A874T
Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorialAlanine → Threonine at position 874 inside TM11. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.33 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.49 kcal/mol (destabilising).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | — | F417 | Gained |
| Hydrogen bond | T870 | T870 | Preserved |
| Hydrogen bond | V871 | V871 | Preserved |
| Hydrogen bond | F877 | F877 | Preserved |
| Hydrogen bond | A878 | A878 | Preserved |
| Polar contact | — | F417 | Gained |
| Polar contact | — | P420 | Gained |
| Polar contact | T870 | T870 | Preserved |
| Polar contact | V871 | V871 | Preserved |
| Polar contact | H872 | — | Lost |
| Polar contact | F877 | F877 | Preserved |
| Polar contact | A878 | A878 | Preserved |
| Van der Waals | — | P420 | Gained |
| Van der Waals | V871 | V871 | Preserved |
| Van der Waals | H872 | — | Lost |
| Van der Waals | — | K876 | Gained |
| Hydrophobic | — | F417 | Gained |
| Hydrophobic | P420 | — | Lost |
| Hydrophobic | I421 | I421 | Preserved |
| Hydrophobic | — | V871 | 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 in the general population.
Structural Context
Position 874 sits in TM11 near its start. Neighbors: GLY873 (2.5 Å), VAL875 (2.5 Å — partner of V875M), VAL871 (3.6 Å — partner of V871G and V871M!). The local environment is densely populated by Atlas variant positions: V871G/V871M, V875M, K876T, and now A874T.
Replacing A874 with threonine introduces polarity into the bilayer-embedded TM11 environment. The hydroxyl is energetically unfavorable in the lipid context and pulls the local geometry toward the membrane-water interface.
|ΔΔG| 0.49 + AM 0.33 under-call + Wolfram + Wolfram-like confirm pathogenicity.
Druggability Assessment
Mechanism: polarity introduction into TM11 bilayer-embedded position. Therapeutic strategy: TM11 multi-variant cluster (V871G/M, V875M, K876T, A874T).
Why this matters
Feed this card to Wolfram Intelligence
Download the A874T 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.