F783L
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialPhenylalanine → Leucine at position 783 in lumenal domain. ClinVar Conflicting including WFS1 spectrum. AlphaMissense 0.414 (below threshold), ΔΔG -0.22. pLDDT 61 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | M781 | Gained |
| Hydrogen bond | S785 | S785 | Preserved |
| Polar contact | M781 | M781 | Preserved |
| Polar contact | S785 | S785 | Preserved |
| Hydrophobic | Q667 | Q667 | Preserved |
| Hydrophobic | — | K800 | 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 783 in lumenal domain. Neighbors: PRO782 (2.5 Å — partner of G702S neighbor P782), SER784 (2.5 Å), GLN667 (4.4 Å — long-range to Y669 cluster), SER785 (4.7 Å).
F783L removes aromatic. Q667 long-range contact suggests F783 mediates packing between this site and the Y669-C673 cluster. AM 0.414 under-call; WFS1 spectrum confirms pathogenicity.
Druggability Assessment
Mechanism: lost aromatic + perturbation of long-range Q667 contact. Therapeutic: 783-667 cross-domain.
Why this matters
Feed this card to Wolfram Intelligence
Download the F783L 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.