S443R
Category 3/4 — Most DruggablePathogenic/Likely pathogenicTransmembrane · predictedEditorialSerine → Arginine at position 443 inside wolframin's fourth transmembrane helix (TM4). ClinVar Pathogenic/Likely pathogenic. AlphaMissense 0.999 (near-maximum pathogenicity score), DynaMut2 ΔΔG -0.31 kcal/mol (destabilising). A pathogenic variant whose mechanism is charge-into-membrane disruption.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | F365 | — | Lost |
| Hydrogen bond | F439 | F439 | Preserved |
| Hydrogen bond | S446 | S446 | Preserved |
| Hydrogen bond | L447 | L447 | Preserved |
| Polar contact | — | T361 | Gained |
| Polar contact | F365 | — | Lost |
| Polar contact | F439 | F439 | Preserved |
| Polar contact | L445 | L445 | Preserved |
| Polar contact | S446 | S446 | Preserved |
| Polar contact | L447 | L447 | Preserved |
| Polar contact | — | P533 | Gained |
| Van der Waals | — | T361 | Gained |
| Van der Waals | — | V364 | Gained |
| Van der Waals | — | F365 | Gained |
| Van der Waals | L445 | L445 | Preserved |
| Van der Waals | — | S446 | Gained |
| Van der Waals | — | C537 | Gained |
| Hydrophobic | — | F365 | Gained |
| Hydrophobic | — | L447 | Gained |
| Hydrophobic | — | V536 | Gained |
| Hydrophobic | — | C537 | Gained |
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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 443 sits inside TM4, one of wolframin's eleven transmembrane helices. The AlphaFold model places S443 within 5 Å of THR442 (2.5 Å) and TYR444 (2.5 Å), and into a packed environment with PHE439 (3.5 Å), SER446 (3.6 Å), PHE365 (3.7 Å, from TM3), and THR440 (3.9 Å). The wild-type serine's small polar hydroxyl fits well in this membrane-embedded context, possibly forming a hydrogen bond with SER446 or with the backbone carbonyl of a nearby residue.
Replacing serine with arginine here introduces three layered structural costs. First, the volume difference: arginine is one of the larger amino acids by side-chain volume, while serine is among the smaller. The local packing has to accommodate roughly four-fold more side-chain mass. Second, the charge: arginine's guanidinium group carries a positive charge that is thermodynamically penalized in the bilayer hydrophobic core. Third, the H-bonding capacity changes — the lost serine hydroxyl is replaced by the guanidinium's strong H-bond donor character, which would prefer to engage water or polar partners outside the membrane.
DynaMut2's |ΔΔG| of 0.31 kcal/mol underestimates the structural disruption. The variant probably forces local rearrangement: the arginine side chain extends toward the membrane-water interface (where its charge can be partially satisfied), pulling nearby residues out of their wild-type positions. The PHE365 contact from TM3 (3.7 Å) is particularly important — that's a helix-helix interaction, and disrupting it perturbs the relative geometry of TM3 and TM4.
AlphaMissense's score of 0.999 reflects the severity of this mechanism even with a small structural ΔΔG. The variant is pathogenic because it disrupts helix-helix packing in the membrane, not because it unfolds the protein.
Druggability Assessment
The mechanism is charge-into-membrane plus TM3-TM4 helix-helix interface disruption. S443R is one of several Atlas variants where a charged residue is introduced into a bilayer-embedded position (compare T641K, V536E). Across these cases, the therapeutic target is the helix-helix interface that the wild-type residue stabilized, not the helix itself.
The therapeutic strategy is site-specific: a small molecule that occupies the TM3-TM4 interface near the PHE365 contact would compensate for the disrupted packing. The atlas-derived structural framework makes this target geometry visible — pre-atlas, the small ΔΔG would have deprioritized this variant for structure-based drug design.
Why this matters
Feed this card to Wolfram Intelligence
Download the S443R 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.