 251 – 890 (640 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 1–141 retained; aa 142–310 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

Pathogenic/Likely pathogenic — for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Retinal dystrophy (inheritance not specified); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965)

ClinVar classifies this variant as Pathogenic/Likely pathogenic for WFS1-related spectrum (unresolved mode) (dominant or recessive); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Retinal dystrophy (inheritance not specified); Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.

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: WFS1-Related Spectrum Disorders; Wolfram syndrome; Retinal dystrophy; Cataract 41; Wolfram-like syndrome; Wolfram syndrome 1; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6
• cDNA change: c.409_424dup
• ClinVar accession: VCV000004519
• Last evaluated: 2026/01/12 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 2026-06-08T02:16:54.440705Z. 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.