V415F
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialValine → Phenylalanine at position 415 inside TM3. ClinVar Likely pathogenic, Cataract 41. AlphaMissense 0.574 (just above threshold), DynaMut2 ΔΔG -1.64 kcal/mol (destabilising) — close to Cat 2. Volume increase in TM3.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M357 | — | Lost |
| Hydrogen bond | S411 | S411 | Preserved |
| Hydrogen bond | V412 | V412 | Preserved |
| Hydrogen bond | S418 | S418 | Preserved |
| Hydrogen bond | F419 | F419 | Preserved |
| Polar contact | S353 | — | Lost |
| Polar contact | S411 | S411 | Preserved |
| Polar contact | V412 | V412 | Preserved |
| Polar contact | F413 | F413 | Preserved |
| Polar contact | F417 | — | Lost |
| Polar contact | S418 | S418 | Preserved |
| Polar contact | F419 | F419 | Preserved |
| Aromatic / π | — | F350 | Gained |
| Aromatic / π | — | F354 | Gained |
| Van der Waals | S353 | — | Lost |
| Van der Waals | — | F354 | Gained |
| Van der Waals | — | V412 | Gained |
| Van der Waals | — | F413 | Gained |
| Van der Waals | F417 | — | Lost |
| Van der Waals | F419 | F419 | Preserved |
| Hydrophobic | F350 | F350 | Preserved |
| Hydrophobic | F354 | F354 | Preserved |
| Hydrophobic | M357 | M357 | Preserved |
| Hydrophobic | L543 | L543 | Preserved |
| Hydrophobic | — | I547 | 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 415 sits in TM3. The AlphaFold model places V415 within 5 Å of ILE416 (2.5 Å), PHE414 (2.5 Å — already aromatic), SER418 (3.6 Å), VAL412 (3.6 Å), and SER353 (3.8 Å — TM2-TM3 cross-helix, same S353 as F350I Atlas card neighbor).
Replacing V415 with phenylalanine creates a tandem aromatic motif (F414-F415). The local TM3 packing is reorganized to accommodate the second aromatic ring. The TM2-TM3 cross-helix S353 contact (also touched by F350I) is perturbed.
The |ΔΔG| of 1.64 — close to the Cat 2 threshold — reflects substantial fold cost. AlphaMissense's 0.574 is borderline-pathogenic plus Cataract 41 clinical evidence confirms pathogenic consequence.
Druggability Assessment
Mechanism is volume mismatch in TM3 plus disruption of TM2-TM3 cross-helix contact (S353). Therapeutic strategy: TM2-TM3 interface site-directed design — same target as F350I.
Why this matters
Feed this card to Wolfram Intelligence
Download the V415F 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.