K596M

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Lysine → Methionine 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 · K596M

Mutant M596 — 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	—	E593	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

0.18kcal/mol

Stabilising — mild

AlphaMissense

0.728

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 conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1787A>T

ClinVar accessionVCV001695463

Last evaluated2022/01/11 00:00

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

Full Variant Card

WFS1 Wolframin — K596M Variant Card

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

Lysine → Methionine at position 596. Cytoplasmic loop 5 / pre-lumenal. ClinVar Uncertain significance, AlphaMissense 0.728, DynaMut2 ΔΔG +0.18 kcal/mol (stabilising).

Identity

Field	Value
Variant	K596M (p.Lysine596Methionine)
DNA change	c.1787A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001695463
Amino acid change	Lysine (K) → Methionine (M)

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 hydrophobic sulfur (methionine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.7284
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.18 (Stabilising)
Job ID	178092122932
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092122932

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/01/11 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	K596M 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.18 < 2 kcal/mol (fold intact) + AlphaMissense 0.728 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|=0.18 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.728. 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
K596M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 596 with ball-and-stick + neighbors within 5Å)
K596M_variant_card.md — this card (source of truth)
K596M_variant_card.html — styled printable card
K596M_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)
K596M_wildtype_interactions.pse / K596M_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 K596M 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 K596M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.