# WFS1 Wolframin — K836N Variant Card

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

*Lysine-to-asparagine substitution in a tryptophan-rich lumenal stretch — a positive charge is removed from a position flanked by two tryptophans (W837 covalent neighbor, W678 in through-space contact), suggesting a cation-pi anchor is being broken.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | K836N (p.Lysine836Asparagine) |
| **DNA change** | c.2508G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000228313 |
| **Amino acid change** | Lysine (large, positively charged, long aliphatic side chain ending in a primary amine) to Asparagine (neutral, short side chain ending in an amide) at position 836. The substitution removes both the charge and approximately three carbons of side-chain length. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 836** | **81.75** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | Position 836 sits inside the C-terminal lumenal domain (residues 653-869), the large soluble ATF6-interacting module. pLDDT 81.75 places K836 in an ordered, well-modeled region. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 836-836 in WFSL; dbSNP:rs876657675

> K836 has a minimal contact set — only four neighbors within 5 Angstrom: Trp837 (2.45 Angstrom), Ser835 (2.49 Angstrom), Trp678 (3.37 Angstrom), and Pro838 (4.99 Angstrom). The two tryptophans are the structural feature that makes K836 mechanistically distinctive. Trp837 is the immediate covalent neighbor (the K-W sequence); Trp678 is far away in sequence but only 3.37 Angstrom away in space. Together they form a tryptophan pair that sandwiches the K836 lysine side chain.

The cation-pi interaction is well-documented: positively charged amines (lysine, arginine) and aromatic ring systems (tryptophan, phenylalanine, tyrosine) attract each other through favorable electrostatic interaction with the pi-electron cloud, contributing 2-5 kcal/mol per pair when the geometry is correct. With two tryptophans flanking K836, the lysine almost certainly engages in a cation-pi sandwich — a high-value structural anchor that holds the lumenal domain's local geometry together.

Replacing K836 with asparagine destroys this anchor twice over: the positive charge that drives the cation-pi interaction is gone, and the long aliphatic stem that placed the amine at the correct distance from both tryptophan rings is shortened by three carbons. Asparagine's amide can still form hydrogen bonds (likely with S835 and possibly with one of the tryptophan NH groups), but the cation-pi sandwich is structurally inaccessible.

DynaMut2 reports DeltaDeltaG = -0.64 kcal/mol — destabilising and mild on its face, but the energy function tends to under-read cation-pi losses because these interactions are quantum-mechanical in nature and not fully captured by classical force fields. AlphaMissense at 0.996 reads this position as extremely pathogenic — about as high a score as the model produces. The combination of high AM and modest DeltaDeltaG is the Atlas's clearest signature of a functional-site disruption that energy functions under-report.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9961** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.64 (Destabilising)** |
| Job ID | 177991409629 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991409629 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/06/11 00:00 |
| Inheritance | Wolfram-like syndrome and AD hearing loss 6 documented. |
| WFS1 variant landscape | K836N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Rare genetic deafness
- Wolfram-like syndrome
- Autosomal dominant nonsyndromic hearing loss 6

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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**

Final classification: Category 3 — Most Druggable. The combination of high pLDDT (81.75), mild DeltaDeltaG (0.64 kcal/mol), and extreme AlphaMissense (0.996) is the classic Atlas signature of a high-value site-directed therapeutic target. The mechanism — cation-pi anchor disruption between K836 and the W837-W678 tryptophan pair — is structurally specific and small-molecule-tractable.

The drug design target is the tryptophan pair itself: an aromatic compound that engages the W837-W678 stack and presents a positively charged feature (a guanidinium, a piperidinium, or a similar cation mimic) in the position the wild-type K836 would have occupied. This is exactly the kind of pharmacophore that small-molecule chemistry handles well. K836N is therefore a strong candidate for site-directed docking and chaperone screening.

**Why this card matters.** K836N belongs to the small but important class of variants where the energy function under-reads severity because the disrupted interaction (cation-pi) is not well-captured. The Atlas's dual-metric framing (DeltaDeltaG plus AM) catches it; a stability-only triage would miss it.

For the wolframin program, K836N is also a clinically distinct case — autosomal dominant hearing loss 6 is one of the most clinically penetrant phenotypes in the WFS1 spectrum, and a small-molecule rescue strategy that addresses K836N specifically could have an unusually clear translational path. The tryptophan-pair geometry is a defined, modelable site, and the AlphaMissense score (0.996) makes the case for therapeutic investment as strong as any variant in this batch.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `K836N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 836 with ball-and-stick + neighbors within 5Å)
- `K836N_variant_card.md` — this card (source of truth)
- `K836N_variant_card.html` — styled printable card
- `K836N_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)
- `K836N_wildtype_interactions.pse` / `K836N_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.*