G695D
Category 3/4 — Most DruggableLikely pathogenicLumenal · predictedσ-1 candidateEditorialGlycine → Aspartate at position 695 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic. AlphaMissense 0.954, DynaMut2 ΔΔG -1.77 kcal/mol (destabilising) — second-largest |ΔΔG| in this batch. A glycine-removal variant with substantial structural cost.
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 | Y660 | Preserved |
| Van der Waals | — | E830 | 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 695 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places G695 within 5 Å of GLU694 (2.5 Å), HIS696 (2.5 Å — same H696 contacted by L829P at 3.9 Å), LEU829 (4.0 Å — partner of L829P!), ILE828 (4.0 Å), and LEU693 (4.5 Å).
The G695-L829 contact at 4.0 Å is structurally significant — G695 sits in spatial contact with the L829P-perturbed microregion (133 sequence positions away). The wild-type glycine at 695 enables the backbone geometry that brings these distant residues into contact.
Replacing glycine with aspartate at 695 introduces both backbone constraint and negative charge. The new D695 carboxylate competes with the existing E694 for local H-bonding. The L829 long-range contact is perturbed.
The |ΔΔG| of 1.77 — the second-largest in this batch and close to the Cat 2 threshold — reflects substantial structural cost. AlphaMissense's 0.954 confirms severe functional consequence.
Druggability Assessment
Mechanism is glycine-removal at a position with long-range contact to L829 (133 sequence positions apart). Therapeutic strategy: stabilize the G695-L829 long-range geometry.
Why this matters
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