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E273K

Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorial
Glutamate → Lysine at position 273 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)

Glutamate → Lysine at position 273 in N-terminal cytoplasmic domain. ClinVar Conflicting with broad spectrum — Cataract 41, DFNA6. AlphaMissense 0.15 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.25. pLDDT 29 — Category 5 IDR!

Interactive 3D Structure

Wild-type reference
Wild-type E273 — native residue, no strong sidechain contacts
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DynaMut2 mutant · E273K
Mutant K273 — energy-minimized; local contact network preserved
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Computational Predictions

DynaMut2 ΔΔG
0.25kcal/mol
Stabilising — mild
AlphaMissense
0.148
LBen
AlphaFold pLDDT
29
model confidence
Schema
Cat 5
Category 5 — IDR Exclusion

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity
Review statuscriteria provided, conflicting classifications
Associated conditionsCataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)
InheritanceMulti-phenotype AD.
Population frequency (gnomAD v4)Low frequency · AF 0.010%
cDNA changec.817G>A
ClinVar accessionVCV000215382
Last evaluated2025/12/30 00:00

Observed in the general population.

Structural Context

Position 273 at pLDDT 29 — deep in the IDR region. Sparse neighbor analysis (only sequence neighbors LEU274, ASP272, ALA275 within 5 Å) confirms IDR character. DynaMut2 prediction not trustworthy.

AM 0.15 below threshold. Multi-phenotype clinical evidence (Cataract 41, DFNA6) confirms — but the IDR mechanism is invisible to AM.

Amino-acid chemistry
Glutamate (E) → Lysine (K) — charge reversal.
Position in the protein
N-terminal cytoplasmic domain · position 273 IDR (pLDDT 29 — deep IDR).

Druggability Assessment

Category 5 — IDR Exclusion. pLDDT 29 deep IDR. AlphaMissense 0.15 below threshold. DynaMut2 prediction not trustworthy.

The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity — mechanism likely IDR-mediated.

Why this matters

E273K is another deep-IDR Category 5 variant — Atlas appropriately flags.
Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E273K PDF below and upload it to Wolfram Intelligence to generate therapeutic-strategy proposals — guanidinium mimetics, sigma-1 agonist docking, NAC thiol-capping. NAC is already on the bench-testing list.

Download E273K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin
Region1–321 · Interaction with ATP6V1A