# WFS1 Wolframin — D771H Variant Card

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

*Aspartate → Histidine at position 771 in wolframin's C-terminal lumenal domain. ClinVar Pathogenic. AlphaMissense 0.857, DynaMut2 ΔΔG -0.34 kcal/mol (destabilising). A charge-sign-change-plus-aromatic variant in a polar network position.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | D771H (p.Aspartate771Histidine) |
| **DNA change** | c.2311G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001458820 |
| **Amino acid change** | Aspartate (D) → Histidine (H) — a small negatively-charged carboxylate-bearing residue replaced by a larger aromatic titratable basic residue. Charge sign reverses (negative to neutral/positive); aromatic character is added. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 771** | **88.06** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | C-terminal lumenal domain · position 771 in the ER lumen (pLDDT 88). |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal

> Position 771 sits in wolframin's C-terminal lumenal domain. The AlphaFold model places D771 within 5 Å of ARG772 (2.4 Å — likely salt-bridge partner), PHE770 (2.5 Å), LYS768 (3.8 Å), ASP713 (3.8 Å — same residue cluster as N714T atlas card), and ASN714 (4.2 Å — direct N714 contact). The wild-type aspartate likely forms a salt bridge with R772 and contributes to the polar network involving N714 across the fold.

Replacing aspartate with histidine reverses the charge character: the lost negative charge eliminates the salt bridge with R772, and the introduced imidazole — neutral or protonated depending on local pH — cannot maintain the same electrostatic contribution. The ER lumen's mild acidity favors protonated histidine (positively charged), which would now repel R772 rather than attract it.

The N714 contact (4.2 Å) is the second key disruption: D771 and N714 are spatially close and likely form an H-bond. The new H771 is also a potential H-bonder but with different geometry; the network shifts.

The |ΔΔG| of 0.34 indicates fold absorbs the substitution. AlphaMissense's 0.857 score captures functional consequence — the disrupted R772 salt bridge and the perturbed N714 contact together signal severe pathogenic mechanism.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8570** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.34 (Destabilising)** |
| Job ID | 177990265852 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990265852 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2025/01/23 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic. |
| WFS1 variant landscape | D771H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for D771H — ClinVar Pathogenic by review evidence)

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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 3/4 — Most Druggable.</strong> |ΔΔG| = 0.34 kcal/mol — fold survives. AlphaMissense 0.857 confirms pathogenic functional consequence.<br/><br/>The mechanism is loss of the D771-R772 salt bridge plus perturbation of the D771-N714 H-bond contact. Therapeutic strategy: site-directed at the D771-R772-N714 network. Combined with N714T (same network from the other side, atlas card adjacent), drug discovery has two convergent targets in this microregion.

**Why this card matters.** D771H is the third Atlas variant in this batch that targets the D713-N714-D771-K768 polar network in the lumenal domain. The neighbor analysis surfaces this cluster as a recurring therapeutic target across multiple variants. A small molecule that stabilizes this polar network rescues several variants simultaneously.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `D771H_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 771 with ball-and-stick + neighbors within 5Å)
- `D771H_variant_card.md` — this card (source of truth)
- `D771H_variant_card.html` — styled printable card
- `D771H_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)
- `D771H_wildtype_interactions.pse` / `D771H_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.*