P724S
Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorialProline-to-serine substitution removes a backbone-locking residue from a tight lumenal stretch, releasing torsional constraint where the protein evolved to keep it.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | I727 | I727 | Preserved |
| Hydrogen bond | G728 | G728 | Preserved |
| Polar contact | F726 | F726 | Preserved |
| Polar contact | I727 | I727 | Preserved |
| Polar contact | G728 | G728 | Preserved |
| Van der Waals | — | F726 | Gained |
| Hydrophobic | F726 | — | 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
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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Pathogenic/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
- 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.
Highest in East Asian: AF 0.0076% (3 of 39,686 alleles), 36.8x the global figure. The global AF describes the general population, not the at-risk group.
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. |
|---|---|---|---|---|
| East Asian | 0.0076% | 3 / 39,686 | 0 | ~1 in 6610 |
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
P724 is tightly packed between Leu723 (2.46 Angstrom) and Phe725 (2.47 Angstrom), with downstream contacts to Phe726 (4.55 Angstrom) and Ile727 (4.99 Angstrom). The Leu-Pro-Phe sequence is structurally striking: a proline sandwiched between a hydrophobic aliphatic and an aromatic. This is a classical kink site — proline introduces a sharp backbone turn that allows the lumenal domain to redirect chain trajectory between two hydrophobic packing elements. The phenylalanine pair (Phe725, Phe726) one and two residues downstream likely participates in aromatic stacking that requires the proline-induced backbone orientation to maintain register.
Replacing P724 with serine eliminates the geometric constraint. Serine's backbone freedom allows the chain to relax out of the proline-enforced phi angle and into a more standard conformation. The structural consequence: the Phe725-Phe726 aromatic pair likely loses its packing register, and the entire local turn opens up. The newly available amide NH on serine may also form an unintended hydrogen bond with one of the nearby carbonyls, further pulling the backbone away from the wild-type trajectory.
DynaMut2's DeltaDeltaG of -0.81 kcal/mol is consistent with a mild but real destabilization — the protein survives but the turn geometry is degraded. AlphaMissense at 0.889 reads this as clearly pathogenic; the position is evolutionarily constrained for the precise reason the energy function partially captures: only proline holds this turn.
ClinVar documents P724S in Wolfram syndrome 1, with multiple-submitter no-conflict review. The phenotype is consistent with a lumenal-domain misfolding event that interferes with the ATF6-UPR axis.
Druggability Assessment
Why this matters
Feed this card to Wolfram Intelligence
Download the P724S 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.