K596Q

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

Lysine → Glutamine at position 596 · Cytoplasmic loop 5 / pre-lumenal · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K596 — hydrogen bond to T600

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DynaMut2 mutant · K596Q

Mutant Q596 — hydrophobic contact to L592 lost

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Bond changes · DynaMut2 interaction analysis

0 lost2 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E593	E593	Preserved
Hydrogen bond	T600	T600	Preserved
Polar contact	E593	E593	Preserved
Polar contact	V599	V599	Preserved
Polar contact	T600	T600	Preserved
Van der Waals	—	A598	Gained
Van der Waals	—	T600	Gained
Hydrophobic	L592	L592	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

-0.11kcal/mol

Destabilising — mild

AlphaMissense

0.381

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.0025%

cDNA changec.1786A>C

ClinVar accessionVCV002976544

Last evaluated2025/09/04 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K596Q Variant Card

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

Lysine → Glutamine at position 596. Cytoplasmic loop 5 / pre-lumenal. ClinVar Uncertain significance, AlphaMissense 0.381, DynaMut2 ΔΔG -0.11 kcal/mol (destabilising).

Identity

Field	Value
Variant	K596Q (p.Lysine596Glutamine)
DNA change	c.1786A>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002976544
Amino acid change	Lysine (K) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 596	62.06 — confident
Domain	Cytoplasmic loop 5 / pre-lumenal
Position context	C-terminal lumenal domain · position 596 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 596 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is positively charged (lysine — primary amine); the mutant is polar amide (glutamine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3810
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.11 (Destabilising)
Job ID	178094713449
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094713449

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/09/04 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	K596Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

(no conditions catalogued)

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|=0.11 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.11 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.381. 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
K596Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 596 with ball-and-stick + neighbors within 5Å)
K596Q_variant_card.md — this card (source of truth)
K596Q_variant_card.html — styled printable card
K596Q_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)
K596Q_wildtype_interactions.pse / K596Q_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 K596Q 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 K596Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.