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
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 Pathogenic/Likely pathogenic for Cataract 41 (autosomal dominant, OMIM 116400); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). These are two clinically distinct disease families: classic Wolfram syndrome requires two affected copies, while the dominant WFS1-related disorders do not. One label covers both, and it does not tell you which applies to a given person.
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- 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: 2★ multiple submitters, no conflicts. 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 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.