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E273A
Category 5 — IDR ExclusionConflictingCytoplasmic · predictedEditorialGlutamate → Alanine at position 273 · N-terminal cytoplasmic domain (87-313) · WFS1 (Wolframin)
Glutamate → Alanine at position 273 in N-terminal cytoplasmic domain. ClinVar Conflicting with broad spectrum — Cataract 41, DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG +0.22. pLDDT 29 — Category 5 IDR! Same position as E273K.
Interactive 3D Structure
Wild-type reference
Wild-type E273 — native residue, no strong sidechain contacts
DynaMut2 mutant · E273A
Mutant A273 — energy-minimized; local contact network preserved
Computational Predictions
DynaMut2 ΔΔG
0.22kcal/mol
Stabilising — mild
AlphaMissense
0.123
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)
InheritanceAD multi-phenotype.
Population frequency (gnomAD v4)Ultra-rare · AF 0.0029%
cDNA changec.818A>C
ClinVar accessionVCV001614420
Last evaluated2025/09/22 00:00
Observed at very low frequency in gnomAD.
Structural Context
Position 273 same as E273K — DEEP IDR (pLDDT 29). DynaMut2 untrustworthy here.
E273A is the second substitution at 273 (with E273K). Both deep-IDR Category 5. AM 0.12 under-call; multi-phenotype confirms clinical pathogenicity.
Amino-acid chemistry
Glutamate (E) → Alanine (A) — charge lost + side chain reduced.
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 0.12 below threshold. DynaMut2 prediction not trustworthy.
The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.
The Atlas routes Category 5 variants to wet-lab characterization. Multi-phenotype confirms clinical pathogenicity.
Why this matters
E273A + E273K at same IDR position — both Cat 5, both flagged for wet-lab.
Therapeutic Strategy Handoff · prediction
Feed this card to Wolfram Intelligence
Download the E273A 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 E273A PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.
UniProt Domain Annotation
Chain1–890 · Wolframin
Region1–321 · Interaction with ATP6V1A