W314R
Category 3/4 — Most DruggablePathogenicTransmembrane · predictedEditorialTryptophan → Arginine at position 314 inside wolframin's first transmembrane helix (TM1). ClinVar Pathogenic. AlphaMissense 0.975, DynaMut2 ΔΔG +0.44 kcal/mol — STABILISING. pLDDT 59 — borderline confidence region. A pathogenic stabilising variant in a critical membrane-anchoring helix.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | A310 | A310 | Preserved |
| Hydrogen bond | G311 | G311 | Preserved |
| Hydrogen bond | T317 | T317 | Preserved |
| Hydrogen bond | I318 | I318 | Preserved |
| Polar contact | A310 | A310 | Preserved |
| Polar contact | G311 | G311 | Preserved |
| Polar contact | M312 | — | Lost |
| Polar contact | T317 | T317 | Preserved |
| Polar contact | I318 | I318 | Preserved |
| Van der Waals | A310 | A310 | Preserved |
| Van der Waals | M312 | — | Lost |
| Van der Waals | T317 | T317 | Preserved |
| Hydrophobic | I318 | — | 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
Clinical Evidence
Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).
Structural Context
Position 314 sits at the start of TM1. The AlphaFold model places W314 within 5 Å of LEU315 (2.5 Å), HIS313 (2.5 Å), THR317 (3.4 Å), GLY311 (3.8 Å), and ALA310 (4.0 Å). The position sits at the boundary between the N-terminal cytoplasmic domain (which ends near residue 313) and the first transmembrane helix.
The wild-type tryptophan at this boundary position likely serves as a 'membrane anchor' — tryptophan residues are common at lipid-water interfaces in transmembrane proteins, where their indole rings engage with phospholipid headgroups. The W314 indole probably contributes to TM1's initial insertion into the bilayer.
Replacing tryptophan with arginine has unusual effects. The lost indole eliminates the membrane-anchor contribution. The introduced arginine is positively charged — at the membrane-cytosol interface, this charge can interact with anionic phospholipid headgroups, potentially providing a different (but functional) form of membrane anchoring. The DynaMut2 ΔΔG of +0.44 (stabilising) reflects that the variant fold is energetically favorable, possibly because R314 makes a productive electrostatic contact with phospholipid headgroups that the wild-type W314 did not.
Yet the variant is pathogenic — AlphaMissense 0.975, ClinVar Pathogenic. The mechanism is functional: the precise membrane-anchoring geometry of TM1, which the indole ring established through aromatic-headgroup interactions, is replaced by an electrostatic anchoring that has different geometric requirements. TM1's insertion register and the overall topology of wolframin may shift.
Druggability Assessment
The mechanism is loss of tryptophan-mediated membrane anchoring with replacement by arginine-headgroup electrostatic anchoring — different geometry, different TM1 insertion register, different overall protein topology.
Therapeutic strategy: small molecules that stabilize the wild-type W314 indole-headgroup contact, or that compensate for the topological shift at the membrane interface.
Why this matters
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