W399G
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialTryptophan → Glycine at position 399 in a connecting loop. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.713, ΔΔG -1.06. Bulky aromatic → smallest amino acid.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | V395 | V395 | Preserved |
| Hydrogen bond | L402 | L402 | Preserved |
| Polar contact | V395 | V395 | Preserved |
| Polar contact | N396 | N396 | Preserved |
| Polar contact | F397 | F397 | Preserved |
| Polar contact | H401 | H401 | Preserved |
| Polar contact | L402 | L402 | Preserved |
| Van der Waals | — | H401 | Gained |
| Hydrophobic | L402 | — | 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 399 in connecting loop. Neighbors: ASN400 (2.5 Å), GLY398 (2.5 Å — adjacent existing glycine!), ASN396 (3.9 Å), VAL395 (4.0 Å — near E394V).
Replacing W399 with glycine creates G398-G399 double-glycine motif (extra backbone flexibility) and removes the aromatic side chain entirely. Two adjacent glycines in a loop produce unusual conformational freedom. ΔΔG 1.06 reflects this. AM 0.713 + Cataract 41 + DFNA6 confirm severe consequence.
Druggability Assessment
Mechanism: massive volume loss + creation of G398-G399 double-glycine motif. Therapeutic: loop region site-directed.
Why this matters
Feed this card to Wolfram Intelligence
Download the W399G 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.