# WFS1 Wolframin — N714T Variant Card

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

*Asparagine → Threonine at position 714 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic, associated with rare genetic deafness. AlphaMissense 0.927, DynaMut2 ΔΔG -0.23 kcal/mol (destabilising). A conservative polar-to-polar substitution with subtle but consequential mechanism.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | N714T (p.Asparagine714Threonine) |
| **DNA change** | c.2141A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000045447 |
| **Amino acid change** | Asparagine (N) → Threonine (T) — a polar amide-bearing residue replaced by a polar hydroxyl-bearing residue. Both are small polar, but H-bonding chemistry differs: asparagine has an amide donor/acceptor pair, threonine has a single hydroxyl donor/acceptor. |

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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). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 714 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places N714 within 5 Å of SER715 (2.4 Å), ASP713 (2.5 Å — likely H-bond partner), PHE770 (4.4 Å, long-range), ALA716 (4.4 Å), and ASP771 (4.7 Å, long-range). The local environment is unusual — two adjacent aspartates in spatial proximity (D713 immediately upstream, D771 across the fold), suggesting N714 sits in a polar interaction network.

The wild-type asparagine's amide carries both H-bond donor (NH2) and acceptor (C=O) capacity. The wild-type N714 likely engages D713 and possibly D771 across the fold through this dual H-bond chemistry.

Replacing asparagine with threonine swaps the amide for a hydroxyl. Threonine's hydroxyl has H-bond donor AND acceptor capacity through the same oxygen, but the geometry differs from asparagine's amide. The H-bond network to D713/D771 reorganizes; some contacts may be preserved, others lost.

The |ΔΔG| of 0.23 is small — the fold barely registers the swap. But AlphaMissense's 0.927 score and the clinical evidence (rare genetic deafness) confirm functional consequence. The mechanism is likely subtle reorganization of the local H-bond network that perturbs partner-protein recognition geometry.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9269** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.23 (Destabilising)** |
| Job ID | 177990266041 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990266041 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2013/08/15 00:00 |
| Inheritance | Documented in association with rare genetic deafness. AD-leaning presentation pattern. |
| WFS1 variant landscape | N714T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Rare genetic deafness

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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| = 0.23 kcal/mol — fold barely perturbed. AlphaMissense 0.927 confirms pathogenic functional consequence.<br/><br/>The mechanism is reorganization of the H-bond network involving D713 (immediate neighbor) and D771 (longer-range). Therapeutic strategy: site-directed small molecules at the D713-N714-D771 network. The pathogenic mechanism is fine-grained H-bond geometry rather than gross structural disruption.

**Why this card matters.** N714T is a conservative substitution whose pathogenicity is invisible to crude analysis but clear to AlphaMissense and clinical evidence. The Atlas captures the specific H-bond network involving two distant aspartates (D713 and D771) that the wild-type asparagine maintained — a structural feature that fine-grained drug discovery can target.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `N714T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 714 with ball-and-stick + neighbors within 5Å)
- `N714T_variant_card.md` — this card (source of truth)
- `N714T_variant_card.html` — styled printable card
- `N714T_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)
- `N714T_wildtype_interactions.pse` / `N714T_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.*