A326E
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialAlanine → Glutamate at position 326 inside TM1. ClinVar Likely pathogenic, DFNA6 hearing loss. AlphaMissense 0.940, DynaMut2 ΔΔG -0.33 kcal/mol (destabilising). Charge-introduction variant in TM1.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | H322 | H322 | Preserved |
| Hydrogen bond | H323 | — | Lost |
| Hydrogen bond | F329 | F329 | Preserved |
| Hydrogen bond | F330 | F330 | Preserved |
| Polar contact | H322 | H322 | Preserved |
| Polar contact | H323 | H323 | Preserved |
| Polar contact | I324 | I324 | Preserved |
| Polar contact | F329 | F329 | Preserved |
| Polar contact | F330 | F330 | Preserved |
| Van der Waals | I324 | I324 | Preserved |
| Hydrophobic | F330 | F330 | 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 326 sits in TM1. The AlphaFold model places A326 within 5 Å of ASN325 (2.5 Å), LEU327 (2.5 Å), HIS322 (3.6 Å), HIS323 (3.7 Å — partner of H323R Atlas card), and PHE329 (4.2 Å). The local environment includes two adjacent histidines (H322, H323).
Replacing alanine with glutamate introduces a negative charge into the bilayer-embedded TM1 environment. The carboxylate can interact with the nearby H322/H323 imidazoles when they're protonated, potentially forming a stable salt-bridge that differs from the wild-type fold geometry. But this rearrangement comes at a structural cost.
The |ΔΔG| of 0.33 reflects fold accommodation. AlphaMissense's 0.940 + DFNA6 confirm severe functional consequence. Mechanism is charge introduction at the TM1 H322-H323 cluster.
Druggability Assessment
Mechanism is charge introduction into the TM1 H322-H323 cluster. Therapeutic strategy: site-directed at TM1 mid-helix.
Why this matters
Feed this card to Wolfram Intelligence
Download the A326E 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.