# WFS1 Wolframin — G437R Variant Card

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

*A buried glycine in transmembrane helix TM4 is replaced by arginine — the bilayer interior has no business hosting a fully solvated guanidinium, and the helix packing against TM5 collapses.*

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## Identity

| Field | Value |
|---|---|
| **Variant** | G437R (p.Glycine437Arginine) |
| **DNA change** | c.1309G>C |
| **Gene · Protein** | WFS1 · Wolframin (890 aa) |
| **UniProt** | O76024 · WFS1_HUMAN |
| **ClinVar accession** | VCV001199427 |
| **Amino acid change** | Glycine (no side chain, smallest residue, the only amino acid that fits inside tightly packed helix-helix interfaces) to Arginine (large, positively charged, fully solvated guanidinium group with substantial desolvation penalty in apolar environments) at position 437. |

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## Structural Context

| Field | Value |
|---|---|
| **AlphaFold model** | AF-O76024-F1, v6 |
| **pLDDT at residue 437** | **90.31** — well-folded |
| **Domain** | TM4 (427-447), helical transmembrane |
| **Position context** | Position 437 sits inside transmembrane helix TM4 (residues 427-447). This is one of the eleven TM helices that anchor wolframin in the ER membrane; the residue is buried in the hydrophobic bilayer interior and packs against neighboring helices. pLDDT 90.31 confirms an ordered, well-modeled region. |
| **IDR flag** | No — pLDDT above 50 threshold |

**UniProt features at this position:**

  - Chain: 1-890 Wolframin
  - Transmembrane: 427-447 Helical
  - Natural variant: 437-437 in WFS1; dbSNP:rs147974629

> G437 sits inside TM4's helical core, with Thr436 (2.46 Angstrom) and Phe438 (2.46 Angstrom) as covalent neighbors. The through-space cluster is dense and hydrophobic: Ala433 (3.68 Angstrom), Ser544 (3.80 Angstrom) — note that Ser544 is on a neighboring helix or loop, indicating an inter-helix contact — Val434 (3.83 Angstrom), Thr440 (4.13 Angstrom), Ile435 (4.41 Angstrom), Phe439 (4.42 Angstrom). The wild-type glycine occupies the position where TM4 meets its partner helix; only glycine is small enough to allow that close approach.

Substituting arginine here is a near-worst-case lipid-bilayer mutation. Arginine's guanidinium group carries a delocalized positive charge and requires solvation — typically by water or by phosphate headgroups at the membrane interface. Burying it in the middle of TM4 forces one of two outcomes: either the guanidinium snorkels upward toward the lipid headgroups, dragging the helix backbone out of register, or it remains buried at a substantial desolvation cost (estimated 8-12 kcal/mol for an ionized arginine in low dielectric). Both outcomes destabilize the helix-helix interface that requires glycine's small footprint.

DynaMut2's DeltaDeltaG of -0.59 kcal/mol substantially underestimates the cost, because the energy function does not fully capture transmembrane desolvation. AlphaMissense at 0.935 reads the true severity: G437R is essentially incompatible with normal TM4 packing. The structural prediction is that TM4 either ejects from its native register against TM5 or that the protein fails to insert into the membrane co-translationally — exactly the kind of misfolding that triggers ER retention and ER-associated degradation.

ClinVar records this variant for Wolfram syndrome 1 — consistent with a classical loss-of-function mechanism via misfolding and degradation.

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## Computational Predictions

### AlphaMissense
| Field | Value |
|---|---|
| am_pathogenicity | **0.9347** |
| am_class | **LPath** |
| Interpretation | Likely pathogenic (threshold 0.564) |

### DynaMut2
| Field | Value |
|---|---|
| ΔΔG (kcal/mol) | **-0.59 (Destabilising)** |
| Job ID | 177991405079 |
| Result URL | https://biosig.lab.uq.edu.au/dynamut2/results_prediction/177991405079 |

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## Clinical Evidence

| Field | Value |
|---|---|
| Classification | **Pathogenic/Likely pathogenic** |
| Review status | criteria provided, multiple submitters, no conflicts |
| Last evaluated | 2025/08/30 00:00 |
| Inheritance | Autosomal recessive (Wolfram syndrome 1). |
| WFS1 variant landscape | G437R is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar) |

- Wolfram syndrome 1

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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 a caveat. The schema places G437R in the small-magnitude DeltaDeltaG bucket, but the true thermodynamic cost of a buried guanidinium in TM4 is likely much larger than DynaMut2 reports. The convergent evidence — high AlphaMissense (0.935), bilayer-interior placement, glycine-only geometric constraint — argues this variant behaves more like Category 2 (pharmacological chaperone) or even Category 1 (gene therapy) in practice.

For docking and small-molecule design, G437R is a hard target: the lesion is buried in the membrane, and the rescue molecule would need to occupy the inter-helix interface that TM4 normally packs against. Pharmacological chaperones that bind the unfolded form and stabilize TM4 insertion are the more plausible route. For severe carriers, AAV-delivered wild-type WFS1 should be on the table as a parallel track. The Atlas should flag this variant as one where the DeltaDeltaG number under-reads the biology.

**Why this card matters.** G437R is a useful counterexample to the schema's strict ΔΔG bucketing. The published energy function calls it mild; the chemistry calls it severe. Glycine-to-arginine substitutions in transmembrane helices are among the most-disruptive single-residue swaps known — the literature on CFTR, rhodopsin, and aquaporins is consistent on this point. The Atlas should treat such substitutions as exceptions where a structural-chemistry override is warranted.

For the wolframin program more broadly, identifying the TM helix glycines is high-leverage: each one is a potential severe-variant locus, and any therapeutic that recovers TM packing for one likely generalizes to others. This is the same logic that drove the CFTR field toward correctors like lumacaftor and tezacaftor.

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## Files in this folder

- `AF-O76024-F1-model_v6.pdb` — AlphaFold structure
- `G437R_molstar_viewer.html` — interactive 3D viewer (auto-highlights position 437 with ball-and-stick + neighbors within 5Å)
- `G437R_variant_card.md` — this card (source of truth)
- `G437R_variant_card.html` — styled printable card
- `G437R_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)
- `G437R_wildtype_interactions.pse` / `G437R_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.*