R285C
AlphaMissense: likely benign (0.15)Uncertain significanceCytoplasmic · predictedInteractive 3D Structure
Computational Predictions
AlphaMissense + AlphaFold card. This variant is mapped from AlphaMissense pathogenicity and AlphaFold confidence. The DynaMut2 ΔΔG stability prediction and the wild-type/mutant structural comparison (dual-pane + bond network) are computed per-variant and backfill here — they require a DynaMut2 submission, unlike the precomputed AlphaMissense score.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Uncertain significance 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 African / African American: AF 0.0040% (3 of 74,874 alleles), 3.2x 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. |
|---|---|---|---|---|
| Middle Eastern · under-sampled | 0.020% | 1 / 5,112 | 0 | — |
| African / African American | 0.0040% | 3 / 74,874 | 0 | ~1 in 12480 |
| East Asian · under-sampled | 0.0022% | 1 / 44,894 | 0 | — |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,354 | 0 | — |
| European (non-Finnish) | 0.0012% | 14 / 1,180,054 | 0 | ~1 in 42140 |
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.
Full Variant Card
R285C — WFS1 Molecular Atlas Card
Variant type: Missense Substitution: Arginine (R) → Cysteine (C) at position 285 Domain context: N-terminal cytoplasmic (intrinsically disordered)
AlphaMissense
- Pathogenicity score: 0.1506
- Class: likely benign
AlphaFold confidence
- pLDDT at residue 285: 54.34
DynaMut2 ΔΔG: not yet computed for this variant — AlphaMissense + AlphaFold confidence shown above. Stability ΔΔG and the wild-type/mutant structural comparison backfill behind this note.
Clinical evidence
Inheritance and scope
Uncertain significance — 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 Uncertain significance 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: Uncertain significance
- 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.853C>T
- ClinVar accession: VCV002145674
- Last evaluated: 2025/08/07 00:00
- Submissions: 1
Card generated by wolfram-atlas-batch (missense AlphaMissense mint) on 2026-06-08T02:27:33.433237Z.
AlphaMissense (Cheng et al. 2023) · AlphaFold model v6 · UniProt O76024.
Feed this card to Wolfram Intelligence
Download the R285C PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.