# WFS1 Wolframin — D171N Variant Card

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

*Aspartate → Asparagine at position 171 in N-terminal cytoplasmic domain. ClinVar Conflicting. AlphaMissense 0.20 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.08 (neutral).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D171N (p.Aspartate171Asparagine) |
| **DNA change** | c.511G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001330801 |
| **Amino acid change** | Aspartate (D) → Asparagine (N) — carboxylate replaced by amide. Charge lost; H-bonding preserved. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 171** | **85.19** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 171 (pLDDT 85). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A
  - Natural variant: 171-171 in DFNA6; dbSNP:rs758281375

> Position 171 in cytoplasmic domain. Neighbors: THR170 (2.5 Å), LEU172 (2.5 Å), ARG174 (3.8 Å — R174 partner of R177C cluster region). The R174-D171 likely salt bridge.

D171N eliminates negative charge while preserving amide H-bond. R174 loses salt-bridge partner. ΔΔG ≈ 0; AM 0.20 under-call. ClinVar Conflicting with low evidence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1990** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.08 (Destabilising)** |
| Job ID | 177992498845 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992498845 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/10/24 00:00 |
| Inheritance | Not specified. |
| WFS1 variant landscape | D171N is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued)

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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 4 — Stable Fold, Function Disrupted**

<strong>Category 4 — Stable Fold, Function Disrupted (AM under-call, low evidence).</strong> ΔΔG ≈ 0. AlphaMissense 0.20 below threshold. Limited clinical evidence.<br/><br/>Mechanism: loss of D171-R174 salt bridge. Therapeutic: same R174/R177 cluster microregion.

**Why this card matters.** D171N targets the R174 microregion that R177C also disrupts.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D171N_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 171 with ball-and-stick + neighbors within 5Å)
- `D171N_variant_card.md` — this card (source of truth)
- `D171N_variant_card.html` — styled printable card
- `D171N_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)
- `D171N_wildtype_interactions.pse` / `D171N_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.*