L382P
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialLeucine → Proline at position 382 in a connecting loop. ClinVar Conflicting including Wolfram-like syndrome. AlphaMissense 0.922, ΔΔG -0.40 (mild destabilising). Proline-introduction in a loop region.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | T378 | T378 | Preserved |
| Hydrogen bond | D379 | — | Lost |
| Hydrogen bond | E385 | E385 | Preserved |
| Polar contact | T378 | T378 | Preserved |
| Polar contact | — | D379 | Gained |
| Polar contact | — | F384 | Gained |
| Polar contact | — | E385 | Gained |
| Polar contact | P386 | P386 | Preserved |
| Carbonyl | E385 | E385 | Preserved |
| Van der Waals | L380 | — | Lost |
| Van der Waals | F384 | — | Lost |
| Hydrophobic | L388 | — | Lost |
| Hydrophobic | V390 | — | 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
- transmembrane position; predictor benchmarked on soluble proteins
This variant sits in the transmembrane band. The stability value was computed with a predictor benchmarked on water-soluble proteins. Published benchmarks of ddG predictors on membrane proteins report correlation below 0.4. Treat the magnitude as unreliable and the sign as weak evidence only.
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 Conflicting classifications of pathogenicity for Wolfram-like syndrome (autosomal dominant, OMIM 614296). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- Submitters conflict on this classification (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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Admixed American: AF 0.0050% (3 of 60,012 alleles), 13.4x 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. |
|---|---|---|---|---|
| Admixed American | 0.0050% | 3 / 60,012 | 0 | ~1 in 10000 |
| African / African American | 0.0027% | 2 / 74,938 | 0 | ~1 in 18730 |
| Remaining individuals · under-sampled | 0.0016% | 1 / 62,488 | 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 382 sits in a connecting loop. Neighbors: ARG383 (2.5 Å — partner of R383H — not yet in Atlas), LEU381 (2.5 Å), GLU385 (3.6 Å — partner of E385K), THR378 (3.8 Å).
Replacing L382 with proline introduces a backbone kink in the loop. The R383 partner residue (with E385 forming a likely salt-bridge or H-bond network) experiences perturbed geometry. The |ΔΔG| of 0.40 reflects modest fold cost; AlphaMissense 0.922 + Wolfram-like confirm severe consequence.
Druggability Assessment
Mechanism: proline-induced backbone kink in the R383-E385 microregion. Therapeutic: same loop region (E385K adjacent).
Why this matters
Feed this card to Wolfram Intelligence
Download the L382P 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.