A684G
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialAlanine → Glycine at position 684 in lumenal domain. ClinVar Conflicting including type 2 diabetes. AlphaMissense 0.808, ΔΔG -0.38. THIRD substitution at position 684 (with A684T, A684V).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | Q687 | Q687 | Preserved |
| Hydrogen bond | I688 | I688 | Preserved |
| Polar contact | N682 | N682 | Preserved |
| Polar contact | Q687 | Q687 | Preserved |
| Polar contact | I688 | I688 | Preserved |
| Van der Waals | N682 | N682 | Preserved |
| Van der Waals | I688 | I688 | 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 684 same neighbors as A684T/V: MET683 (2.5 Å), ARG685 (2.5 Å — R685P), GLN687 (4.0 Å — Q687H), ASN682 (4.0 Å), THR686 (4.4 Å).
A684G is the third substitution at position 684 — eliminating side chain entirely, introducing glycine backbone flexibility. The variant fold may shift more substantially than A684T's hydroxyl-introduction or A684V's volume-increase because of the backbone freedom.
ΔΔG 0.38 + AM 0.808 + T2D confirm severe consequence.
Druggability Assessment
Mechanism: backbone-flexibility introduction in the R685 microregion. Therapeutic: same A684 cluster.
Why this matters
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