E462G
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialGlutamate → Glycine at position 462 in a connecting loop. ClinVar Likely pathogenic. AlphaMissense 0.805, DynaMut2 ΔΔG -1.10 kcal/mol (destabilising). Loss of charge plus loss of side chain entirely.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A458 | A458 | Preserved |
| Hydrogen bond | L459 | L459 | Preserved |
| Hydrogen bond | A465 | — | Lost |
| Hydrogen bond | G466 | G466 | Preserved |
| Hydrogen bond | F538 | — | Lost |
| Hydrogen bond | C541 | — | Lost |
| Hydrogen bond | E542 | — | Lost |
| Polar contact | A458 | A458 | Preserved |
| Polar contact | L459 | L459 | Preserved |
| Polar contact | T464 | — | Lost |
| Polar contact | A465 | A465 | Preserved |
| Polar contact | G466 | G466 | Preserved |
| Polar contact | Y534 | — | Lost |
| Polar contact | F538 | — | Lost |
| Polar contact | C541 | — | Lost |
| Van der Waals | T464 | T464 | Preserved |
| Van der Waals | A465 | — | Lost |
| Van der Waals | F538 | — | Lost |
| Hydrophobic | L511 | — | Lost |
| Hydrophobic | F538 | — | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 462 sits in a connecting loop. The AlphaFold model places E462 within 5 Å of VAL463 (2.5 Å), THR461 (2.5 Å), LEU459 (3.7 Å), ALA458 (3.8 Å), and THR464 (4.3 Å). The local environment is hydrophobic-leaning with two threonines providing H-bond options.
The wild-type glutamate's carboxylate likely engages T461 or T464 through H-bonding while extending the negative charge toward solvent. Replacing E462 with glycine eliminates both the charge and the side chain — substantial loss for a single substitution.
The |ΔΔG| of 1.10 reflects this. AlphaMissense's 0.805 confirms pathogenic functional consequence. Mechanism is loss of E462's H-bonding role in the loop's polar network plus introduction of backbone flexibility where the wild-type constrained.
Druggability Assessment
Mechanism is loss of E462 H-bonding plus backbone flexibility gain. Therapeutic strategy: site-directed at the loop polar network.
Why this matters
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