E809K
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 809 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with Wolfram-like syndrome. AlphaMissense 0.718 (moderately pathogenic), DynaMut2 ΔΔG +0.41 kcal/mol — STABILISING. A clean charge-flip variant with structural stabilization.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Polar contact | S807 | S807 | Preserved |
| Polar contact | K811 | K811 | Preserved |
| Polar contact | I863 | — | Lost |
| Van der Waals | K811 | — | Lost |
| Van der Waals | I863 | — | Lost |
| Hydrophobic | I863 | I863 | Preserved |
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 809 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places E809 within 5 Å of SER808 (2.5 Å), PHE810 (2.5 Å), SER807 (4.3 Å), LYS811 (4.3 Å), and ILE863 (4.8 Å, long-range). The local environment contains a nearby existing lysine (K811) — the wild-type E809 may have formed an intramolecular salt bridge with K811.
Replacing glutamate with lysine reverses the charge sign at position 809. The E809-K811 salt bridge breaks; the local environment now has two adjacent positive charges (K809 and K811) instead of one positive and one negative. The DynaMut2 ΔΔG of +0.41 (stabilising) reflects that the new local geometry is more energetically favorable than the wild-type — likely because both lysines can extend their flexible side chains toward solvent.
Yet AlphaMissense places this at 0.718 (moderately pathogenic, above the 0.564 likely-pathogenic threshold) and ClinVar classifies it as Pathogenic. The mechanism is functional: the lost E809 negative charge was part of the lumenal interaction surface; the introduced K809 creates a new positive patch that disrupts whatever partner recognition the wild-type surface enabled.
Druggability Assessment
The mechanism is charge-flip at a lumenal interaction surface — broken E809-K811 salt bridge plus a new positive patch where the wild-type contributed negative charge. Therapeutic strategy: site-directed at the recognition surface, restoring or compensating for the lost negatively-charged contribution.
Why this matters
Feed this card to Wolfram Intelligence
Download the E809K 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.