P724L
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialProline → Leucine at position 724 in lumenal domain. ClinVar Conflicting. AlphaMissense 0.906, ΔΔG -0.24. Same position as P724S (Atlas card adjacent) — proline-removal pair.
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 | F726 | 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
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Conflicting classifications of pathogenicity, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in African / African American: AF 0.017% (13 of 74,936 alleles), 6.0x 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. |
|---|---|---|---|---|
| African / African American | 0.017% | 13 / 74,936 | 0 | ~1 in 2880 |
| Finnish | 0.013% | 8 / 62,812 | 0 | ~1 in 3930 |
| East Asian | 0.0067% | 3 / 44,874 | 0 | ~1 in 7480 |
| Remaining individuals | 0.0048% | 3 / 62,464 | 0 | ~1 in 10410 |
| European (non-Finnish) | 0.0016% | 19 / 1,179,948 | 0 | ~1 in 31050 |
| South Asian · under-sampled | 0.0011% | 1 / 91,068 | 0 | — |
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 724 same neighbors as P724S: LEU723 (2.5 Å — partner of L723P), PHE725 (2.5 Å), PHE726 (4.6 Å), ILE727 (5.0 Å).
P724L is the second substitution at 724 (with P724S). Where P724S added polarity into hydrophobic environment, P724L is conservative hydrophobic-to-hydrophobic. Both lose the backbone kink. Combined with L723P, three Atlas variants converge on the 723-724 Leu-Pro motif.
|ΔΔG| 0.24 + AlphaMissense 0.906 confirm severe consequence.
Druggability Assessment
Mechanism: loss of wild-type Leu-Pro backbone geometry. Therapeutic: same target as L723P, P724S.
Why this matters
Feed this card to Wolfram Intelligence
Download the P724L 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.