# WFS1 Wolframin — N714S Variant Card

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

*Asparagine → Serine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for DFNA6 hearing loss. AlphaMissense 0.640 (just above threshold), DynaMut2 ΔΔG -0.49 kcal/mol (destabilising). Third Atlas variant at position 714 (with N714T, N714K).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | N714S (p.Asparagine714Serine) |
| **DNA change** | c.2141A>G |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003387796 |
| **Amino acid change** | Asparagine (N) → Serine (S) — polar amide replaced by polar hydroxyl. Both H-bond capable but different geometry. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 714** | **87.12** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 714 in the ER lumen (pLDDT 87). Same position as N714T and N714K. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 714 same neighbor environment as N714T and N714K: SER715 (2.4 Å), ASP713 (2.5 Å), PHE770 (4.4 Å), ALA716 (4.4 Å), ASP771 (4.7 Å — partner of D771H Atlas card).

N714S is the most conservative substitution in the N714 series — replacing asparagine with serine preserves H-bonding capacity but changes the geometry from amide to hydroxyl. The D713-N714-D771 polar network reorganizes; the new S714 hydroxyl is shorter than asparagine's amide arm.

The |ΔΔG| of 0.49 reflects fold accommodation. AlphaMissense's 0.640 is the lowest in the N714 series — borderline above the 0.564 threshold — yet ClinVar Likely Pathogenic with DFNA6 establishes clinical pathogenicity. The mechanism is fine-grained H-bond network adjustment.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6402** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.49 (Destabilising)** |
| Job ID | 177992009621 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992009621 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2024/11/08 00:00 |
| Inheritance | DFNA6 hearing loss documented. |
| WFS1 variant landscape | N714S is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- 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| = 0.49 — fold survives. AlphaMissense 0.640 borderline + DFNA6 confirm pathogenic consequence.<br/><br/>Mechanism is fine-grained H-bond network reorganization at the D713-N714-D771 polar cluster. Therapeutic strategy: same microregion as N714T, N714K, D771H.

**Why this card matters.** N714S is the THIRD pathogenic substitution at position 714 (with N714T, N714K). Position 714 + the D713-D771-K768 polar network is one of the most multi-variant target hubs in the Atlas.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `N714S_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 714 with ball-and-stick + neighbors within 5Å)
- `N714S_variant_card.md` — this card (source of truth)
- `N714S_variant_card.html` — styled printable card
- `N714S_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)
- `N714S_wildtype_interactions.pse` / `N714S_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.*