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
- pLDDT 54.16 below 70
The underlying AlphaFold model has pLDDT below 70 at this position, so the structure the stability calculation was run on is itself uncertain.
Do not rank this value against a variant from a different region on ΔΔG alone.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300). Classic Wolfram syndrome is recessive: a single copy does not produce it, and this classification says nothing about a carrier's own risk.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- This rests on a single submitter (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.0014% (16 of 1,111,968 alleles), in line with the global figure.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| European (non-Finnish) | 0.0014% | 16 / 1,111,968 | 0 | ~1 in 34750 |
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 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.