V707F
Category 3/4 — Most DruggablePathogenicLumenal · predictedσ-1 candidateEditorialValine → Phenylalanine at position 707 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic for classical autosomal recessive Wolfram syndrome 1. AlphaMissense 0.935, DynaMut2 ΔΔG -0.31 kcal/mol (destabilising). A conservative-to-aromatic substitution in a critical lumenal position.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | E776 | E776 | Preserved |
| Aromatic / π | — | F704 | Gained |
| Hydrophobic | F704 | F704 | Preserved |
| Hydrophobic | F775 | — | Lost |
| Hydrophobic | I777 | — | Lost |
| Hydrophobic | L814 | — | Lost |
| Hydrophobic | — | L815 | 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 707 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places V707 within 5 Å of ARG708 (2.4 Å), TYR706 (2.5 Å), GLU776 (3.5 Å — long-range contact), PHE704 (4.2 Å — another long-range), and ILE777 (4.5 Å). The local environment combines basic (R708), aromatic (Y706, F704), and acidic (E776) residues.
The wild-type valine at 707 provides moderate hydrophobic packing into this mixed-character pocket. The branched aliphatic side chain fits cleanly between the surrounding residues without crowding.
Replacing valine with phenylalanine introduces a substantial volume increase plus an aromatic ring system. The local pocket — sized for valine — must rearrange to accommodate the larger phenyl ring. The two nearby aromatics (Y706 at 2.5 Å, F704 at 4.2 Å) could engage in π-stacking with the new F707, creating a three-aromatic cluster that the wild-type fold did not have. Whether this rearrangement is productive (stable three-aromatic stack) or destructive (disrupting Y706/F704 contacts with their own partners) depends on the specific geometry the variant fold adopts.
The |ΔΔG| of 0.31 indicates the fold absorbs the substitution. AlphaMissense's 0.935 score reflects the functional consequence — the rearranged aromatic cluster disrupts whatever interaction the wild-type valine geometry enabled.
Druggability Assessment
The mechanism is local volume mismatch creating an aromatic cluster (F707 + Y706 + F704) where the wild-type valine maintained a smaller hydrophobic pocket. Therapeutic strategy: site-directed small molecules that compensate for the disrupted Y706/F704 geometry by occupying the wild-type V707 niche.
Why this matters
Feed this card to Wolfram Intelligence
Download the V707F 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.