# WFS1 Wolframin — G695S Variant Card

**Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill**

*Glycine → 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).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G695S (p.Glycine695Serine) |
| **DNA change** | c.2083G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV002630486 |
| **Amino acid change** | Glycine (G) → Serine (S) — smallest replaced by small polar hydroxyl. Loss of backbone flexibility, gain of H-bond. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 695** | **82.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 695 (pLDDT 82). Same as G695D. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 695-695 in WFS1; dbSNP:rs28937891

> 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.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9059** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.9 (Destabilising)** |
| Job ID | 177992457967 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992457967 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/07/16 00:00 |
| Inheritance | Both AD (DFNA6, Cataract 41) and AR documented. |
| WFS1 variant landscape | G695S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Cataract 41
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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## Research Path Decision Tree

```
ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking
```

## Final Schema Categorization

**Category 3/4 — Most Druggable**

<strong>Category 3/4 — Most Druggable.</strong> |ΔΔG| = 0.90 — fold survives. AlphaMissense 0.906 + three phenotypes confirm severe consequence.<br/><br/>Mechanism: glycine removal + perturbed L829 long-range contact. Therapeutic: same target as G695D.

**Why this card matters.** G695S + G695D at same position; both connect to L829P long-range. Position 695 is structurally critical for the L829-H696 microregion.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G695S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 695 with ball-and-stick + neighbors within 5Å)
- `G695S_variant_card.md` — this card (source of truth)
- `G695S_variant_card.html` — styled printable card
- `G695S_dynamut2_summary.html` — clean offline DynaMut2 result card
- `dynamut2_result.json` — structured result data
- `dynamut2_result_page.html` — local snapshot of the Biosig result page (asset URLs absolutized)
- `G695S_wildtype_interactions.pse` / `G695S_mutant_interactions.pse` — PyMOL sessions

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*Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas*
*Every assumption documented. Every score sourced.*