D339N

Category 4 — Stable Fold, Function DisruptedConflictingTransmembrane · predictedEditorial

Aspartate → Asparagine at position 339 · Connecting loop · WFS1 (Wolframin)

Aspartate → Asparagine at position 339 in connecting loop. ClinVar Conflicting including Wolfram. AlphaMissense 0.14 (below threshold) — AM under-call. DynaMut2 ΔΔG -0.04 (neutral).

Interactive 3D Structure

Wild-type reference

Wild-type D339 — ionic bond to H865

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DynaMut2 mutant · D339N

Mutant N339 — ionic bond to H865 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost1 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	H865	—	Lost
Hydrogen bond	—	T337	Gained
Hydrogen bond	A342	A342	Preserved
Hydrogen bond	F343	F343	Preserved
Polar contact	T337	T337	Preserved
Polar contact	A342	A342	Preserved
Polar contact	F343	F343	Preserved
Polar contact	H865	—	Lost
Van der Waals	F343	—	Lost

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

-0.04kcal/mol

Destabilising — mild

AlphaMissense

0.139

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 conditionsWolfram syndrome 1

InheritanceWolfram syndrome 1.

Population frequency (gnomAD v4)Ultra-rare · AF 0.0012%

cDNA changec.1015G>A

ClinVar accessionVCV000215354

Last evaluated2025/05/14 00:00

Observed at very low frequency in gnomAD.

Structural Context

Position 339 in connecting loop. Neighbors: ILE338 (2.5 Å), PHE340 (2.5 Å — TM2 start), ALA342 (3.8 Å — A342T position).

D339N at boundary with TM2. The T337I-I338-D339-F340 region — adjacent to T337I Atlas card. AM 0.14 under-call; Wolfram confirms.

Amino-acid chemistry

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

Position in the protein

Connecting loop · position 339 (pLDDT 67).

Druggability Assessment

Category 4 — Stable Fold, Function Disrupted (AM under-call). ΔΔG ≈ 0. AlphaMissense 0.14 below threshold but Wolfram 1 confirms.

Mechanism: charge loss in 337-339 loop microregion. Therapeutic: same loop as T337I.

Why this matters

D339N + T337I in same loop region — A342T just downstream — multi-variant cluster.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the D339N 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 D339N PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.

UniProt Domain Annotation

Chain1–890 · Wolframin