G695S
Category 3/4 — Most DruggableConflictingLumenal · predictedσ-1 candidateEditorialGlycine → Serine at position 695 in lumenal domain. ClinVar Conflicting including Cataract 41 and DFNA6. AlphaMissense 0.906, ΔΔG -0.90. Same position as G695D (Atlas card adjacent).
Interactive 3D Structure
Bond changes · DynaMut2 interaction analysis
| Interaction type | Wild-type partner | Mutant partner | Status |
|---|---|---|---|
| Hydrogen bond | V659 | V659 | Preserved |
| Hydrogen bond | Y660 | Y660 | Preserved |
| Hydrogen bond | L829 | L829 | Preserved |
| Polar contact | V659 | V659 | Preserved |
| Polar contact | Y660 | Y660 | Preserved |
| Polar contact | L829 | L829 | Preserved |
| Van der Waals | V659 | V659 | Preserved |
| Van der Waals | Y660 | — | 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
Observed at very low frequency in gnomAD.
Structural Context
Position 695 same neighbors as G695D: GLU694 (2.5 Å), HIS696 (2.5 Å), LEU829 (4.0 Å — partner of L829P), ILE828 (4.0 Å), LEU693 (4.5 Å).
G695S is the second substitution at position 695 (with G695D). The serine introduces polarity rather than charge, but both substitutions disrupt the wild-type glycine's backbone-flexibility role and perturb the long-range contact with L829.
|ΔΔG| 0.90 + AlphaMissense 0.906 + Cataract 41 + DFNA6 confirm severe multi-tissue consequence.
Druggability Assessment
Mechanism: glycine removal + perturbed L829 long-range contact. Therapeutic: same target as G695D.
Why this matters
Feed this card to Wolfram Intelligence
Download the G695S 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.