I802T
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialIsoleucine → Threonine at position 802 in lumenal domain. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.851, ΔΔG -1.99 — RIGHT AT Cat 2 boundary.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T778 | T778 | Preserved |
| Hydrogen bond | V779 | V779 | Preserved |
| Hydrogen bond | M781 | — | Lost |
| Polar contact | T778 | — | Lost |
| Polar contact | V779 | V779 | Preserved |
| Van der Waals | M781 | — | Lost |
| Van der Waals | F840 | F840 | Preserved |
| Hydrophobic | W666 | — | Lost |
| Hydrophobic | W700 | — | Lost |
| Hydrophobic | M781 | — | Lost |
| Hydrophobic | L804 | L804 | Preserved |
| Hydrophobic | F825 | — | Lost |
| Hydrophobic | P838 | P838 | Preserved |
| Hydrophobic | F840 | F840 | 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 802 sits in the lumenal domain. Neighbors: VAL803 (2.4 Å), ASP801 (2.5 Å — partner of D801G), VAL779 (3.9 Å — V779G outlier region!), PRO838 (4.1 Å).
Replacing I802 with threonine introduces polarity into a hydrophobic environment near both D801G's salt-bridge region and V779G's Cat 2 outlier site. The |ΔΔG| of 1.99 is the largest in this batch — RIGHT AT the Category 2 threshold. The variant nearly bridges the fold-intact / moderately-destabilizing boundary.
AlphaMissense 0.851 + Wolfram + Wolfram-like confirm severe consequence.
Druggability Assessment
Mechanism: polarity in hydrophobic environment + perturbation of V779 outlier region. Therapeutic: site-directed at the V779-D801-I802 microregion — chaperone screening may also be warranted given near-Cat-2 stability.
Why this matters
Feed this card to Wolfram Intelligence
Download the I802T 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.