E231K

Category 3/4 — Most DruggableLikely benignCytoplasmic · predictedSource card

Glutamic acid → Lysine at position 231 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E231 — ionic bond to R227

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DynaMut2 mutant · E231K

Mutant K231 — ionic bond to R227 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained6 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	R227	—	Lost
Hydrogen bond	R227	R227	Preserved
Hydrogen bond	R228	R228	Preserved
Hydrogen bond	S235	S235	Preserved
Polar contact	R227	R227	Preserved
Polar contact	—	M229	Gained
Polar contact	L233	—	Lost
Polar contact	V234	—	Lost
Polar contact	S235	S235	Preserved
Van der Waals	R227	—	Lost
Van der Waals	—	M229	Gained
Hydrophobic	L201	L201	Preserved
Hydrophobic	R227	—	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

-0.78kcal/mol

Destabilising — mild

AlphaMissense

0.703

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 3/4

Category 3/4 — Most Druggable

Clinical Evidence

ClinVar classificationLikely benign

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.691G>A

ClinVar accessionVCV001078282

Last evaluated2024/10/26 00:00

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

Full Variant Card

WFS1 Wolframin — E231K Variant Card

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

Glutamic acid → Lysine at position 231. N-terminal cytoplasmic (intrinsically disordered). ClinVar Likely benign, AlphaMissense 0.703, DynaMut2 ΔΔG -0.78 kcal/mol (destabilising).

Identity

Field	Value
Variant	E231K (p.Glutamic acid231Lysine)
DNA change	c.691G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001078282
Amino acid change	Glutamic acid (E) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 231	75.94 — 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 231 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	0.7027
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.78 (Destabilising)
Job ID	178094554964
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094554964

Clinical Evidence

Field	Value
Classification	Likely benign
Review status	criteria provided, single submitter
Last evaluated	2024/10/26 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E231K 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|=0.78 < 2 kcal/mol (fold intact) + AlphaMissense 0.703 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|=0.78 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.703. 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
E231K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 231 with ball-and-stick + neighbors within 5Å)
E231K_variant_card.md — this card (source of truth)
E231K_variant_card.html — styled printable card
E231K_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)
E231K_wildtype_interactions.pse / E231K_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 E231K 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 E231K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.