K143E

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

Lysine → Glutamic acid at position 143 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type K143 — ionic bond to E140

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DynaMut2 mutant · K143E

Mutant E143 — ionic bond contact to E140 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained10 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	—	R139	Gained
Ionic bond	E140	—	Lost
Hydrogen bond	R139	R139	Preserved
Hydrogen bond	E140	E140	Preserved
Hydrogen bond	R146	R146	Preserved
Hydrogen bond	R147	R147	Preserved
Polar contact	R139	R139	Preserved
Polar contact	E140	E140	Preserved
Polar contact	A141	A141	Preserved
Polar contact	R146	R146	Preserved
Polar contact	R147	R147	Preserved
Van der Waals	R139	R139	Preserved
Van der Waals	—	A141	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

-0.34kcal/mol

Destabilising — mild

AlphaMissense

0.488

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.427A>G

ClinVar accessionVCV002830614

Last evaluated2023/01/20 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — K143E Variant Card

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

Lysine → Glutamic acid at position 143. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.488, DynaMut2 ΔΔG -0.34 kcal/mol (destabilising).

Identity

Field	Value
Variant	K143E (p.Lysine143Glutamic acid)
DNA change	c.427A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002830614
Amino acid change	Lysine (K) → Glutamic acid (E)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 143	92.56 — 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 143 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	0.4876
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.34 (Destabilising)
Job ID	178094706411
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094706411

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/01/20 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	K143E 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|=0.34 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.34 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.488. 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
K143E_molstar_viewer.html — interactive 3D viewer (auto-highlights position 143 with ball-and-stick + neighbors within 5Å)
K143E_variant_card.md — this card (source of truth)
K143E_variant_card.html — styled printable card
K143E_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)
K143E_wildtype_interactions.pse / K143E_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 K143E 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 K143E PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.