# WFS1 Wolframin — A874T Variant Card

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

*Alanine → Threonine at position 874 inside TM11. ClinVar Conflicting including Wolfram + Wolfram-like. AlphaMissense 0.33 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.49 kcal/mol (destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A874T (p.Alanine874Threonine) |
| **DNA change** | c.2620G>A |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000283864 |
| **Amino acid change** | Alanine (A) → Threonine (T) — small methyl-bearing hydrophobic replaced by small polar hydroxyl. Polarity introduced into bilayer-embedded position. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 874** | **83.75** — well-folded |
| **Domain** | TM11 (870-890), helical transmembrane |
| **Position context** | TM11 (residues 870–890) · position 874 near TM11 start (pLDDT 84). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 870-890 Helical

> Position 874 sits in TM11 near its start. Neighbors: GLY873 (2.5 Å), VAL875 (2.5 Å — partner of V875M), VAL871 (3.6 Å — partner of V871G and V871M!). The local environment is densely populated by Atlas variant positions: V871G/V871M, V875M, K876T, and now A874T.

Replacing A874 with threonine introduces polarity into the bilayer-embedded TM11 environment. The hydroxyl is energetically unfavorable in the lipid context and pulls the local geometry toward the membrane-water interface.

|ΔΔG| 0.49 + AM 0.33 under-call + Wolfram + Wolfram-like confirm pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3254** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.49 (Destabilising)** |
| Job ID | 177992499643 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992499643 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/11/01 00:00 |
| Inheritance | AD and AR. |
| WFS1 variant landscape | A874T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Wolfram-like syndrome

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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| = 0.49. AlphaMissense 0.33 below threshold but multi-phenotype confirms pathogenicity.<br/><br/>Mechanism: polarity introduction into TM11 bilayer-embedded position. Therapeutic strategy: TM11 multi-variant cluster (V871G/M, V875M, K876T, A874T).

**Why this card matters.** A874T extends the TM11 multi-variant cluster — six variants now (V871G, V871M, A874T, V875M, K876T, P885L) converge on this final transmembrane helix.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A874T_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 874 with ball-and-stick + neighbors within 5Å)
- `A874T_variant_card.md` — this card (source of truth)
- `A874T_variant_card.html` — styled printable card
- `A874T_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)
- `A874T_wildtype_interactions.pse` / `A874T_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.*