P533S
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialProline → Serine at position 533 inside TM7. ClinVar Conflicting classifications including optic atrophy and DFNA6. AlphaMissense 0.979, DynaMut2 ΔΔG -1.33 kcal/mol (destabilising). Proline-removal in TM7 with substantial structural cost.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Y405 | Y405 | Preserved |
| Hydrogen bond | Y528 | — | Lost |
| Hydrogen bond | C529 | — | Lost |
| Hydrogen bond | Y530 | — | Lost |
| Hydrogen bond | V536 | V536 | Preserved |
| Hydrogen bond | C537 | C537 | Preserved |
| Polar contact | — | Y405 | Gained |
| Polar contact | — | L531 | Gained |
| Polar contact | V536 | V536 | Preserved |
| Polar contact | C537 | C537 | Preserved |
| Hydrophobic | Y405 | — | 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 in the general population.
Structural Context
Position 533 sits in TM7 near its start. The AlphaFold model places P533 within 5 Å of TYR534 (2.5 Å), VAL532 (2.5 Å), TYR405 (4.0 Å — TM3-TM7 cross-helix!), TYR530 (4.2 Å), and LEU535 (4.4 Å). The TYR405 contact at 4.0 Å is structurally significant — a TM3-TM7 helix-helix interaction through this proline position.
The wild-type proline at 533 defines TM7's helix-initiation geometry. Removing it eliminates that controlled kink, freeing the backbone. The introduced serine adds a polar hydroxyl into the bilayer-embedded environment, slightly unfavorable.
The |ΔΔG| of 1.33 reflects meaningful fold cost. The TM3-TM7 cross-helix contact at TYR405 is perturbed. AlphaMissense's 0.979 + WFS1-Related Spectrum Disorders + optic atrophy + DFNA6 clinical evidence confirm severe functional consequence across multiple tissue contexts.
Druggability Assessment
Mechanism is loss of TM7 helix-initiation geometry plus disruption of TM3-TM7 cross-helix contact at TYR405. Therapeutic strategy: TM3-TM7 interface site-directed.
Why this matters
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