F775V
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialPhenylalanine → Valine at position 775. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.941, ΔΔG -1.57 (substantial destabilization). Aromatic loss in a cross-domain contact position.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R708 | R708 | Preserved |
| Hydrogen bond | R805 | R805 | Preserved |
| Hydrogen bond | A806 | A806 | Preserved |
| Polar contact | R708 | R708 | Preserved |
| Polar contact | R805 | R805 | Preserved |
| Polar contact | A806 | A806 | Preserved |
| Carbonyl | R708 | R708 | Preserved |
| Van der Waals | R708 | R708 | Preserved |
| Van der Waals | Y773 | — | Lost |
| Van der Waals | — | A806 | Gained |
| Hydrophobic | V707 | V707 | Preserved |
| Hydrophobic | V709 | V709 | Preserved |
| Hydrophobic | Y773 | — | Lost |
| Hydrophobic | — | I777 | Gained |
| Hydrophobic | A806 | A806 | Preserved |
| Hydrophobic | K811 | — | Lost |
| Hydrophobic | L814 | L814 | Preserved |
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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
Structural Context
Position 775 sits in the lumenal domain. Neighbors: GLU776 (2.4 Å — partner of R708 salt-bridge), LYS774 (2.5 Å), ARG708 (3.3 Å — direct R708 contact!), ALA806 (3.7 Å — partner of A806P).
The wild-type phenylalanine at 775 likely participates in the R708-E776 salt-bridge geometry through cation-π interaction between F775's ring and R708's guanidinium. Replacing F775 with valine eliminates this cation-π contribution and reduces the aromatic packing supporting the R708-E776 salt bridge.
The |ΔΔG| of 1.57 reflects substantial fold cost. AlphaMissense 0.941 + Wolfram 1 confirm severe consequence. F775V joins R708L, R708C, A806P as multi-variant convergence on the 775-806 microregion.
Druggability Assessment
Mechanism: loss of F775 cation-π contribution to R708-E776 salt-bridge geometry. Therapeutic: same R708-E776-F775 microregion (multi-variant target).
Why this matters
Feed this card to Wolfram Intelligence
Download the F775V 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.