# WFS1 Wolframin — D118A Variant Card

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

*Aspartate → Alanine at position 118 in N-terminal cytoplasmic domain. ClinVar Conflicting including monogenic diabetes. AlphaMissense 0.35 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.14 kcal/mol (mild destabilising).*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D118A (p.Aspartate118Alanine) |
| **DNA change** | c.353A>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000178584 |
| **Amino acid change** | Aspartate (D) → Alanine (A) — small negatively-charged carboxylate replaced by small methyl-bearing hydrophobic. Charge lost + side chain reduced. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 118** | **82.19** — well-folded |
| **Domain** | N-terminal cytoplasmic domain (87-313) |
| **Position context** | N-terminal cytoplasmic domain · position 118 (pLDDT 82). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

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

> Position 118 sits in wolframin's N-terminal cytoplasmic domain. Neighbors: GLU119 (2.5 Å — adjacent existing glutamate), THR117 (2.5 Å), ASN122 (4.4 Å). The wild-type D118 + adjacent E119 form a charged surface patch in the cytoplasmic domain — likely a recognition surface for partner proteins.

Replacing D118 with alanine eliminates one of two negative charges from this patch. The local electrostatic surface is reduced; the partner-recognition geometry that depended on the D118-E119 double-negative signature is perturbed.

The |ΔΔG| of 0.14 is small — the fold absorbs the substitution. AlphaMissense's 0.35 is below threshold (AM under-call). Monogenic diabetes clinical evidence confirms pathogenicity through cytoplasmic partner-recognition disruption.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.3519** |
| am_class | **Amb** |
| Interpretation | Likely benign (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.14 (Destabilising)** |
| Job ID | 177992493372 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177992493372 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Conflicting classifications of pathogenicity** |
| Review status | criteria provided, conflicting classifications |
| Last evaluated | 2026/01/21 00:00 |
| Inheritance | Monogenic diabetes. |
| WFS1 variant landscape | D118A is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Monogenic diabetes

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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 4 — Stable Fold, Function Disrupted (AM under-call).</strong> |ΔΔG| = 0.14. AlphaMissense 0.35 below threshold but monogenic diabetes confirms pathogenicity.<br/><br/>Mechanism: charge loss from D118-E119 cytoplasmic surface patch. Therapeutic strategy: site-directed at the cytoplasmic recognition surface.

**Why this card matters.** D118A is part of the charge-cluster-loss class in the N-terminal cytoplasmic domain (with similar patterns at E158K, E169K, E202G, E301K).

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D118A_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 118 with ball-and-stick + neighbors within 5Å)
- `D118A_variant_card.md` — this card (source of truth)
- `D118A_variant_card.html` — styled printable card
- `D118A_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)
- `D118A_wildtype_interactions.pse` / `D118A_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.*