K758M

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

Lysine → Methionine at position 758 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K758 — hydrogen bond to Y739

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DynaMut2 mutant · K758M

Mutant M758 — hydrogen bond contact to Y739 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained11 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y739	—	Lost
Hydrogen bond	L754	L754	Preserved
Hydrogen bond	C755	C755	Preserved
Hydrogen bond	—	A761	Gained
Hydrogen bond	K762	K762	Preserved
Polar contact	L754	L754	Preserved
Polar contact	C755	C755	Preserved
Polar contact	R756	R756	Preserved
Polar contact	L760	L760	Preserved
Polar contact	A761	A761	Preserved
Van der Waals	C755	C755	Preserved
Van der Waals	R756	R756	Preserved
Van der Waals	—	L760	Gained
Hydrophobic	Y739	Y739	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

0.10kcal/mol

Stabilising — mild

AlphaMissense

0.407

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.00014%

cDNA changec.2273A>T

ClinVar accessionVCV003003479

Last evaluated2024/03/07 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K758M Variant Card

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

Lysine → Methionine at position 758. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.407, DynaMut2 ΔΔG +0.10 kcal/mol (stabilising).

Identity

Field	Value
Variant	K758M (p.Lysine758Methionine)
DNA change	c.2273A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003003479
Amino acid change	Lysine (K) → Methionine (M)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 758	82.88 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 758 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 758 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	0.4075
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.1 (Stabilising)
Job ID	178094716053
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094716053

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/03/07 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	K758M 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|=0.10 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.10 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.407. 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
K758M_molstar_viewer.html — interactive 3D viewer (auto-highlights position 758 with ball-and-stick + neighbors within 5Å)
K758M_variant_card.md — this card (source of truth)
K758M_variant_card.html — styled printable card
K758M_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)
K758M_wildtype_interactions.pse / K758M_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 K758M 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 K758M PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.