RareResearch.AI
← Back to atlas

p.Arg517fs

FrameshiftF2Likely pathogenicTransmembrane · predicted
Frameshift variant · frameshift point at position 517 · Transmembrane helix 7 · WFS1 (Wolframin)

F2 — Frameshift, NMD-escape — scrambled C-terminus produced

Wild-type vs Translated Product

Wild-type · full length
Full wild-type wolframin · 890 aa — frameshift point at residue 517
Fullscreen ↗
Translated product
Native sequence to residue 516; everything highlighted is non-native (scrambled) or lost
Fullscreen ↗

Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 517 marked. Right: the same model with the non-native (scrambled) and lost region (residues 517–890) marked — what the frameshift transcript fails to produce as native protein.

Structural / NMD Prediction

Variant type
Frameshift
NMD status
NMD-escape
high confidence
Schema
F2
Frameshift, NMD-escape — scrambled C-terminus produced
Native protein retained
58%
PTC at aa 526

Stop codon at position 526 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 · F2

The premature stop falls in the last exon (exon 8), so NMD does not degrade the transcript and a protein IS produced — native sequence up to the frameshift point, then a non-native (scrambled) stretch to the new stop. The garbled C-terminus may misfold or mis-insert and can interfere with folding/membrane insertion of the upstream domains. Behavior is highly variable and typically too compromised for chaperone rescue; gene therapy is the primary path. Wet-lab validation recommended.

Protein Domains

Retained (aa 1–516)
  • 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
Lost / non-native (downstream)
  • 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

ClinVar classificationLikely pathogenic
Review statusno assertion criteria provided
Associated conditionsWFS1-related disorder
Population frequency (gnomAD v4)Absent from gnomAD v4
cDNA changec.1536_1549dup
Protein consequencep.Arg517fs
ClinVar variantNM_006005.3(WFS1):c.1536_1549dup (p.Arg517fs)
ClinVar accessionVCV002631364
Last evaluated2024/03/20 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the p.Arg517fs card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this F2 frameshift variant and its domain context.

Download p.Arg517fs PDF card ↓or markdown ↓

Full Variant Card

c.1536_1549dup — WFS1 Molecular Atlas Card

Variant type: Frameshift Frameshift point: residue 517 Predicted premature stop (PTC): residue 526 Domain context (where the frame breaks): Transmembrane helix 7

Schema category: F2 — Frameshift, NMD-escape — scrambled C-terminus produced

The premature stop falls in the last exon (exon 8), so NMD does not degrade the transcript and a protein IS produced — native sequence up to the frameshift point, then a non-native (scrambled) stretch to the new stop. The garbled C-terminus may misfold or mis-insert and can interfere with folding/membrane insertion of the upstream domains. Behavior is highly variable and typically too compromised for chaperone rescue; gene therapy is the primary path. Wet-lab validation recommended.

Premature-stop prediction

  • Frameshift point: aa 517
  • Predicted PTC: aa 526 (9 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-escape
  • Confidence: high
  • Reasoning: Stop codon at position 526 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.

Protein consequence

  • Native (wild-type) sequence retained: aa 1 – 516 (58.0% of full-length protein)
  • Non-native scrambled stretch: aa 517 – 525 (9 residues of out-of-frame sequence)
  • Lost beyond the PTC: aa 526 – 890 (365 residues)

Native domains retained (upstream of the frameshift)

  • 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)

Domain interrupted at the frameshift point

  • Transmembrane helix 7 — native aa 497–516 retained; aa 517–517 replaced by non-native sequence

Native domains downstream of the frameshift (lost or non-native)

  • 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

  • Classification: Likely pathogenic
  • Review status: no assertion criteria provided
  • Associated conditions: WFS1-related disorder
  • cDNA change: c.1536_1549dup
  • ClinVar accession: VCV002631364
  • Last evaluated: 2024/03/20 00:00
  • Submissions: 1

Why this variant matters

Because the frame breaks late, in the last exon, the transcript escapes NMD and a protein is actually made: wild-type wolframin up to the break, then a stretch of non-native sequence to a new stop. That scrambled C-terminus is the wildcard — it can drag the upstream domains out of fold. The atlas quantifies exactly how much native protein survives and how long the non-native tail is — the data a wet-lab needs to predict behavior.

Card generated by wolfram-atlas-batch skill (v2 — frameshift pipeline) on 2026-06-08T02:15:38.917988Z. 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.