M781I

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

Methionine → Isoleucine at position 781 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M781 — hydrogen bond to I802

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DynaMut2 mutant · M781I

Mutant I781 — hydrogen bond to I802 lost (8 contacts lost)

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Bond changes · DynaMut2 interaction analysis

8 lost3 gained2 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	—	K800	Gained
Hydrogen bond	I802	—	Lost
Polar contact	T701	—	Lost
Polar contact	F783	—	Lost
Polar contact	—	K800	Gained
Van der Waals	W666	—	Lost
Van der Waals	I802	—	Lost
Hydrophobic	W666	W666	Preserved
Hydrophobic	W700	—	Lost
Hydrophobic	V779	—	Lost
Hydrophobic	—	K800	Gained
Hydrophobic	I802	I802	Preserved
Hydrophobic	F825	—	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

-0.72kcal/mol

Destabilising — mild

AlphaMissense

0.660

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, multiple submitters, no conflicts

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00012%

cDNA changec.2343G>A

ClinVar accessionVCV001678045

Last evaluated2025/10/26 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M781I Variant Card

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

Methionine → Isoleucine at position 781. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.660, DynaMut2 ΔΔG -0.72 kcal/mol (destabilising).

Identity

Field	Value
Variant	M781I (p.Methionine781Isoleucine)
DNA change	c.2343G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001678045
Amino acid change	Methionine (M) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 781	84.12 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 781 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 781 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 medium hydrophobic (isoleucine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.6605
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.72 (Destabilising)
Job ID	178092128367
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092128367

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2025/10/26 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	M781I 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|=0.72 < 2 kcal/mol (fold intact) + AlphaMissense 0.660 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|=0.72 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.660. 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
M781I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 781 with ball-and-stick + neighbors within 5Å)
M781I_variant_card.md — this card (source of truth)
M781I_variant_card.html — styled printable card
M781I_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)
M781I_wildtype_interactions.pse / M781I_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 M781I 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 M781I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.