p.Arg772fs
FrameshiftF2Pathogenic/Likely pathogenicLumenal · predictedF2 — Frameshift, NMD-escape — scrambled C-terminus produced
Wild-type vs Translated Product
Left: full-length wild-type wolframin (890 aa) with the frameshift point at residue 772 marked. Right: the same model with the non-native (scrambled) and lost region (residues 772–890) marked — what the frameshift transcript fails to produce as native protein.
Structural / NMD Prediction
Stop codon at position 776 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
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 Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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.
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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 Finnish: AF 0.0032% (2 of 62,794 alleles), 17.1x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| Finnish | 0.0032% | 2 / 62,794 | 0 | ~1 in 15700 |
| European (non-Finnish) · under-sampled | 0.000085% | 1 / 1,180,024 | 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.
Feed this card to Wolfram Intelligence
Download the p.Arg772fs card below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals matched to this F2 frameshift variant and its domain context.
Full Variant Card
c.2314_2315insT — WFS1 Molecular Atlas Card
Variant type: Frameshift Frameshift point: residue 772 Predicted premature stop (PTC): residue 776 Domain context (where the frame breaks): C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
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 772
- Predicted PTC: aa 776 (4 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 776 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 – 771 (86.6% of full-length protein)
- Non-native scrambled stretch: aa 772 – 775 (4 residues of out-of-frame sequence)
- Lost beyond the PTC: aa 776 – 890 (115 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)
- 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)
Domain interrupted at the frameshift point
- C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) — native aa 600–771 retained; aa 772–890 replaced by non-native sequence
Native domains downstream of the frameshift (lost or non-native)
(no full native domains downstream)
Clinical evidence
Inheritance and scope
Pathogenic/Likely pathogenic — for Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300)
ClinVar classifies this variant as Pathogenic/Likely pathogenic for Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400); WFS1-related diabetes (autosomal dominant); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). 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: Wolfram-like syndrome; Cataract 41; Type 2 diabetes mellitus; Autosomal dominant nonsyndromic hearing loss 6; Wolfram syndrome 1
- cDNA change: c.2314_2315insT
- ClinVar accession: VCV002734648
- Last evaluated: 2024/04/26 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 2026-06-08T02:16:29.203400Z.
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.