K862N
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialLysine → Asparagine at position 862 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.981, DynaMut2 ΔΔG -0.20 kcal/mol (mild destabilising). pLDDT 64 borderline. A charge-loss variant near the C-terminus.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | E864 | — | Lost |
| Ionic bond | D866 | — | Lost |
| Hydrogen bond | K843 | K843 | Preserved |
| Hydrogen bond | E864 | — | Lost |
| Hydrogen bond | D866 | — | Lost |
| Polar contact | K843 | — | Lost |
| Polar contact | E864 | — | Lost |
| Polar contact | D866 | — | Lost |
| Hydrophobic | A844 | A844 | Preserved |
| Hydrophobic | E864 | — | Lost |
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 862 sits near the C-terminus of wolframin's lumenal domain. The AlphaFold model places K862 within 5 Å of ILE863 (2.5 Å), VAL861 (2.5 Å), LYS843 (3.5 Å — second nearby lysine), ALA844 (4.0 Å), and GLU864 (4.6 Å — partner of E864K Atlas card).
The wild-type lysine likely forms a long-range salt bridge with E864 or contributes positive charge to a C-terminal surface patch including K843. Replacing K862 with N862 eliminates the positive charge and shortens the side chain. The mild |ΔΔG| of 0.20 reflects fold accommodation; AlphaMissense's 0.981 + Wolfram syndrome 1 clinical evidence confirm severe functional consequence.
Notably E864K (Atlas card adjacent) and K862N together establish the K862-E864 microregion as having multiple pathogenic variants — drug discovery here has convergent rescue opportunities.
Druggability Assessment
The mechanism is C-terminal surface charge loss. Therapeutic strategy: site-directed at the K862-E864 microregion — same target region as E864K.
Why this matters
Feed this card to Wolfram Intelligence
Download the K862N 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.