E717K
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialGlutamate → Lysine at position 717 in lumenal domain. ClinVar Conflicting with broad clinical spectrum — Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome. AlphaMissense 0.36 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.18 kcal/mol (mild destabilising). Charge-flip adjacent to the N714 polar network.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Ionic bond | K768 | — | Lost |
| Hydrogen bond | N714 | N714 | Preserved |
| Hydrogen bond | N721 | N721 | Preserved |
| Hydrogen bond | K768 | — | Lost |
| Polar contact | N714 | N714 | Preserved |
| Polar contact | A719 | A719 | Preserved |
| Polar contact | I720 | I720 | Preserved |
| Polar contact | N721 | N721 | Preserved |
| Polar contact | K768 | — | Lost |
| Van der Waals | N714 | N714 | Preserved |
| Van der Waals | A719 | A719 | Preserved |
| Hydrophobic | N714 | N714 | Preserved |
| Hydrophobic | I767 | I767 | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 717 sits in wolframin's C-terminal lumenal domain. Neighbors: SER718 (2.5 Å), ALA716 (2.5 Å — adjacent to N714 cluster), ASN714 (3.8 Å — the N714T/N714S/N714K position!). The N714 contact at 3.8 Å places E717 in direct structural proximity to the densest multi-variant target in the Atlas (the D713-N714-D771-K768 polar network).
The wild-type E717 likely contributes negative charge to the polar network surrounding N714. Replacing E717 with lysine reverses the charge sign — the network now has K717 + the existing K768 plus N714's amide where the wild-type had E717 + N714.
The |ΔΔG| of 0.18 is mild. AlphaMissense's 0.36 is below threshold (AM under-call). The broad clinical spectrum (three phenotypes: Cataract 41, Wolfram syndrome 1, Wolfram-like syndrome) plus the structural mechanism confirm pathogenicity.
Druggability Assessment
Mechanism: charge-flip immediately adjacent to the N714 polar network. Therapeutic strategy: same D713-N714-D771-K768 microregion as N714T/S/K, D771H, D771Y.
Why this matters
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