WFS1 Wolframin — L543R Variant Card

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

Prepared: May 26, 2026 · Schema target: Category 1 or 2 (TBD from DynaMut2)

Identity

Structural Context

• Chain: 1-890 Wolframin
• Transmembrane: 529-549 Helical

Position 543 is in TM7 (residues 529–549), pLDDT 90.94 (very high confidence). Leucine → Arginine inserts a permanent positive charge into the hydrophobic lipid bilayer interior. This is one of the most thermodynamically costly substitutions a transmembrane helix can tolerate — equivalent to dragging a charged ion into a greasy environment.

Computational Predictions

AlphaMissense

DynaMut2

Clinical Evidence

Inheritance and scope

Pathogenic/Likely pathogenic — for Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965)

ClinVar classifies this variant as Pathogenic/Likely pathogenic for Wolfram-like syndrome (autosomal dominant, OMIM 614296); Nonsyndromic hearing loss (DFNA6/14/38) (autosomal dominant, OMIM 600965). These are dominant WFS1-related disorders and are clinically distinct from classic recessive Wolfram syndrome. This classification is not a statement about Wolfram syndrome severity.

Phenotype scope is interpretation of submitted records. The computed values on this card (AlphaMissense, DynaMut2 ΔΔG, pLDDT) are measurements of the model, not of a patient. Presentation cannot be generalised from neighbouring variants: one nucleotide over can present very differently. Structural similarity supports a mechanistic hypothesis, never a phenotype claim.

Computational vs Clinical Tension

AlphaMissense 0.969 (LPath). ClinVar Pathogenic/Likely pathogenic, multi-submitter. Strong agreement.

Phenotype focus

Wolfram spectrum + autosomal dominant hearing loss + diabetes + cataract

Carrier story

L543R sits in transmembrane helix 7 — the same helix that anchors R558. Two pathogenic variants, one helix, telling a 'structural neighborhood' story when you rotate the Mol* viewer.

Mechanism hypothesis

Likely severely destabilizing in the TM context. Two possible mechanisms: (1) the protein never inserts properly into the membrane (translocon rejects the malformed helix), or (2) it inserts but the bilayer interfacial penalty distorts neighboring helices — including TM7's connection to R558's loop. Predicting Category 1 or upper Category 2.

Files in this folder

• AF-O76024-F1-model_v6.pdb — AlphaFold structure
• L543R_molstar_viewer.html — interactive 3D viewer (auto-loads and highlights position 543)
• L543R_variant_card.md — this card
• L543R_variant_card.html — demo-ready styled version

Final Schema Categorization

Category 2/3 — Most Druggable (chaperone candidate, upper boundary)

L543R produced the largest magnitude of the pilot set (-1.75 kcal/mol) — consistent with inserting a charge into the transmembrane helix interior, but still below the Cat 2 boundary of |ΔΔG| ≥ 2. The fold accommodates the charged residue better than expected, possibly because nearby polar residues in TM7 provide partial compensation. Same druggable category as R558C, but a stronger destabilization signal — likely the higher-yield chaperone screening candidate.

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