N500K

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Asparagine → Lysine at position 500 · Transmembrane helix 7 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type N500 — hydrogen bond to S888

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DynaMut2 mutant · N500K

Mutant K500 — hydrogen bond to P885 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost3 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I489	I489	Preserved
Hydrogen bond	T490	—	Lost
Hydrogen bond	P885	—	Lost
Hydrogen bond	F886	F886	Preserved
Hydrogen bond	S888	S888	Preserved
Polar contact	T490	—	Lost
Polar contact	V498	—	Lost
Polar contact	C505	C505	Preserved
Polar contact	F886	F886	Preserved
Polar contact	S888	—	Lost
Van der Waals	T490	—	Lost
Van der Waals	—	C505	Gained
Hydrophobic	T487	T487	Preserved
Hydrophobic	—	T490	Gained
Hydrophobic	—	V498	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

-0.15kcal/mol

Destabilising — mild

AlphaMissense

0.435

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditionsAutosomal dominant nonsyndromic hearing loss 6; Cataract 41; Wolfram syndrome 1; Wolfram-like syndrome; Type 2 diabetes mellitus

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1500C>G

ClinVar accessionVCV003590696

Last evaluated2024/01/07 00:00

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

Full Variant Card

WFS1 Wolframin — N500K Variant Card

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

Asparagine → Lysine at position 500. Transmembrane helix 7. ClinVar Uncertain significance, AlphaMissense 0.435, DynaMut2 ΔΔG -0.15 kcal/mol (destabilising).

Identity

Field	Value
Variant	N500K (p.Asparagine500Lysine)
DNA change	c.1500C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003590696
Amino acid change	Asparagine (N) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 500	79.12 — well-folded
Domain	Transmembrane helix 7
Position context	Inside Transmembrane helix 7 · position 500 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 500 sits in a transmembrane helix (Transmembrane helix 7). 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 positively charged (lysine — primary amine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4348
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.15 (Destabilising)
Job ID	178094710198
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094710198

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/01/07 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	N500K is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Autosomal dominant nonsyndromic hearing loss 6
Cataract 41
Wolfram syndrome 1
Wolfram-like syndrome
Type 2 diabetes mellitus

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.15 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.15 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.435. 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
N500K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 500 with ball-and-stick + neighbors within 5Å)
N500K_variant_card.md — this card (source of truth)
N500K_variant_card.html — styled printable card
N500K_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)
N500K_wildtype_interactions.pse / N500K_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 N500K 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 N500K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.