# WFS1 Wolframin — W314R Variant Card

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

*Tryptophan → Arginine at position 314 inside wolframin's first transmembrane helix (TM1). ClinVar Pathogenic. AlphaMissense 0.975, DynaMut2 ΔΔG +0.44 kcal/mol — STABILISING. pLDDT 59 — borderline confidence region. A pathogenic stabilising variant in a critical membrane-anchoring helix.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | W314R (p.Tryptophan314Arginine) |
| **DNA change** | c.940T>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001298954 |
| **Amino acid change** | Tryptophan (W) → Arginine (R) — the bulkiest aromatic residue replaced by a long, positively-charged guanidinium-bearing residue. Loss of aromatic character; introduction of charge into a transmembrane context. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 314** | **59.22** — confident |
| **Domain** | TM1 (314-334), helical transmembrane |
| **Position context** | TM1 (residues 314–334) · position 314 is at the very start of TM1, the first transmembrane helix anchoring wolframin in the ER membrane. pLDDT of 59 reflects borderline AlphaFold confidence — interpret structural details with some caution. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 314-334 Helical
  - Region: 1-321 Interaction with ATP6V1A

> Position 314 sits at the start of TM1. The AlphaFold model places W314 within 5 Å of LEU315 (2.5 Å), HIS313 (2.5 Å), THR317 (3.4 Å), GLY311 (3.8 Å), and ALA310 (4.0 Å). The position sits at the boundary between the N-terminal cytoplasmic domain (which ends near residue 313) and the first transmembrane helix.

The wild-type tryptophan at this boundary position likely serves as a 'membrane anchor' — tryptophan residues are common at lipid-water interfaces in transmembrane proteins, where their indole rings engage with phospholipid headgroups. The W314 indole probably contributes to TM1's initial insertion into the bilayer.

Replacing tryptophan with arginine has unusual effects. The lost indole eliminates the membrane-anchor contribution. The introduced arginine is positively charged — at the membrane-cytosol interface, this charge can interact with anionic phospholipid headgroups, potentially providing a different (but functional) form of membrane anchoring. The DynaMut2 ΔΔG of +0.44 (stabilising) reflects that the variant fold is energetically favorable, possibly because R314 makes a productive electrostatic contact with phospholipid headgroups that the wild-type W314 did not.

Yet the variant is pathogenic — AlphaMissense 0.975, ClinVar Pathogenic. The mechanism is functional: the precise membrane-anchoring geometry of TM1, which the indole ring established through aromatic-headgroup interactions, is replaced by an electrostatic anchoring that has different geometric requirements. TM1's insertion register and the overall topology of wolframin may shift.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9745** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **0.44 (Stabilising)** |
| Job ID | 177990264167 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177990264167 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic** |
| Review status | criteria provided, single submitter |
| Last evaluated | 2021/09/01 00:00 |
| Inheritance | Inheritance not specified. ClinVar Pathogenic. |
| WFS1 variant landscape | W314R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- (no specific conditions catalogued for W314R — 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 (with pLDDT caveat).</strong> ΔΔG = +0.44 kcal/mol — stabilising. AlphaMissense 0.975 + ClinVar Pathogenic confirm severe functional consequence. pLDDT of 59 is borderline; structural details should be confirmed experimentally.<br/><br/>The mechanism is loss of tryptophan-mediated membrane anchoring with replacement by arginine-headgroup electrostatic anchoring — different geometry, different TM1 insertion register, different overall protein topology.<br/><br/>Therapeutic strategy: small molecules that stabilize the wild-type W314 indole-headgroup contact, or that compensate for the topological shift at the membrane interface.

**Why this card matters.** W314R demonstrates the value of the Atlas's pLDDT-aware framing. Even at borderline confidence (59), the variant is captured with appropriate caveats. The mechanism (membrane-anchor tryptophan replaced by interfacial arginine) is biologically specific and surfaces a drug-discovery target — the TM1 lipid-water interface — that wouldn't be obvious without the structural framework.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `W314R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 314 with ball-and-stick + neighbors within 5Å)
- `W314R_variant_card.md` — this card (source of truth)
- `W314R_variant_card.html` — styled printable card
- `W314R_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)
- `W314R_wildtype_interactions.pse` / `W314R_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.*