Y508C
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialTyrosine → Cysteine at position 508 inside TM6. ClinVar Conflicting including Wolfram. AlphaMissense 0.419 (below threshold), ΔΔG -1.22.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P504 | P504 | Preserved |
| Hydrogen bond | C505 | C505 | Preserved |
| Hydrogen bond | L511 | L511 | Preserved |
| Hydrogen bond | L512 | L512 | Preserved |
| Polar contact | P504 | P504 | Preserved |
| Polar contact | C505 | C505 | Preserved |
| Polar contact | Y510 | — | Lost |
| Polar contact | L511 | L511 | Preserved |
| Polar contact | L512 | L512 | Preserved |
| Polar contact | F882 | — | Lost |
| Van der Waals | — | L506 | Gained |
| Van der Waals | Y510 | Y510 | Preserved |
| Van der Waals | L511 | — | Lost |
| Hydrophobic | L512 | — | Lost |
| Hydrophobic | — | P885 | Gained |
| Hydrophobic | F886 | F886 | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 508 in TM6. Neighbors: LEU507 (2.5 Å), VAL509 (2.5 Å), CYS505 (3.7 Å — C505Y region!), PRO504 (3.8 Å — P504L). The C505 contact at 3.7 Å is structurally significant.
Replacing Y508 with cysteine creates a potential new cysteine pair with the adjacent C505. The wild-type Y508 + C505 microregion now becomes a C505 + C508 cluster — two cysteines within 3.7 Å, geometrically capable of forming a new disulfide. This is potentially structurally disruptive.
|ΔΔG| 1.22 + AM 0.419 below threshold + Wolfram 1 confirm pathogenicity.
Druggability Assessment
Mechanism: aberrant C505-C508 disulfide creation + lost Y508 aromatic packing. Therapeutic: TM6 P504-C505-Y508 microregion.
Why this matters
Feed this card to Wolfram Intelligence
Download the Y508C 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.