M722I

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Methionine → Isoleucine at position 722 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type M722 — hydrogen bond to S718

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DynaMut2 mutant · M722I

Mutant I722 — hydrogen bond contact to S718 lost

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Bond changes · DynaMut2 interaction analysis

0 lost0 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	S718	S718	Preserved
Hydrogen bond	A719	A719	Preserved
Polar contact	A719	A719	Preserved
Polar contact	I720	I720	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

0.22kcal/mol

Stabilising — mild

AlphaMissense

0.415

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

Population frequency (gnomAD v4)Ultra-rare · AF 0.00027%

cDNA changec.2166G>A

ClinVar accessionVCV001320496

Last evaluated2024/12/02 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — M722I Variant Card

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

Methionine → Isoleucine at position 722. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.415, DynaMut2 ΔΔG +0.22 kcal/mol (stabilising).

Identity

Field	Value
Variant	M722I (p.Methionine722Isoleucine)
DNA change	c.2166G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001320496
Amino acid change	Methionine (M) → Isoleucine (I)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 722	85.19 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 722 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 722 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	0.4149
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.22 (Stabilising)
Job ID	178094705422
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094705422

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/12/02 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	M722I is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

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

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|=0.22 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.22 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.415. 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
M722I_molstar_viewer.html — interactive 3D viewer (auto-highlights position 722 with ball-and-stick + neighbors within 5Å)
M722I_variant_card.md — this card (source of truth)
M722I_variant_card.html — styled printable card
M722I_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)
M722I_wildtype_interactions.pse / M722I_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 M722I 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 M722I PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.