T641K
Category 3/4 — Most DruggableConflictingTransmembrane · predictedEditorialThreonine → Lysine at position 641 inside wolframin's tenth transmembrane helix (TM10). ClinVar carries conflicting classifications — pathogenicity is documented but not universally confirmed. AlphaMissense 0.980, DynaMut2 ΔΔG -0.08 kcal/mol (essentially no destabilization). A near-zero-ΔΔG pathogenic variant with a striking mechanism.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | L637 | L637 | Preserved |
| Hydrogen bond | V638 | V638 | Preserved |
| Hydrogen bond | L645 | L645 | Preserved |
| Polar contact | L637 | L637 | Preserved |
| Polar contact | V638 | — | Lost |
| Polar contact | V644 | V644 | Preserved |
| Polar contact | L645 | L645 | Preserved |
| Van der Waals | L637 | L637 | Preserved |
| Van der Waals | L645 | — | Lost |
| Hydrophobic | F414 | F414 | 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.
Structural Context
Position 641 sits inside TM10, one of wolframin's eleven transmembrane helices anchoring the protein in the ER membrane. The AlphaFold model places T641 within 5 Å of immediate sequence neighbors LEU640 (2.5 Å) and ALA642 (2.5 Å), and into a hydrophobic cluster with LEU637 (3.8 Å), VAL638 (4.0 Å), PHE414 (4.1 Å, from TM3 — indicating helix-helix contact), and ILE643 (4.5 Å). The wild-type threonine's small polar character fits well in this membrane-embedded helix — its hydroxyl can participate in a localized hydrogen bond pattern within the helix backbone.
Replacing threonine with lysine in this position is striking. Lysine's positively-charged primary amine and its long alkyl chain are exceptionally costly in a transmembrane context: charge buried in the bilayer hydrophobic core is thermodynamically unfavorable, and the larger volume cannot be accommodated without local rearrangement. Yet DynaMut2 returns a |ΔΔG| of only 0.08 kcal/mol — essentially no destabilization.
The explanation is geometric. The lysine side chain, despite being large and charged, is flexible and can extend outward toward the membrane-water interface where the charge can be partially satisfied by interaction with lipid headgroups or water. The fold can absorb the substitution. But — and this is the mechanistic insight — the functional integrity of TM10 depends on its packing against TM3 (the PHE414 contact at 4.1 Å). Introducing a charge into that interface, even if the fold accommodates it, disrupts the helix-helix geometry that the wild-type relied on. The result is a variant the protein can fold but cannot function correctly.
AlphaMissense's score of 0.980 reflects this functional severity even though the structural cost is near-zero. The variant is pathogenic by mechanism, not by misfolding.
Druggability Assessment
The most likely mechanism is disrupted TM3-TM10 helix-helix packing: the introduced charge at the helix-helix interface (4.1 Å from PHE414 in TM3) is unfavorable in the bilayer hydrophobic core and would perturb the relative geometry of the two helices. The therapeutic strategy is site-specific: a small molecule that stabilizes the TM3-TM10 packing interface, occupying the geometric niche the wild-type threonine maintained.
This is a variant the Atlas captures particularly well — pre-atlas, the near-zero ΔΔG might have led screeners to deprioritize this position. The atlas tells you which interface to target.
Why this matters
Feed this card to Wolfram Intelligence
Download the T641K 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.