P292S
Category 3/4 — Most DruggableLikely pathogenicCytoplasmic · predictedEditorialProline → Serine at position 292 in wolframin's N-terminal cytoplasmic domain. ClinVar Likely pathogenic for classical Wolfram syndrome 1. AlphaMissense 0.957, DynaMut2 ΔΔG -0.74 kcal/mol (destabilising). Critically, pLDDT at this position is 54 — just above the Category 5 IDR threshold but in a low-confidence region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I296 | I296 | Preserved |
| Polar contact | H294 | H294 | Preserved |
| Polar contact | A295 | A295 | Preserved |
| Polar contact | I296 | I296 | Preserved |
| Van der Waals | H294 | — | Lost |
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 292 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places P292 within 5 Å of LEU293 (2.5 Å), TYR291 (2.5 Å), VAL288 (3.6 Å), HIS294 (4.4 Å), and ALA295 (4.7 Å). The local environment is mixed hydrophobic-polar.
The wild-type proline at 292 likely plays a deliberate structural role — proline residues in cytoplasmic domains often define loop boundaries or contribute backbone constraints that orient the domain for partner binding. Replacing it with serine removes that backbone constraint and adds a hydroxyl group with H-bond capacity.
The |ΔΔG| of 0.74 kcal/mol is interpretively complicated by the pLDDT of 54. DynaMut2 assumes a meaningful input structure; at pLDDT 54 the local AlphaFold prediction has lower confidence than the typical Atlas variant. The ΔΔG should be read as a directional indicator rather than a quantitative claim. AlphaMissense's 0.957 score is independently supportive — the substitution is pathogenic even if the structural mechanism is partially obscured by model uncertainty.
ClinVar Likely Pathogenic for classical Wolfram syndrome 1 confirms the variant's clinical relevance.
Druggability Assessment
The mechanism is removal of a deliberate proline backbone constraint plus introduction of a polar hydroxyl. Therapeutic strategy: a small molecule that stabilizes the wild-type backbone geometry around the position 292 loop region. Pharmacological chaperone screening is the safer initial approach given the structural confidence caveat.
Why this matters
Feed this card to Wolfram Intelligence
Download the P292S 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.