WFS1 Wolframin — R558C Variant Card

Molecular Atlas Pilot Variant · RareResearch.AI · Windsor Symposium Demo

Prepared: May 26, 2026 · Source artifacts archived in this folder

Identity

Structural Context

Why this matters: Wolframin has eleven transmembrane helices anchoring it in the ER membrane. R558 sits in a short cytoplasmic loop directly preceding TM8. A positively charged arginine at this position likely contributes to membrane-proximal helix packing and electrostatic interactions with anionic phospholipid headgroups. Substituting cysteine removes the positive charge, introduces a free thiol capable of forming aberrant disulfide bonds, and is expected to perturb helix anchoring and ER folding fidelity.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

R558C is one of 326 pathogenic-spectrum variants identified for WFS1 in ClinVar (out of 2,243 total variants catalogued).

Patient Population

R558C is the most common WFS1 mutation in the Ashkenazi Jewish population — approximately 1 in 3 individuals carries this variant. This makes it the largest single identifiable carrier group for any WFS1 mutation worldwide and the highest-yield starting point for any clinical intervention targeting WFS1.

Druggability Assessment

Final classification: Category 3 / Category 4 — Most Druggable.

The convergent evidence:

• pLDDT 84.56 — region is well-structured and modelable (NOT IDR; safe for docking)
• DynaMut2 ΔΔG = −0.5 kcal/mol — mild destabilization. The fold survives the mutation; this is NOT a gross misfolding mutation requiring gene therapy
• DynaMut2 interaction map — R558's guanidinium group makes specific ionic and polar contacts with neighboring residues in the TM7–TM8 region. The R→C swap eliminates these contacts, disrupting the local interaction network without globally unfolding the protein
• AlphaMissense 0.849 (LPath) — confirms the mutation has functional consequence, despite mild structural cost
• ClinVar Pathogenic/Likely pathogenic with no conflicts — clinical penetrance is real

Therapeutic implication: R558C is exactly the kind of variant the Atlas was built to identify — pathogenic but structurally tractable. The protein folds; the lost interactions define a specific local site that can be targeted by small molecules. Priority for docking experiments and pharmacological chaperone screening. Gene therapy is not required and likely not warranted given the largely-intact fold.

This is also the highest-value variant in the Atlas pilot because the carrier population (1-in-3 Ashkenazi Jewish individuals) is large enough to support a real clinical pathway.

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 validation
Stable fold + functional site hit  → CATEGORY 4 — site-specific docking

R558C pLDDT 84.56 rules out Category 5. Final assignment pending ΔΔG.

Artifacts in this folder

Modeling assumptions (documented per Atlas standard)

1. AlphaFold predicts the monomer structure only. Wolframin's native oligomeric state in the ER membrane is not modeled here.
2. DynaMut2 ΔΔG is computed on the static AlphaFold structure; dynamic ensemble effects are not captured.
3. AlphaMissense is trained on missense variants observed in primates; novel substitutions in less-conserved regions may be less reliable.
4. ClinVar classifications reflect aggregated clinical evidence as of February 2026; new submissions may update.
5. Ashkenazi carrier frequency cited at 1-in-3 reflects the published population genetics literature for the founder mutation; individual study estimates range 27–34%.

Every assumption documented. Every score sourced. The Atlas standard.