M731K

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Methionine → Lysine at position 731 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M731 — hydrogen bond to Y735

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DynaMut2 mutant · M731K

Mutant K731 — hydrogen bond to G728 lost (6 contacts lost)

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Bond changes · DynaMut2 interaction analysis

6 lost1 gained12 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	I727	I727	Preserved
Hydrogen bond	G728	—	Lost
Hydrogen bond	L734	L734	Preserved
Hydrogen bond	Y735	Y735	Preserved
Polar contact	I727	I727	Preserved
Polar contact	G728	G728	Preserved
Polar contact	D729	—	Lost
Polar contact	C733	C733	Preserved
Polar contact	L734	L734	Preserved
Polar contact	Y735	Y735	Preserved
Van der Waals	—	L723	Gained
Van der Waals	D729	—	Lost
Van der Waals	C733	C733	Preserved
Van der Waals	Y735	—	Lost
Hydrophobic	I720	I720	Preserved
Hydrophobic	L723	L723	Preserved
Hydrophobic	I727	I727	Preserved
Hydrophobic	L734	—	Lost
Hydrophobic	Y735	—	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

-0.49kcal/mol

Destabilising — mild

AlphaMissense

0.886

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)Ultra-rare · AF 0.00066%

cDNA changec.2192T>A

ClinVar accessionVCV001404886

Last evaluated2022/10/19 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M731K Variant Card

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

Methionine → Lysine at position 731. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.886, DynaMut2 ΔΔG -0.49 kcal/mol (destabilising).

Identity

Field	Value
Variant	M731K (p.Methionine731Lysine)
DNA change	c.2192T>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001404886
Amino acid change	Methionine (M) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 731	84.56 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 731 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 731 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 hydrophobic sulfur (methionine); 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	0.8859
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.49 (Destabilising)
Job ID	178090202531
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178090202531

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/10/19 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	M731K 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|=0.49 < 2 kcal/mol (fold intact) + AlphaMissense 0.886 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|=0.49 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.886. 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
M731K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 731 with ball-and-stick + neighbors within 5Å)
M731K_variant_card.md — this card (source of truth)
M731K_variant_card.html — styled printable card
M731K_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)
M731K_wildtype_interactions.pse / M731K_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 M731K 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 M731K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.