# WFS1 Wolframin — T699M Variant Card

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

*Threonine → Methionine at position 699 in lumenal domain. ClinVar Conflicting including monogenic hearing loss. AlphaMissense 0.603, ΔΔG +0.01 (neutral). Same position as T699P (Atlas card).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | T699M (p.Threonine699Methionine) |
| **DNA change** | c.2096C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000004522 |
| **Amino acid change** | Threonine (T) → Methionine (M) — small polar hydroxyl replaced by flexible sulfur-containing hydrophobic. |

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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 (pLDDT 89). Same as T699P. |
| **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 same neighbors as T699P: TRP700 (2.4 Å — Cat 2 outlier W700S region), VAL698 (2.5 Å), PHE825 (3.4 Å — W700-F825 π-stacking partner), SER826 (4.3 Å).

T699M is the second pathogenic substitution at 699 (with T699P). Where T699P introduced a backbone kink, T699M conservatively swaps small polar for small hydrophobic. Both perturb the W700-F825 π-stacking geometry that pulls W700S into Cat 2 destabilization.

ΔΔG neutral; AM 0.603 + monogenic hearing loss confirm severe consequence.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.6028** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.01 (Stabilising)** |
| Job ID | 177992467372 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992467372 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/10 00:00 |
| Inheritance | Monogenic hearing loss. |
| WFS1 variant landscape | T699M is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic hearing loss

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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 4 — Stable Fold, Function Disrupted.</strong> ΔΔG ≈ 0. AlphaMissense 0.603 confirms severe consequence.<br/><br/>Mechanism: W700-F825 π-stacking perturbation via T699 contact. Therapeutic: same W700-F825 microregion as T699P, W700C, W700S.

**Why this card matters.** T699M + T699P + W700C + W700S — four Atlas variants converge on the W700-F825 π-stacking interface.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `T699M_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 699 with ball-and-stick + neighbors within 5Å)
- `T699M_variant_card.md` — this card (source of truth)
- `T699M_variant_card.html` — styled printable card
- `T699M_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)
- `T699M_wildtype_interactions.pse` / `T699M_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.*