F350I
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialPhenylalanine → Isoleucine at position 350 inside TM2. ClinVar Likely pathogenic. AlphaMissense 0.934, DynaMut2 ΔΔG +0.52 kcal/mol — STABILISING. Aromatic-to-branched-aliphatic substitution in a TM helix.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | P346 | P346 | Preserved |
| Hydrogen bond | L347 | L347 | Preserved |
| Hydrogen bond | S353 | S353 | Preserved |
| Hydrogen bond | F354 | F354 | Preserved |
| Hydrogen bond | — | S418 | Gained |
| Polar contact | P346 | P346 | Preserved |
| Polar contact | L347 | L347 | Preserved |
| Polar contact | V348 | V348 | Preserved |
| Polar contact | L352 | L352 | Preserved |
| Polar contact | S353 | S353 | Preserved |
| Polar contact | F354 | F354 | Preserved |
| Polar contact | S418 | S418 | Preserved |
| Aromatic / π | F419 | — | Lost |
| Van der Waals | V348 | V348 | Preserved |
| Van der Waals | F354 | F354 | Preserved |
| Van der Waals | S418 | — | Lost |
| Hydrophobic | V415 | — | Lost |
| Hydrophobic | F419 | — | Lost |
| Hydrophobic | — | A422 | Gained |
| Hydrophobic | I427 | I427 | Preserved |
| Hydrophobic | L432 | — | 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 350 sits in TM2. The AlphaFold model places F350 within 5 Å of ILE349 (2.5 Å), TYR351 (2.5 Å), SER418 (3.3 Å — TM2-TM3 cross-helix contact), SER353 (3.5 Å), and LEU347 (3.7 Å). The F350-S418 contact across helices is the structurally significant observation.
The wild-type phenylalanine's aromatic ring likely makes π-stacking or edge-face contact with Y351 and aromatic packing with the surrounding helices. Replacing it with isoleucine eliminates the aromatic character and replaces it with branched aliphatic packing. The DynaMut2 ΔΔG of +0.52 (stabilising) reflects that isoleucine packs efficiently into the local hydrophobic environment.
But AlphaMissense's 0.934 confirms severe functional consequence. The mechanism is loss of aromatic π-stacking with Y351 plus perturbation of the F350-S418 TM2-TM3 cross-helix contact.
Druggability Assessment
Mechanism is loss of aromatic packing with Y351 plus TM2-TM3 interface disruption at S418. Therapeutic strategy: site-directed at the F350-Y351-S418 contact cluster.
Why this matters
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