V503G
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialValine → Glycine at position 503 inside TM6. ClinVar Pathogenic for DFNA6 hearing loss. AlphaMissense 0.38 (below threshold) — AM under-call. DynaMut2 ΔΔG -1.88 kcal/mol — close to Cat 2 boundary. Cavity creation in dense TM6 multi-variant cluster.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L484 | — | Lost |
| Hydrogen bond | L506 | L506 | Preserved |
| Hydrogen bond | L507 | L507 | Preserved |
| Polar contact | L484 | — | Lost |
| Polar contact | C505 | C505 | Preserved |
| Polar contact | L506 | L506 | Preserved |
| Polar contact | L507 | L507 | Preserved |
| Van der Waals | — | C505 | Gained |
| Van der Waals | L506 | — | Lost |
| Hydrophobic | L468 | — | Lost |
| Hydrophobic | F488 | — | 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 503 sits in TM6, immediately upstream of P504 (P504L Atlas card) and C505 (C505Y, Y508C Atlas region). Neighbors: SER502 (2.5 Å), PRO504 (2.5 Å), CYS505 (4.3 Å). The TM6 mid-helix region is now extensively characterized in the Atlas — V503G, P504L, C505Y, Y508C all converge here.
Replacing V503 with glycine eliminates the branched aliphatic side chain entirely, creating a substantial cavity in the bilayer-embedded core. The local packing — sized for valine + the surrounding P504 backbone constraint — cannot fill the void without local rearrangement. The TM6-TM11 register through the C505/P885 cross-helix contact (discussed in C505Y, P885L Atlas cards) is perturbed.
The |ΔΔG| of 1.88 — close to the Cat 2 moderate-destabilization threshold — reflects substantial structural cost. AlphaMissense's 0.38 is below the 0.564 pathogenic threshold (AM under-call), but the documented DFNA6 hearing loss plus the substantial ΔΔG confirm pathogenicity.
Druggability Assessment
Mechanism: hydrophobic cavity creation in TM6 plus perturbation of the TM6-TM11 cross-helix register. Therapeutic strategy: same TM6 mid-helix microregion as P504L, C505Y, Y508C — pharmacological chaperone screening warranted given near-Cat-2 stability cost.
Why this matters
Feed this card to Wolfram Intelligence
Download the V503G 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.