L829P
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialLeucine → Proline at position 829 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic/Likely pathogenic with the full clinical spectrum — DFNA6 hearing loss, type 2 diabetes, inborn genetic diseases. AlphaMissense 0.997 (near-maximum), DynaMut2 ΔΔG -1.02 kcal/mol (destabilising). Another proline-introduction variant with substantial structural cost.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | L693 | Gained |
| Hydrogen bond | E694 | — | Lost |
| Hydrogen bond | G695 | — | Lost |
| Hydrogen bond | H696 | — | Lost |
| Hydrogen bond | — | L833 | Gained |
| Polar contact | L693 | L693 | Preserved |
| Polar contact | E694 | — | Lost |
| Polar contact | G695 | — | Lost |
| Polar contact | H696 | H696 | Preserved |
| Polar contact | — | L833 | Gained |
| Polar contact | — | F840 | Gained |
| Carbonyl | E694 | — | Lost |
| Van der Waals | E694 | — | Lost |
| Van der Waals | — | F840 | Gained |
| Hydrophobic | L664 | — | Lost |
| Hydrophobic | Y669 | — | Lost |
| Hydrophobic | L693 | — | Lost |
| Hydrophobic | H696 | H696 | Preserved |
| Hydrophobic | V698 | — | Lost |
| Hydrophobic | W700 | — | Lost |
| Hydrophobic | L833 | L833 | Preserved |
| Hydrophobic | F840 | F840 | 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 829 sits in wolframin's C-terminal lumenal domain near the C-terminus. The AlphaFold model places L829 within 5 Å of GLU830 (2.4 Å), ILE828 (2.5 Å), HIS696 (3.9 Å — long-range across the fold), LEU833 (4.2 Å), and PHE840 (4.4 Å). The HIS696 contact at 3.9 Å is particularly notable: a residue 133 sequence positions away brought into structural contact through the folded geometry of the lumenal domain.
The wild-type leucine at 829 contributes branched hydrophobic packing into this multi-residue contact environment. Replacing it with proline introduces backbone constraint where flexibility was needed, breaks any α-helical character of the local region, and likely perturbs the long-range L829-H696 contact.
The |ΔΔG| of 1.02 is larger than the other proline-introduction variants in the Atlas (L723P 0.19, L402P +0.16, L543P 0.34) — reflecting that this position is more structurally constrained, and the proline kink has farther to propagate. AlphaMissense's 0.997 (near-maximum) confirms severe functional consequence.
The broad clinical spectrum (DFNA6 hearing loss, type 2 diabetes, inborn genetic diseases) reflects the multi-tissue impact of disrupting this fold-locking position.
Druggability Assessment
The mechanism is proline-induced backbone disruption at a position with long-range structural contact (HIS696 at 3.9 Å, 133 residues away in sequence). Therapeutic strategy: stabilize the L829-H696 long-range contact via small molecules engaging both sides of the contact.
The clinical breadth makes this a high-value docking target across multiple tissue contexts.
Why this matters
Feed this card to Wolfram Intelligence
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