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
- 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
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
ClinVar classifies this variant as Pathogenic/Likely pathogenic, 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: 2★ multiple submitters, no conflicts. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
No population breakdown — the variant is absent from gnomAD v4, so no ancestry group has an observed frequency.
No homozygotes — the variant is absent from gnomAD v4 altogether.
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 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.