E169K
Category 3/4 — Most DruggablePathogenic/Likely pathogenicCytoplasmic · predictedEditorialGlutamate → Lysine at position 169 in wolframin's N-terminal cytoplasmic domain. ClinVar Pathogenic/Likely pathogenic across both AD and AR WFS1-related disorders. AlphaMissense 0.948, DynaMut2 ΔΔG -0.39 kcal/mol (destabilising). A clean charge-flip variant with documented dual-inheritance impact.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | R177 | — | Lost |
| Ionic bond | K252 | — | Lost |
| Hydrogen bond | Q165 | Q165 | Preserved |
| Hydrogen bond | L166 | L166 | Preserved |
| Hydrogen bond | E173 | E173 | Preserved |
| Hydrogen bond | R174 | R174 | Preserved |
| Hydrogen bond | K252 | — | Lost |
| Polar contact | Q165 | Q165 | Preserved |
| Polar contact | — | E173 | Gained |
| Polar contact | R174 | R174 | Preserved |
| Polar contact | R177 | — | Lost |
| Polar contact | K252 | — | Lost |
| Van der Waals | S167 | — | Lost |
| Van der Waals | — | E173 | Gained |
| Van der Waals | — | R174 | Gained |
| Van der Waals | R177 | — | Lost |
| Hydrophobic | E173 | E173 | Preserved |
| Hydrophobic | — | K252 | 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 169 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places E169 within 5 Å of THR170 (2.4 Å), SER168 (2.5 Å), GLU173 (3.9 Å), LEU166 (4.2 Å), and GLN165 (4.2 Å). The local environment is polar-leaning, with a nearby second glutamate (E173) suggesting the wild-type E169 may contribute to a charged surface patch.
Replacing glutamate with lysine here reverses the charge sign at this position. Where the wild-type contributed a negative charge to the local electrostatic environment, the mutant contributes a positive one. The two glutamate residues E169 and E173 may have been forming a negatively-charged cytoplasmic surface patch — a recognition signature for a partner protein with a complementary positively-charged surface. Flipping E169 to lysine destroys that recognition surface and replaces it with one of opposite character.
The |ΔΔG| of 0.39 kcal/mol is modest because the fold itself accommodates the charge-flip — both glutamate and lysine are flexible polar residues. The structural cost is minor. But the functional cost — disrupted electrostatic recognition surface for partner proteins — is severe, captured by AlphaMissense's 0.948 score and the documented dual-inheritance clinical impact.
Druggability Assessment
The mechanism is charge-sign reversal at a cytoplasmic recognition surface. The lost negative charge plus the new positive charge together disrupt whatever partner-protein recognition the wild-type E169/E173 patch enabled.
Therapeutic strategy: this is a functional-site disruption rather than a fold problem. Site-directed small-molecule design at the recognition surface — restoring or compensating for the lost negatively-charged patch — is the rational vector. Alternatively, if the disrupted recognition target can be identified, indirect rescue via the partner protein.
Why this matters
Feed this card to Wolfram Intelligence
Download the E169K 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.