T337I
Category 3/4 — Most DruggableLikely pathogenicTransmembrane · predictedEditorialThreonine → Isoleucine at position 337 in a connecting loop. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.865, DynaMut2 ΔΔG -0.48 kcal/mol (destabilising). pLDDT 65 borderline.
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | N335 | N335 | Preserved |
| Hydrogen bond | F340 | F340 | Preserved |
| Hydrogen bond | F341 | F341 | Preserved |
| Polar contact | N335 | N335 | Preserved |
| Polar contact | D339 | D339 | Preserved |
| Polar contact | F340 | F340 | Preserved |
| Polar contact | F341 | F341 | Preserved |
| Van der Waals | — | N335 | Gained |
| Van der Waals | F340 | — | Lost |
| Van der Waals | F341 | — | Lost |
| Hydrophobic | — | D339 | 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 337 sits in a connecting loop near TM2. The AlphaFold model places T337 within 5 Å of ILE338 (2.4 Å), LEU336 (2.5 Å), ASN335 (4.1 Å), ASP339 (4.2 Å), and PHE340 (4.4 Å). The local environment is mixed polar-hydrophobic.
The wild-type threonine's hydroxyl likely H-bonds with the nearby N335 or D339. Replacing it with isoleucine eliminates the H-bonding capacity. The fold absorbs the substitution (|ΔΔG| 0.48), but the local H-bond network reorganizes.
AlphaMissense 0.865 + Wolfram 1 confirm pathogenic consequence. The mechanism is loss of T337's H-bonding role in the loop's polar network. pLDDT 65 is borderline; structural details deserve wet-lab confirmation.
Druggability Assessment
Mechanism is loss of T337 H-bonding role. Therapeutic strategy: site-directed at the connecting loop polar network.
Why this matters
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