D729N

Category 4 — Stable Fold, Function DisruptedConflictingLumenal · predictedσ-1 candidateEditorial

Aspartate → Asparagine at position 729 · C-terminal lumenal domain (653-869) · WFS1 (Wolframin)

Aspartate → Asparagine at position 729 in lumenal domain. ClinVar Conflicting including Cataract 41 + DFNA6. AlphaMissense 0.12 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.86.

Interactive 3D Structure

Wild-type reference

Wild-type D729 — ionic bond to R732

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DynaMut2 mutant · D729N

Mutant N729 — ionic bond to H763 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	R732	—	Lost
Ionic bond	H763	—	Lost
Hydrogen bond	F725	F725	Preserved
Hydrogen bond	R732	R732	Preserved
Hydrogen bond	C733	C733	Preserved
Hydrogen bond	H763	H763	Preserved
Polar contact	F725	F725	Preserved
Polar contact	—	I727	Gained
Polar contact	M731	—	Lost
Polar contact	R732	R732	Preserved
Polar contact	C733	C733	Preserved
Polar contact	H763	H763	Preserved
Van der Waals	M731	—	Lost
Van der Waals	—	C733	Gained

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

-0.86kcal/mol

Destabilising — mild

AlphaMissense

0.122

LBen

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationConflicting classifications of pathogenicity

Review statuscriteria provided, conflicting classifications

Associated conditionsCataract 41; Autosomal dominant nonsyndromic hearing loss 6 (DFNA6)

InheritanceAD: Cataract + DFNA6.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0076%

cDNA changec.2185G>A

ClinVar accessionVCV000212613

Last evaluated2026/01/05 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 729 in lumenal domain. Neighbors: TRP730 (2.5 Å), GLY728 (2.5 Å), PHE725 (3.8 Å). Near the L723P/P724S/P724L cluster.

D729N charge loss adjacent to L723-P724 loop variant cluster. |ΔΔG| 0.86; AM 0.12 under-call; multi-phenotype confirms.

Amino-acid chemistry

Aspartate (D) → Asparagine (N) — charge loss; H-bonding preserved.

Position in the protein

C-terminal lumenal domain · position 729 (pLDDT 87).

Druggability Assessment

Category 3/4 — Most Druggable (AM under-call). |ΔΔG| 0.86. AlphaMissense 0.12 below threshold but multi-phenotype confirms.

Mechanism: charge loss near L723-P724 loop region. Therapeutic: site-directed at the 725-734 lumenal microregion.

Why this matters

D729N continues charge-loss class — adjacent to L723-P724 cluster region.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D729N 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 D729N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin

Topological domain653–869 · Lumenal