K225E

Category 4 — Stable Fold, Function DisruptedUncertain significanceCytoplasmic · predictedSource card

Lysine → Glutamic acid at position 225 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K225 — hydrogen bond to K221

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DynaMut2 mutant · K225E

Mutant E225 — hydrogen bond to R228 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K221	K221	Preserved
Hydrogen bond	S222	S222	Preserved
Hydrogen bond	R228	—	Lost
Hydrogen bond	M229	M229	Preserved
Polar contact	K221	K221	Preserved
Polar contact	S222	S222	Preserved
Polar contact	L223	L223	Preserved
Polar contact	R227	—	Lost
Polar contact	R228	R228	Preserved
Polar contact	M229	M229	Preserved
Van der Waals	L223	L223	Preserved
Van der Waals	R227	—	Lost
Hydrophobic	—	T376	Gained

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

-0.44kcal/mol

Destabilising — mild

AlphaMissense

0.483

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)Absent from gnomAD v4

cDNA changec.673A>G

ClinVar accessionVCV001352912

Last evaluated2022/09/13 00:00

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

Full Variant Card

WFS1 Wolframin — K225E Variant Card

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

Lysine → Glutamic acid at position 225. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.483, DynaMut2 ΔΔG -0.44 kcal/mol (destabilising).

Identity

Field	Value
Variant	K225E (p.Lysine225Glutamic acid)
DNA change	c.673A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001352912
Amino acid change	Lysine (K) → Glutamic acid (E)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 225	72.00 — well-folded
Domain	N-terminal cytoplasmic (intrinsically disordered)
Position context	N-terminal cytoplasmic (intrinsically disordered)
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 225 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is positively charged (lysine — primary amine); the mutant is negatively charged (glutamate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4831
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.44 (Destabilising)
Job ID	178094716846
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094716846

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/09/13 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	K225E 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|=0.44 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.44 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.483. 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
K225E_molstar_viewer.html — interactive 3D viewer (auto-highlights position 225 with ball-and-stick + neighbors within 5Å)
K225E_variant_card.md — this card (source of truth)
K225E_variant_card.html — styled printable card
K225E_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)
K225E_wildtype_interactions.pse / K225E_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 K225E 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 K225E PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.