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
Clinical Evidence
Observed at very low frequency in gnomAD.
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
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