T461I
Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorialThreonine → Isoleucine at position 461 in a connecting loop. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.30 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.30 kcal/mol. Adjacent to E462G (Atlas card).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | R457 | R457 | Preserved |
| Hydrogen bond | A458 | A458 | Preserved |
| Hydrogen bond | T464 | T464 | Preserved |
| Hydrogen bond | A465 | A465 | Preserved |
| Hydrogen bond | — | L507 | Gained |
| Polar contact | R457 | R457 | Preserved |
| Polar contact | A458 | A458 | Preserved |
| Polar contact | L459 | L459 | Preserved |
| Polar contact | — | T464 | Gained |
| Polar contact | A465 | A465 | Preserved |
| Van der Waals | A458 | A458 | Preserved |
| Van der Waals | L459 | L459 | Preserved |
| Van der Waals | A465 | A465 | Preserved |
| Van der Waals | Y510 | — | Lost |
| Van der Waals | — | L511 | Gained |
| Hydrophobic | — | L507 | Gained |
| Hydrophobic | Y510 | Y510 | Preserved |
| Hydrophobic | — | L511 | Gained |
| Hydrophobic | — | L514 | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 461 sits in a connecting loop, immediately upstream of E462 (E462G Atlas card). Neighbors: GLU462 (2.5 Å — the E462G variant position!), ALA460 (2.5 Å), ALA458 (3.6 Å). The E462 contact at 2.5 Å places T461 in direct sequence contact with the E462G pathogenic variant.
The wild-type T461 hydroxyl likely H-bonds with E462's carboxylate, stabilizing the local loop geometry. Replacing T461 with isoleucine eliminates the H-bonding capacity; the E462 carboxylate loses its sequence-neighbor H-bond partner.
|ΔΔG| 0.30 + AM 0.30 below threshold + Wolfram syndrome 1 confirm pathogenicity. The mechanism is loss of T461-E462 H-bond — perturbing the same loop microregion that E462G disrupts.
Druggability Assessment
Mechanism: loss of T461-E462 H-bond. Therapeutic strategy: same E462 loop microregion as E462G.
Why this matters
Feed this card to Wolfram Intelligence
Download the T461I 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.