E249K

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Glutamic acid → Lysine at position 249 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E249 — ionic bond to K252

Fullscreen ↗

DynaMut2 mutant · E249K

Mutant K249 — ionic bond to K252 lost (2 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

2 lost0 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K252	—	Lost
Hydrogen bond	D245	D245	Preserved
Hydrogen bond	D246	D246	Preserved
Hydrogen bond	K252	K252	Preserved
Hydrogen bond	K253	K253	Preserved
Polar contact	D245	D245	Preserved
Polar contact	D246	D246	Preserved
Polar contact	K252	K252	Preserved
Polar contact	K253	K253	Preserved
Hydrophobic	K253	—	Lost

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

-0.64kcal/mol

Destabilising — mild

AlphaMissense

0.596

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.745G>A

ClinVar accessionVCV002866513

Last evaluated2025/03/17 00:00

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

Full Variant Card

WFS1 Wolframin — E249K Variant Card

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

Glutamic acid → Lysine at position 249. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.596, DynaMut2 ΔΔG -0.64 kcal/mol (destabilising).

Identity

Field	Value
Variant	E249K (p.Glutamic acid249Lysine)
DNA change	c.745G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002866513
Amino acid change	Glutamic acid (E) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 249	86.06 — 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 249 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	0.5960
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.64 (Destabilising)
Job ID	178092133384
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092133384

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/03/17 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E249K 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 3/4 — Most Druggable

<strong>Category 3/4 — Most Druggable</strong><br/><br/>|ΔΔG|=0.64 < 2 kcal/mol (fold intact) + AlphaMissense 0.596 confirms functional impact. Specific local contacts disrupted — priority for docking and pharmacological chaperone screening.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.64 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.596. 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
E249K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 249 with ball-and-stick + neighbors within 5Å)
E249K_variant_card.md — this card (source of truth)
E249K_variant_card.html — styled printable card
E249K_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)
E249K_wildtype_interactions.pse / E249K_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 E249K 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 E249K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.