P724S

Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorial

Proline → Serine at position 724 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Proline-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

Wild-type reference

Wild-type P724 — hydrogen bond to I727

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DynaMut2 mutant · P724S

Mutant S724 — hydrophobic contact to F726 lost

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Bond changes · DynaMut2 interaction analysis

1 lost1 gained5 preserved

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

DynaMut2 ΔΔG

-0.81kcal/mol

Destabilising — mild

AlphaMissense

0.889

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsWolfram syndrome 1

InheritanceAutosomal recessive (Wolfram syndrome 1).

Population frequency (gnomAD v4)Ultra-rare · AF 0.00020%

cDNA changec.2170C>T

ClinVar accessionVCV000379865

Last evaluated2026/01/26 00:00

Observed at very low frequency in gnomAD.

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.

Amino-acid chemistry

Proline (cyclic, locks backbone phi near -60 degrees, no amide NH for hydrogen-bonding) to Serine (small polar, hydroxyl side chain, full backbone phi/psi flexibility, amide NH is now available as a hydrogen-bond donor) at position 724.

Position in the protein

Position 724 sits inside the C-terminal lumenal domain (residues 653-869), the large soluble ATF6-interacting module facing the ER lumen. pLDDT 89.25 places P724 in an ordered, well-modeled region.

Druggability Assessment

Final classification: Category 3 — Most Druggable. The combination — pLDDT 89.25 (ordered), DeltaDeltaG 0.81 kcal/mol (mild), AlphaMissense 0.889 (functionally constrained), lumenal location — places P724S squarely inside the pharmacological-chaperone window. The lesion is the loss of a single backbone constraint; a small molecule that recovers the wild-type turn geometry, either by hydrogen-bonding to the new serine hydroxyl in a way that mimics the proline kink or by stabilizing the Phe725-Phe726 stack independently, should rescue the phenotype. For docking experiments, the Phe725-Phe726 stack is the obvious anchor: two aromatic rings within 4.5-5 Angstrom of P724 provide a built-in pharmacophore. Compounds that engage that stack and impose backbone constraint at residue 724 are the design target. P724S joins the lumenal-domain Category 3 cluster as a likely chaperone-rescuable variant.

Why this matters

Proline-loss mutations are a recurring class in the Atlas — distinct from glycine-loss mutations in that the protein loses backbone restraint rather than backbone freedom, but mechanistically similar in being purely geometric. The Atlas should cross-reference all proline-substitution variants in the lumenal domain (P724S, P504L, P292S, etc.) because the same chaperone chemistry may rescue them. Clinically, P724S contributes to the Wolfram syndrome 1 incidence in the documented carrier populations. Its membership in the lumenal-domain Category 3 cluster makes it a useful representative case: if a single chaperone screen produces hits against R558C, P724S, and one other lumenal Category 3 variant, the molecule warrants broader development.

Therapeutic Strategy Handoff · prediction

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.

Download P724S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant724–724 · in WFS1; dbSNP:rs28937890