N325D

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Asparagine → Aspartic acid at position 325 · Transmembrane helix 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type N325 — hydrogen bond to F329

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DynaMut2 mutant · N325D

Mutant D325 — polar contact contact to T321 lost

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Bond changes · DynaMut2 interaction analysis

0 lost3 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	T321	T321	Preserved
Hydrogen bond	—	I328	Gained
Hydrogen bond	F329	F329	Preserved
Polar contact	T321	T321	Preserved
Polar contact	F329	F329	Preserved
Van der Waals	—	T321	Gained
Van der Waals	—	F329	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

0.05kcal/mol

Stabilising — mild

AlphaMissense

0.611

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditionsWFS1-related disorder

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.973A>G

ClinVar accessionVCV002635787

Last evaluated2023/04/10 00:00

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

Full Variant Card

WFS1 Wolframin — N325D Variant Card

Molecular Atlas Pilot · RareResearch.AI · Generated by wolfram-variant-card skill

Asparagine → Aspartic acid at position 325. Transmembrane helix 1. ClinVar Uncertain significance, AlphaMissense 0.611, DynaMut2 ΔΔG +0.05 kcal/mol (stabilising).

Identity

Field	Value
Variant	N325D (p.Asparagine325Aspartic acid)
DNA change	c.973A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002635787
Amino acid change	Asparagine (N) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 325	75.75 — well-folded
Domain	Transmembrane helix 1
Position context	Inside Transmembrane helix 1 · position 325 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 325 sits in a transmembrane helix (Transmembrane helix 1). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is polar amide (asparagine — H-bond donor/acceptor); the mutant is negatively charged (aspartate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6109
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.05 (Stabilising)
Job ID	178092131193
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092131193

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/04/10 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	N325D is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-related disorder

Research Path Decision Tree

ΔΔG < 2  + binding site affected   →  CATEGORY 3 — docking experiments
ΔΔG 2–4                            →  CATEGORY 2 — pharmacological chaperones
ΔΔG > 4                            →  CATEGORY 1 — gene therapy
pLDDT < 50                         →  CATEGORY 5 — IDR, experimental only
Stable fold + functional site hit  →  CATEGORY 4 — site-specific docking

Final Schema Categorization

Category 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.05 < 2 kcal/mol (fold intact) + AlphaMissense 0.611 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.05 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.611. Protein still folds, but a specific local site is broken. Pharmacological chaperones and small-molecule binders are the rational therapeutic vector.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
N325D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 325 with ball-and-stick + neighbors within 5Å)
N325D_variant_card.md — this card (source of truth)
N325D_variant_card.html — styled printable card
N325D_dynamut2_summary.html — clean offline DynaMut2 result card
dynamut2_result.json — structured result data
dynamut2_result_page.html — local snapshot of the Biosig result page (asset URLs absolutized)
N325D_wildtype_interactions.pse / N325D_mutant_interactions.pse — PyMOL sessions

Generated by wolfram-variant-card skill · RareResearch.AI Molecular Atlas Every assumption documented. Every score sourced.

Therapeutic Strategy Handoff · prediction

Feed this card to Wolfram Intelligence

Download the N325D 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 N325D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.