# WFS1 Wolframin — A684V Variant Card

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

*A conservative alanine-to-valine swap in the lumenal domain with an outsized clinical footprint — UniProt annotation explicitly notes greatly reduced protein expression, locating A684V mechanistically downstream of an ER-quality-control checkpoint.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | A684V (p.Alanine684Valine) |
| **DNA change** | c.2051C>T |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV000030556 |
| **Amino acid change** | Alanine (small, hydrophobic, methyl side chain) to Valine (slightly larger, hydrophobic, beta-branched isopropyl side chain) at position 684. The substitution adds two carbons and beta-branching to an otherwise structurally similar residue. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 684** | **87.94** — well-folded |
| **Domain** | C-terminal lumenal domain (653-869) |
| **Position context** | Position 684 sits inside the C-terminal lumenal domain (residues 653-869), wolframin's largest soluble module — the same region that mediates ATF6 binding, Na+/K+ ATPase beta1 contact, and calcium handling. pLDDT 87.94 places A684 in an ordered, well-modeled environment. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Topological domain: 653-869 Lumenal
  - Natural variant: 684-684 in WFSL; greatly reduces protein expression compared to wild-type; dbSNP:rs387906930

> A684 is held tightly between Met683 (2.46 Angstrom) and Arg685 (2.47 Angstrom), with through-space neighbors Gln687 (3.99 Angstrom), Asn682 (4.00 Angstrom), and Thr686 (4.43 Angstrom). The contact set is small and almost entirely polar — Met683's thioether sulfur, Arg685's guanidinium, Gln687's amide, Asn682's amide, and Thr686's hydroxyl. The wild-type alanine's compact methyl side chain fits neatly into this polar surround without participating in the hydrogen-bond network that the surrounding residues maintain.

Valine introduces an isopropyl side chain — beta-branched, sterically larger, and chemically hydrophobic in a position the protein has evolved to keep small. The most likely structural consequence is not catastrophic packing failure but a subtle reorganization: the isopropyl group displaces one of the polar contacts (likely the Thr686 hydroxyl at 4.43 Angstrom, the most peripheral), and the local hydrogen-bond network rearranges to compensate. This is consistent with DynaMut2's mild DeltaDeltaG of -0.81 kcal/mol — the fold is intact but the contact register is shifted.

The critical functional data does not come from the energy function, however. The UniProt natural-variant annotation for A684V records greatly reduced protein expression compared to wild-type — a direct experimental observation. This locates the mechanism downstream of folding per se and inside the ER's quality-control machinery: A684V folds well enough by computational metrics, but the cell flags it as substandard and degrades it via ERAD (ER-associated degradation). The mild backbone perturbation is sufficient to expose a degron or to delay maturation enough that the protein is removed before reaching the membrane in productive form.

AlphaMissense scores this 0.886 — clearly pathogenic, consistent with the experimental expression data. ClinVar links A684V to an unusually broad phenotypic spectrum: Wolfram syndrome 1, Wolfram-like syndrome, optic atrophy, autosomal dominant nonsyndromic hearing loss 6, and the WFS1 spectrum disorders. This breadth implies that residual A684V wolframin produces graded dysfunction depending on tissue and modifier background.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.8856** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.81 (Destabilising)** |
| Job ID | 177991405428 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991405428 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2026/01/25 00:00 |
| Inheritance | Autosomal dominant and autosomal recessive forms both documented. |
| WFS1 variant landscape | A684V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1
- Wolfram-like syndrome
- Autosomal dominant nonsyndromic hearing loss 6
- Optic atrophy
- WFS1 Spectrum Disorder
- Rare genetic deafness

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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**

Final classification: Category 3 — Most Druggable, with strong druggability arguments. The reduced-expression phenotype documented in UniProt is exactly the mechanism CFTR-corrector pharmacological chaperones rescue: a protein that folds, but not fast enough or stably enough to survive ER quality control. Compounds that stabilize the lumenal contact network around A684-Arg685-Gln687 should slow ERAD targeting and recover protein levels at the membrane.

The lesion is contained (DeltaDeltaG 0.81 kcal/mol), the position is modelable (pLDDT 87.94), the surface is lumenal and accessible, and there is published experimental evidence that the cellular phenotype is dosage-rescuable. A684V is a high-priority candidate for pharmacological chaperone screening — possibly the cleanest such candidate in this batch.

**Why this card matters.** A684V is the kind of variant the Atlas was designed to surface and the kind of variant that disproportionately rewards investment. Wolfram-like syndrome and autosomal dominant deafness 6 are clinically diverse but share A684V as a recurrent locus; the breadth of phenotype across tissues suggests a partial loss-of-function that scales with cellular WFS1 levels. That is the precise signature pharmacological chaperones can shift.

For the wolframin program, A684V sits at the intersection of three Atlas priorities: high AlphaMissense, lumenal-domain placement, and published expression-level evidence. The variant should be on the short list for chaperone screening, alongside R558C and the other Category 3 lumenal residues. If a corrector molecule restores A684V expression to 50-70% of wild-type, that is plausibly clinically meaningful across the spectrum disorders this variant produces.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `A684V_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 684 with ball-and-stick + neighbors within 5Å)
- `A684V_variant_card.md` — this card (source of truth)
- `A684V_variant_card.html` — styled printable card
- `A684V_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)
- `A684V_wildtype_interactions.pse` / `A684V_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.*