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
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 Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Wolfram-like syndrome (autosomal dominant, OMIM 614296); Cataract 41 (autosomal dominant, OMIM 116400). 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.
- 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; Wolfram syndrome 1
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- 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 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
Download the L829P 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.