E140K

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

Glutamic acid → Lysine at position 140 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E140 — ionic bond to K143

Fullscreen ↗

DynaMut2 mutant · E140K

Mutant K140 — ionic bond to K143 lost (3 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

3 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K143	—	Lost
Hydrogen bond	K143	K143	Preserved
Hydrogen bond	L144	L144	Preserved
Polar contact	R138	R138	Preserved
Polar contact	V142	—	Lost
Polar contact	K143	K143	Preserved
Polar contact	L144	L144	Preserved
Van der Waals	V142	—	Lost
Van der Waals	L144	L144	Preserved
Hydrophobic	T104	T104	Preserved
Hydrophobic	—	R138	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

-0.57kcal/mol

Destabilising — mild

AlphaMissense

0.444

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 conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.0016%

cDNA changec.418G>A

ClinVar accessionVCV001299985

Last evaluated2024/10/07 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — E140K Variant Card

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

Glutamic acid → Lysine at position 140. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.444, DynaMut2 ΔΔG -0.57 kcal/mol (destabilising).

Identity

Field	Value
Variant	E140K (p.Glutamic acid140Lysine)
DNA change	c.418G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001299985
Amino acid change	Glutamic acid (E) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 140	91.25 — 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 140 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is negatively charged (glutamate — carboxylate); the mutant is positively charged (lysine — primary amine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.4443
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.57 (Destabilising)
Job ID	178094715044
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094715044

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/10/07 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E140K 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|=0.57 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.57 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.444. 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
E140K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 140 with ball-and-stick + neighbors within 5Å)
E140K_variant_card.md — this card (source of truth)
E140K_variant_card.html — styled printable card
E140K_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)
E140K_wildtype_interactions.pse / E140K_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 E140K 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 E140K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.