E864K

Category 3/4 — Most DruggablePathogenic/Likely pathogenicLumenal · predictedσ-1 candidateEditorial

Glutamate → Lysine at position 864 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Charge-flip mutation at the very C-terminal edge of the lumenal domain — glutamate's negative carboxylate replaced by lysine's positive amine, in a region where pLDDT (59) signals borderline confidence and the structural interpretation requires explicit caution.

Interactive 3D Structure

Wild-type reference

Wild-type E864 — ionic bond to R697

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DynaMut2 mutant · E864K

Mutant K864 — ionic bond to R697 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	R697	—	Lost
Ionic bond	K862	—	Lost
Hydrogen bond	R697	—	Lost
Hydrogen bond	K862	K862	Preserved
Hydrogen bond	D866	D866	Preserved
Polar contact	R697	—	Lost
Polar contact	K862	—	Lost
Polar contact	D866	D866	Preserved
Van der Waals	—	D866	Gained
Hydrophobic	K843	—	Lost
Hydrophobic	K862	K862	Preserved

Lost / gained / preserved interatomic contacts at the variant residue, from the DynaMut2 (Arpeggio) interaction analysis of the wild-type and energy-minimized mutant structures.

Computational Predictions

DynaMut2 ΔΔG

-0.26kcal/mol

Destabilising — mild

AlphaMissense

0.842

LPath

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationPathogenic/Likely pathogenic

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Wolfram-like syndrome; Retinal dystrophy; Rare genetic deafness; Nonsyndromic genetic hearing loss

InheritanceAutosomal dominant (deafness 6) and Wolfram-like spectrum forms documented.

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2590G>A

ClinVar accessionVCV000004526

Last evaluated2024/11/08 00:00

Not observed in ~730k individuals — consistent with a rare allele (ACMG PM2_supporting).

Structural Context

E864 has only four neighbors within 5 Angstrom: His865 (2.41 Angstrom), Ile863 (2.43 Angstrom), Asp866 (4.75 Angstrom), and Lys862 (4.80 Angstrom). The minimal contact set is itself diagnostic — at pLDDT 59, AlphaFold is signaling that the local conformation is partially ordered or solvent-exposed rather than packed against a stable core. The neighborhood is locally informative nonetheless: a histidine, a downstream aspartate, and an upstream lysine all sit within the polar shell.

In the wild-type configuration, E864's carboxylate plausibly forms a salt bridge with K862 (4.80 Angstrom is within typical salt-bridge range when sidechain conformations are accounted for), and may hydrogen-bond to His865 depending on the imidazole's protonation state. The downstream Asp866 contributes additional negative charge to the local cluster — two glutamates/aspartates and one lysine, balanced.

E864K flips the charge sign on E864. The K862-E864 salt bridge is destroyed because both residues are now positively charged — they will electrostatically repel rather than attract. The local cluster goes from -E864 ... +K862 ... -D866 (a balanced charge triad) to +K864 ... +K862 ... -D866 (a positive pair next to a negative residue). The geometric consequence is that K862 and K864 likely splay apart, dragging the backbone with them, while D866's carboxylate may rotate to form a new salt bridge with one of the lysines.

DynaMut2's DeltaDeltaG of -0.26 kcal/mol substantially under-reads the disruption — energy functions tend to compensate the electrostatic loss when a new contact forms, even if that contact is geometrically forced. AlphaMissense at 0.842 reads the true severity. The clinical phenotype is broad: retinal dystrophy, autosomal dominant nonsyndromic hearing loss 6, Wolfram-like syndrome — consistent with a C-terminal lumenal disruption affecting the function of the lumenal sensor face.

Amino-acid chemistry

Glutamate (negatively charged carboxylate side chain, ~5 Angstrom long) to Lysine (positively charged primary amine on a long aliphatic side chain, ~6.5 Angstrom long) at position 864. The substitution flips the charge sign in a single mutation — a classical electrostatic-disruption signature.

Position in the protein

Position 864 sits near the C-terminal end of the lumenal domain (residues 653-869), just 5 residues before the lumenal-domain boundary. pLDDT 59.28 is borderline: above the IDR threshold (50) but below high-confidence (70+). The residue is modelable but the precise geometry should be treated with appropriate uncertainty.

Druggability Assessment

Final classification: Category 4 — Stable Fold, Function Disrupted. The DeltaDeltaG magnitude (0.26 kcal/mol) is small, the pLDDT (59) is borderline, and the charge-flip biology is the dominant mechanism. The Atlas should treat E864K as a functional-site disruption variant rather than a misfolding variant: the gross fold survives, but a specific electrostatic signature near the C-terminal edge of the lumenal domain is inverted. For druggability, the borderline pLDDT introduces caveats. Docking against a region with pLDDT 59 requires either local refinement or experimental structure determination — the AlphaFold model is acceptable for hypothesis generation but should not be the sole basis for compound design. The therapeutic frame is still pharmacological chaperone or charge-mimicking small molecule, but the model uncertainty argues for parallel wet-lab validation of the K862-E864-D866 cluster's structural arrangement.

Why this matters

E864K is a useful Atlas example of how the schema must handle borderline pLDDT honestly. A naive interpretation would push this variant into the Cat 5 IDR-exclusion bucket; the structural signal (a clear charge-flip near an annotated salt-bridge candidate) and the AlphaMissense score (0.842) argue against exclusion. The right answer is Category 4 with an explicit modeling caveat — not a default discard. Clinically, the autosomal dominant deafness 6 phenotype at this variant is notable. AD-DFNA6 carries a distinct disease trajectory from classical autosomal recessive Wolfram syndrome, and E864K is one of the lumenal-domain variants where the dominant inheritance pattern is best documented. This makes E864K a clinical reference variant for the dominantly-inherited Wolfram-spectrum hearing loss form.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the E864K 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 E864K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal

Natural variant864–864 · in WFSL; dbSNP:rs74315205