# WFS1 Wolframin — T461I Variant Card

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

*Threonine → Isoleucine at position 461 in a connecting loop. ClinVar Conflicting including Wolfram syndrome 1. AlphaMissense 0.30 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.30 kcal/mol. Adjacent to E462G (Atlas card).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | T461I (p.Threonine461Isoleucine) |
| **DNA change** | c.1382C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000229636 |
| **Amino acid change** | Threonine (T) → Isoleucine (I) — small polar hydroxyl replaced by branched aliphatic hydrophobic. Loss of H-bonding. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 461** | **86.12** — well-folded |
| **Domain** | Connecting loop |
| **Position context** | Connecting loop · position 461 (pLDDT 86). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Natural variant: 461-463 in WFS1

> Position 461 sits in a connecting loop, immediately upstream of E462 (E462G Atlas card). Neighbors: GLU462 (2.5 Å — the E462G variant position!), ALA460 (2.5 Å), ALA458 (3.6 Å). The E462 contact at 2.5 Å places T461 in direct sequence contact with the E462G pathogenic variant.

The wild-type T461 hydroxyl likely H-bonds with E462's carboxylate, stabilizing the local loop geometry. Replacing T461 with isoleucine eliminates the H-bonding capacity; the E462 carboxylate loses its sequence-neighbor H-bond partner.

|ΔΔG| 0.30 + AM 0.30 below threshold + Wolfram syndrome 1 confirm pathogenicity. The mechanism is loss of T461-E462 H-bond — perturbing the same loop microregion that E462G disrupts.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.2957** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.3 (Destabilising)** |
| Job ID | 177992494367 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992494367 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2015/12/31 00:00 |
| Inheritance | Wolfram syndrome 1. |
| WFS1 variant landscape | T461I 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 4 — Stable Fold, Function Disrupted**

<strong>Category 3/4 — Most Druggable (AM under-call).</strong> |ΔΔG| = 0.30. AlphaMissense 0.30 below threshold but Wolfram 1 confirms pathogenicity.<br/><br/>Mechanism: loss of T461-E462 H-bond. Therapeutic strategy: same E462 loop microregion as E462G.

**Why this card matters.** T461I + E462G are sister variants at adjacent positions — both disrupt the T461-E462 H-bond geometry.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `T461I_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 461 with ball-and-stick + neighbors within 5Å)
- `T461I_variant_card.md` — this card (source of truth)
- `T461I_variant_card.html` — styled printable card
- `T461I_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)
- `T461I_wildtype_interactions.pse` / `T461I_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.*