# WFS1 Wolframin — T699P Variant Card

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

*Threonine → Proline at position 699 in wolframin's C-terminal lumenal domain. ClinVar Likely pathogenic for Wolfram syndrome 1. AlphaMissense 0.914, DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising). Proline-introduction adjacent to W700 (Cat 2 outlier region).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | T699P (p.Threonine699Proline) |
| **DNA change** | c.2095A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV003767960 |
| **Amino acid change** | Threonine (T) → Proline (P) — small polar hydroxyl-bearing residue replaced by rigid helix-breaking residue. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 699** | **89.00** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 699 in the ER lumen (pLDDT 89). Immediately adjacent to W700. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 699-699 in DFNA6; dbSNP:rs28937894

> Position 699 sits in wolframin's C-terminal lumenal domain, immediately preceding W700 (the position of W700S — Cat 2 outlier — and W700C in the Atlas). The AlphaFold model places T699 within 5 Å of TRP700 (2.4 Å), VAL698 (2.5 Å), PHE825 (3.4 Å — W700's aromatic-stacking partner), and SER826 (4.3 Å).

The wild-type threonine at 699 sits in immediate contact with W700 and the F825 aromatic neighbor. The hydroxyl group H-bonds locally and stabilizes the geometry that supports W700's aromatic packing with F825.

Replacing T699 with proline introduces a backbone kink immediately upstream of W700, perturbing the precise W700-F825 π-stacking geometry the Atlas's W700C card identifies as the key functional contact. The |ΔΔG| of 0.14 is small (fold absorbs), but the functional consequence — disrupted W700 stacking — is the same severe pathogenic mechanism that pulls W700C into pathogenic territory.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9144** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.14 (Destabilising)** |
| Job ID | 177992005741 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992005741 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Likely pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/01/27 00:00 |
| Inheritance | Wolfram syndrome 1 (AR) documented. |
| WFS1 variant landscape | T699P is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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| = 0.14 — fold survives. AlphaMissense 0.914 + Wolfram 1 confirm severe functional consequence.<br/><br/>Mechanism is backbone kink upstream of W700 that perturbs W700-F825 π-stacking geometry. Therapeutic strategy: same target as W700C/W700S — the W700-F825 aromatic stacking microregion.

**Why this card matters.** T699P, W700C, W700S all converge on the W700-F825 π-stacking interface — three Atlas variants at one therapeutic target. The Atlas surfaces these as a coherent multi-variant rescue opportunity.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `T699P_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 699 with ball-and-stick + neighbors within 5Å)
- `T699P_variant_card.md` — this card (source of truth)
- `T699P_variant_card.html` — styled printable card
- `T699P_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)
- `T699P_wildtype_interactions.pse` / `T699P_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.*