C847Y
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialCysteine → Tyrosine at position 847 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications including Wolfram syndrome 1 and autistic behavior. AlphaMissense 0.994 (near-maximum), DynaMut2 ΔΔG -0.92 kcal/mol (destabilising). Cysteine-removal with potential disulfide loss to C850.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | V813 | Gained |
| Hydrogen bond | C850 | C850 | Preserved |
| Hydrogen bond | R859 | R859 | Preserved |
| Polar contact | — | S816 | Gained |
| Polar contact | C850 | C850 | Preserved |
| Polar contact | R859 | R859 | Preserved |
| Van der Waals | — | C850 | Gained |
| Van der Waals | — | R859 | Gained |
| Hydrophobic | — | V813 | Gained |
| Hydrophobic | L817 | L817 | Preserved |
| Hydrophobic | I823 | — | Lost |
| Hydrophobic | C850 | C850 | Preserved |
| Hydrophobic | — | R859 | Gained |
Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.
Computational Predictions
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity 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
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Also submitted under Autistic behavior — outside the established WFS1 phenotype families; recorded here as a submission, not presented as a WFS1 phenotype.
- 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0010% (12 of 1,179,924 alleles), in line with the global figure.
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 · under-sampled | 0.0016% | 1 / 62,604 | 0 | — |
| European (non-Finnish) | 0.0010% | 12 / 1,179,924 | 0 | ~1 in 49160 |
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.
Structural Context
Position 847 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places C847 within 5 Å of SER846 (2.4 Å), LEU848 (2.5 Å), LEU822 (3.8 Å — long-range), ILE823 (4.3 Å), and CYS850 (4.4 Å — another cysteine!). The C847-C850 distance of 4.4 Å is consistent with a possible structural disulfide bond.
Replacing C847 with tyrosine eliminates this potential disulfide and introduces aromatic volume. The C850 partner residue (partner of C850Y Atlas card) loses its disulfide partner if one existed. The |ΔΔG| of 0.92 reflects substantial fold cost.
AlphaMissense 0.994 confirms severe functional consequence. The C847-C850 microregion has variants at both cysteines (C847Y and C850Y), suggesting both cysteines are structurally important and disulfide-related.
Druggability Assessment
Mechanism is potential C847-C850 disulfide loss plus aromatic volume introduction. Therapeutic strategy: site-directed at the C847-C850 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the C847Y 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.