S430W
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialSerine → Tryptophan at position 430 inside TM4. ClinVar Likely pathogenic. AlphaMissense 0.979, DynaMut2 ΔΔG -0.74 kcal/mol (destabilising). A massive volume increase in a TM helix.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | A433 | Gained |
| Hydrogen bond | V434 | V434 | Preserved |
| Hydrogen bond | — | T552 | Gained |
| Hydrogen bond | G555 | G555 | Preserved |
| Polar contact | P428 | P428 | Preserved |
| Polar contact | V434 | V434 | Preserved |
| Polar contact | — | T552 | Gained |
| Polar contact | A559 | — | Lost |
| Van der Waals | P428 | P428 | Preserved |
| Van der Waals | — | T552 | Gained |
| Van der Waals | — | R558 | Gained |
| Hydrophobic | — | P428 | Gained |
| Hydrophobic | — | A559 | Gained |
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 430 sits near the start of TM4. The AlphaFold model places S430 within 5 Å of CYS429 (2.5 Å), GLU431 (2.5 Å — same E431 contacted by A559D and P428R), SER551 (4.0 Å — TM4-TM7 cross-helix), PRO428 (4.1 Å), and ALA433 (4.4 Å). The E431 contact at 2.5 Å is structurally significant — the wild-type serine's hydroxyl likely H-bonds to E431's carboxylate.
Replacing serine with tryptophan introduces a massive volume increase. The pocket sized for serine cannot accommodate tryptophan without substantial rearrangement. The H-bond to E431 is lost (tryptophan's indole is aromatic, not H-bond-donating in this geometry). The cross-helix contact to S551 in TM7 is perturbed.
The |ΔΔG| of 0.74 reflects fold absorption at meaningful cost. AlphaMissense's 0.979 confirms severe functional consequence.
Druggability Assessment
The mechanism is volume mismatch in TM4 plus loss of the S430-E431 H-bond. Therapeutic strategy: site-directed at the E431 microregion (also touched by A559D and P428R).
Why this matters
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