# WFS1 Wolframin — E273A Variant Card

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

*Glutamate → Alanine at position 273 in N-terminal cytoplasmic domain. ClinVar Conflicting with broad spectrum — Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.22. pLDDT 29 — Category 5 IDR! Same position as E273K.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | E273A (p.Glutamate273Alanine) |
| **DNA change** | c.818A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001614420 |
| **Amino acid change** | Glutamate (E) → Alanine (A) — charge lost + side chain reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 273** | **28.91** — **IDR (below 50 threshold)** |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 273 IDR (pLDDT 29 — deep IDR). |
| **IDR flag** | YES — pLDDT below 50 (Cat 5) |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Region: 1-321 Interaction with ATP6V1A

> Position 273 same as E273K — DEEP IDR (pLDDT 29). DynaMut2 untrustworthy here.

E273A is the second substitution at 273 (with E273K). Both deep-IDR Category 5. AM 0.12 under-call; multi-phenotype confirms clinical pathogenicity.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.1229** |
| am_class | **LBen** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.22 (Stabilising)** |
| Job ID | 177992509115 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992509115 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2025/09/22 00:00 |
| Inheritance | AD multi-phenotype. |
| WFS1 variant landscape | E273A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Cataract 41
- Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

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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 5 — IDR Exclusion**

<strong>Category 5 — IDR Exclusion.</strong> pLDDT 29 deep IDR. AlphaMissense 0.12 below threshold. DynaMut2 prediction not trustworthy.<br/><br/>The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.

**Why this card matters.** E273A + E273K at same IDR position — both Cat 5, both flagged for wet-lab.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `E273A_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 273 with ball-and-stick + neighbors within 5Å)
- `E273A_variant_card.md` — this card (source of truth)
- `E273A_variant_card.html` — styled printable card
- `E273A_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)
- `E273A_wildtype_interactions.pse` / `E273A_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.*