L187F
Category 3/4 — Most DruggablePathogenic/Likely pathogenicCytoplasmic · predictedEditorialLeucine → Phenylalanine at position 187 in wolframin's N-terminal cytoplasmic domain. ClinVar Pathogenic/Likely pathogenic with broad clinical spectrum — Cataract 41, Wolfram-like syndrome, DFNA6. AlphaMissense 0.954, DynaMut2 ΔΔG -1.42 kcal/mol (destabilising). A conservative-looking substitution with substantial structural cost.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M183 | M183 | Preserved |
| Hydrogen bond | Y184 | Y184 | Preserved |
| Hydrogen bond | L200 | — | Lost |
| Hydrogen bond | N203 | N203 | Preserved |
| Polar contact | M183 | M183 | Preserved |
| Polar contact | Y184 | Y184 | Preserved |
| Polar contact | P189 | P189 | Preserved |
| Polar contact | N203 | N203 | Preserved |
| Aromatic / π | — | F247 | Gained |
| Carbonyl | Y184 | — | Lost |
| Van der Waals | Y184 | Y184 | Preserved |
| Van der Waals | L200 | — | Lost |
| Hydrophobic | M183 | M183 | Preserved |
| Hydrophobic | L200 | L200 | Preserved |
| Hydrophobic | — | N203 | Gained |
| Hydrophobic | V204 | V204 | Preserved |
| Hydrophobic | V207 | V207 | Preserved |
| Hydrophobic | L230 | L230 | Preserved |
| Hydrophobic | F247 | F247 | 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 187 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places L187 within 5 Å of ASN188 (2.5 Å), LYS186 (2.5 Å), TYR184 (3.6 Å), MET183 (3.9 Å), and ASN203 (4.1 Å). The local environment is mixed — aromatic (Y184), polar (N188, N203), basic (K186), and hydrophobic (M183, L187 itself).
Replacing leucine with phenylalanine at this position is more disruptive than the chemistry pair suggests. Phenylalanine is roughly 50% larger by side-chain volume and introduces an aromatic ring where leucine had only branched aliphatic carbons. The local pocket — packed against TYR184 (3.6 Å) and MET183 (3.9 Å) — was sized for leucine. Adding a phenyl ring forces local rearrangement.
The |ΔΔG| of 1.42 kcal/mol reflects this volume mismatch. The fold absorbs the substitution but at meaningful energetic cost. The introduced aromatic ring also creates a new potential π-π stacking opportunity with TYR184 — but at a geometry not optimized for it in the wild-type fold, so this contact may or may not form productively.
The clinical breadth — Cataract 41, Wolfram-like syndrome, DFNA6 hearing loss — confirms severe functional consequence across multiple tissue contexts.
Druggability Assessment
The mechanism is volume mismatch in a cytoplasmic packing pocket (TYR184, MET183 environment). Therapeutic strategy: site-directed binders that occupy the disrupted packing region, or pharmacological chaperones biasing the fold toward the wild-type leucine geometry.
The clinical breadth (three phenotypes across both AD and tissue-specific presentations) makes this a high-value docking target.
Why this matters
Feed this card to Wolfram Intelligence
Download the L187F 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.