# WFS1 Wolframin — E169K Variant Card

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

*Glutamate → Lysine at position 169 in wolframin's N-terminal cytoplasmic domain. ClinVar Pathogenic/Likely pathogenic across both AD and AR WFS1-related disorders. AlphaMissense 0.948, DynaMut2 ΔΔG -0.39 kcal/mol (destabilising). A clean charge-flip variant with documented dual-inheritance impact.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E169K (p.Glutamate169Lysine) |
| **DNA change** | c.505G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000215376 |
| **Amino acid change** | Glutamate (E) → Lysine (K) — a negatively-charged carboxylate-bearing residue replaced by a positively-charged primary amine-bearing residue. The charge sign reverses completely; volume is roughly comparable. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 169** | **86.50** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 169 sits in the cytosol-facing region with good AlphaFold confidence (pLDDT 86). The cytosolic environment accommodates charged side chains but the specific charge sign matters for partner interactions. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Natural variant: 169-169 in WFS1; dbSNP:rs148953711

> Position 169 sits in wolframin's N-terminal cytoplasmic domain. The AlphaFold model places E169 within 5 Å of THR170 (2.4 Å), SER168 (2.5 Å), GLU173 (3.9 Å), LEU166 (4.2 Å), and GLN165 (4.2 Å). The local environment is polar-leaning, with a nearby second glutamate (E173) suggesting the wild-type E169 may contribute to a charged surface patch.

Replacing glutamate with lysine here reverses the charge sign at this position. Where the wild-type contributed a negative charge to the local electrostatic environment, the mutant contributes a positive one. The two glutamate residues E169 and E173 may have been forming a negatively-charged cytoplasmic surface patch — a recognition signature for a partner protein with a complementary positively-charged surface. Flipping E169 to lysine destroys that recognition surface and replaces it with one of opposite character.

The |ΔΔG| of 0.39 kcal/mol is modest because the fold itself accommodates the charge-flip — both glutamate and lysine are flexible polar residues. The structural cost is minor. But the functional cost — disrupted electrostatic recognition surface for partner proteins — is severe, captured by AlphaMissense's 0.948 score and the documented dual-inheritance clinical impact.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9479** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.39 (Destabilising)** |
| Job ID | 177991404002 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991404002 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/11/18 00:00 |
| Inheritance | Both autosomal dominant and autosomal recessive WFS1-related disorders documented — a relatively rare profile that reflects the variant's mechanism affecting partner interactions in multiple cellular contexts. |
| WFS1 variant landscape | E169K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Autosomal dominant and autosomal recessive WFS1-related disorders
- Cataract 41

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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| = 0.39 kcal/mol — fold survives. AlphaMissense 0.948 + dual-inheritance clinical impact confirm severe functional consequence.<br/><br/>The mechanism is charge-sign reversal at a cytoplasmic recognition surface. The lost negative charge plus the new positive charge together disrupt whatever partner-protein recognition the wild-type E169/E173 patch enabled.<br/><br/>Therapeutic strategy: this is a functional-site disruption rather than a fold problem. Site-directed small-molecule design at the recognition surface — restoring or compensating for the lost negatively-charged patch — is the rational vector. Alternatively, if the disrupted recognition target can be identified, indirect rescue via the partner protein.

**Why this card matters.** E169K is one of the few Atlas variants with the unusual dual-inheritance ClinVar classification, suggesting the disrupted partner interaction operates in multiple cellular contexts (with different consequences in homozygous, compound heterozygous, and heterozygous settings). The charge-flip mechanism class — where the substitution reverses charge sign without changing volume much — is structurally invisible to ΔΔG analysis but clear to AlphaMissense and clinical evidence.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E169K_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 169 with ball-and-stick + neighbors within 5Å)
- `E169K_variant_card.md` — this card (source of truth)
- `E169K_variant_card.html` — styled printable card
- `E169K_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)
- `E169K_wildtype_interactions.pse` / `E169K_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.*