L543R
Category 3/4 — Most DruggablePathogenic/Likely pathogenicTransmembrane · predictedSource cardInteractive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | M539 | M539 | Preserved |
| Hydrogen bond | V546 | V546 | Preserved |
| Hydrogen bond | I547 | I547 | Preserved |
| Polar contact | M539 | M539 | Preserved |
| Polar contact | C541 | C541 | Preserved |
| Polar contact | V546 | V546 | Preserved |
| Polar contact | I547 | I547 | Preserved |
| Van der Waals | — | V415 | Gained |
| Van der Waals | — | M539 | Gained |
| Van der Waals | — | C541 | Gained |
| Van der Waals | I547 | I547 | Preserved |
| Hydrophobic | F354 | — | Lost |
| Hydrophobic | M357 | — | Lost |
| Hydrophobic | V415 | — | Lost |
| Hydrophobic | T436 | — | Lost |
| Hydrophobic | W540 | — | Lost |
| Hydrophobic | I547 | — | Lost |
| Hydrophobic | F881 | F881 | 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
Clinical Evidence
Observed at very low frequency in gnomAD.
Full Variant Card
WFS1 Wolframin — L543R Variant Card
Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo
Prepared: May 26, 2026 · Schema target: Category 1 or 2 (TBD from DynaMut2)
Identity
| Field | Value |
|---|---|
| Variant | L543R |
| DNA change | c.1628T>G |
| Gene | WFS1 |
| Protein | Wolframin (890 aa) |
| UniProt ID | O76024 |
| ClinVar accession | VCV002203523 |
| Amino acid change | L → R at position 543 |
Structural Context
| Field | Value |
|---|---|
| AlphaFold model | AF-O76024-F1, v6 |
| pLDDT at residue 543 | 90.94 |
| Domain | TM7 (529-549), helical transmembrane |
| UniProt features at this position |
- Chain: 1-890 Wolframin
- Transmembrane: 529-549 Helical
Position 543 is in TM7 (residues 529–549), pLDDT 90.94 (very high confidence). Leucine → Arginine inserts a permanent positive charge into the hydrophobic lipid bilayer interior. This is one of the most thermodynamically costly substitutions a transmembrane helix can tolerate — equivalent to dragging a charged ion into a greasy environment.
Computational Predictions
AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | 0.9686 |
| am_class | LPath |
| Interpretation | Likely pathogenic — strong signal |
DynaMut2
| Field | Value |
|---|---|
| Job ID | 177985958201 |
| ΔΔG (kcal/mol) | -1.75 kcal/mol (Destabilising) |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177985958201 |
Clinical Evidence
| Field | Value |
|---|---|
| ClinVar classification | Pathogenic/Likely pathogenic |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2024/02/16 00:00 |
| Associated conditions | not provided; Wolfram-like syndrome; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus; Cataract 41; Wolfram syndrome 1 |
Computational vs Clinical Tension
AlphaMissense 0.969 (LPath). ClinVar Pathogenic/Likely pathogenic, multi-submitter. Strong agreement.
Phenotype focus
Wolfram spectrum + autosomal dominant hearing loss + diabetes + cataract
Carrier story
L543R sits in transmembrane helix 7 — the same helix that anchors R558. Two pathogenic variants, one helix, telling a 'structural neighborhood' story when you rotate the Mol* viewer.
Mechanism hypothesis
Likely severely destabilizing in the TM context. Two possible mechanisms: (1) the protein never inserts properly into the membrane (translocon rejects the malformed helix), or (2) it inserts but the bilayer interfacial penalty distorts neighboring helices — including TM7's connection to R558's loop. Predicting Category 1 or upper Category 2.
Files in this folder
AF-O76024-F1-model_v6.pdb— AlphaFold structureL543R_molstar_viewer.html— interactive 3D viewer (auto-loads and highlights position 543)L543R_variant_card.md— this cardL543R_variant_card.html— demo-ready styled version
Final Schema Categorization
Category 2/3 — Most Druggable (chaperone candidate, upper boundary)
L543R produced the largest magnitude of the pilot set (-1.75 kcal/mol) — consistent with inserting a charge into the transmembrane helix interior, but still below the Cat 2 boundary of |ΔΔG| ≥ 2. The fold accommodates the charged residue better than expected, possibly because nearby polar residues in TM7 provide partial compensation. Same druggable category as R558C, but a stronger destabilization signal — likely the higher-yield chaperone screening candidate.
Every assumption documented. Every score sourced. The Atlas standard.
Feed this card to Wolfram Intelligence
Download the L543R 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.