L842F
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialLeucine → Phenylalanine at position 842 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.956, DynaMut2 ΔΔG -0.61 kcal/mol (destabilising). Volume increase variant near the L829 region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R805 | R805 | Preserved |
| Hydrogen bond | — | S826 | Gained |
| Hydrogen bond | — | A844 | Gained |
| Polar contact | R805 | R805 | Preserved |
| Polar contact | F810 | F810 | Preserved |
| Polar contact | A844 | A844 | Preserved |
| Aromatic / π | — | F810 | Gained |
| Van der Waals | F810 | F810 | Preserved |
| Van der Waals | — | A844 | Gained |
| Hydrophobic | I777 | I777 | Preserved |
| Hydrophobic | L804 | L804 | Preserved |
| Hydrophobic | A806 | A806 | Preserved |
| Hydrophobic | F810 | F810 | Preserved |
| Hydrophobic | — | L814 | Gained |
| Hydrophobic | F825 | — | Lost |
| Hydrophobic | I845 | I845 | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 842 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places L842 within 5 Å of GLU841 (2.5 Å), LYS843 (2.5 Å — same K843 as the K862-K843 cluster), ARG805 (3.7 Å — long-range, near A806P), SER826 (4.2 Å), and ALA844 (4.7 Å).
The wild-type leucine fits cleanly into this mixed polar-basic environment. Replacing it with phenylalanine adds aromatic volume that the local pocket was not sized for. The K843 + L842 + R805 region is reorganized.
The |ΔΔG| of 0.61 reflects modest fold cost. AlphaMissense's 0.956 confirms severe functional consequence. The proximity to A806P (3.7 Å through R805) and the K843 contact suggest this region is a multi-variant hub.
Druggability Assessment
Mechanism is volume mismatch in the E841-L842-K843-R805 polar-basic environment. Therapeutic strategy: site-directed at this microregion.
Why this matters
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