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
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 Conflicting classifications of pathogenicity for Wolfram syndrome (classic) (autosomal recessive, OMIM 222300); Cataract 41 (autosomal dominant, OMIM 116400); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965); WFS1-related diabetes (autosomal dominant); Wolfram-like syndrome (autosomal dominant, OMIM 614296); WFS1-related spectrum (unresolved mode) (dominant or recessive). ClinVar records this under a WFS1-spectrum label that spans both disease families — recessive Wolfram syndrome (biallelic) and the dominant WFS1-related disorders. The label does not resolve which applies, and it is not a severity statement.
- Wolfram syndrome (classic)autosomal recessive · OMIM 222300submitted as: Wolfram syndrome 1
- Cataract 41autosomal dominant · OMIM 116400submitted as: Cataract 41
- Nonsyndromic hearing loss (DFNA6/14/38)autosomal dominant · OMIM 600965submitted as: Autosomal dominant nonsyndromic hearing loss 6
- WFS1-related diabetesautosomal dominantsubmitted as: Type 2 diabetes mellitus
- Wolfram-like syndromeautosomal dominant · OMIM 614296submitted as: Wolfram-like syndrome
- WFS1-related spectrum (unresolved mode)dominant or recessivesubmitted as: WFS1-related disorder
- Submitters conflict on this classification (1★). Treat the conditions above as submitted, not as documented phenotypes.
- 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★ conflicting classifications. ClinVar "conditions" is the union of all submissions; 0–1★ entries are submitted conditions, not documented phenotypes.
Highest in European (non-Finnish): AF 0.00045% (5 of 1,111,778 alleles), in line with the global figure.
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. |
|---|---|---|---|---|
| European (non-Finnish) | 0.00045% | 5 / 1,111,778 | 0 | ~1 in 111180 |
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 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.