Q687H
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialGlutamine → Histidine at position 687 in wolframin's C-terminal lumenal domain. ClinVar Conflicting classifications. AlphaMissense 0.996 (near-maximum), DynaMut2 ΔΔG -0.19 kcal/mol (mild destabilising). Strong AM signal in the dense 684-688 cluster.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M683 | M683 | Preserved |
| Hydrogen bond | A684 | A684 | Preserved |
| Hydrogen bond | C690 | — | Lost |
| Hydrogen bond | S691 | S691 | Preserved |
| Hydrogen bond | L833 | L833 | Preserved |
| Polar contact | M683 | M683 | Preserved |
| Polar contact | A684 | A684 | Preserved |
| Polar contact | — | R685 | Gained |
| Polar contact | C690 | C690 | Preserved |
| Polar contact | S691 | S691 | Preserved |
| Polar contact | L833 | L833 | Preserved |
| Van der Waals | — | R685 | Gained |
| Van der Waals | L689 | — | Lost |
| Van der Waals | — | L833 | Gained |
| Hydrophobic | M683 | — | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 687 sits in the dense 684-688 cluster discussed in the A684T, A684V, R685P, I688F Atlas cards. The AlphaFold model places Q687 within 5 Å of THR686 (2.5 Å), ILE688 (2.5 Å — partner of I688F), LEU833 (3.6 Å — long-range), ALA684 (3.8 Å — partner of A684T, A684V), and MET683 (3.9 Å).
The wild-type glutamine's amide likely H-bonds with the surrounding polar residues in this cluster. Replacing Q687 with histidine introduces an aromatic imidazole with pH-dependent charge. The H-bond geometry changes substantially.
The |ΔΔG| of 0.19 reflects fold accommodation. AlphaMissense's 0.996 (near-maximum) is strong pathogenic signal. ClinVar conflicting classifications suggest context-dependent functional consequence.
Druggability Assessment
Mechanism is amide-to-aromatic substitution disrupting the 684-688 cluster H-bond network. Therapeutic strategy: same cluster target as A684T, A684V, R685P, I688F.
Why this matters
Feed this card to Wolfram Intelligence
Download the Q687H 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.