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
This variant is in a water-facing region, which is the regime the stability predictor was built and benchmarked for. Ordinary predictor error still applies.
Clinical Evidence
Observed at very low frequency in gnomAD.
ClinVar classifies this variant as Likely pathogenic, but does not state what it is classified for. ClinVar records the condition only as "not provided". A classification without a phenotype and an inheritance mode cannot be read as a statement about Wolfram syndrome risk or severity.
- Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient.
- Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.
Review status: 1★ single submitter. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in Finnish: AF 0.043% (27 of 62,938 alleles), 20.3x the global figure. The global AF describes the general population, not the at-risk group.
No homozygotes reported in gnomAD v4. For a recessive allele this is expected and is not, on its own, evidence either way.
| Ancestry group | Allele freq. | AC / AN | Hom. | Carrier est. |
|---|---|---|---|---|
| Finnish | 0.043% | 27 / 62,938 | 0 | ~1 in 1170 |
| Remaining individuals | 0.0048% | 3 / 62,454 | 0 | ~1 in 10410 |
| South Asian · under-sampled | 0.0011% | 1 / 91,088 | 0 | — |
| European (non-Finnish) | 0.00025% | 3 / 1,179,810 | 0 | ~1 in 196640 |
Source: gnomAD r4, retrieved 2026-08-21. Values are allele frequencies. The carrier estimate is derived from the allele frequency (Hardy-Weinberg, ~2·AF) and is an approximation, not a published figure — where a published carrier frequency exists it outranks this column and is cited on the card.
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
Feed this card to Wolfram Intelligence
Download the G695D 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.