E120K

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Glutamic acid → Lysine at position 120 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E120 — hydrogen bond to C124

Fullscreen ↗

DynaMut2 mutant · E120K

Mutant K120 — polar contact contact to S123 lost

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

1 lost1 gained4 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	C124	C124	Preserved
Polar contact	D118	D118	Preserved
Polar contact	S123	—	Lost
Polar contact	C124	C124	Preserved
Van der Waals	D118	D118	Preserved
Van der Waals	—	C124	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

0.53kcal/mol

Stabilising — mild

AlphaMissense

0.712

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.358G>A

ClinVar accessionVCV001328624

Last evaluated2021/06/16 00:00

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

Full Variant Card

WFS1 Wolframin — E120K Variant Card

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

Glutamic acid → Lysine at position 120. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.712, DynaMut2 ΔΔG +0.53 kcal/mol (stabilising).

Identity

Field	Value
Variant	E120K (p.Glutamic acid120Lysine)
DNA change	c.358G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001328624
Amino acid change	Glutamic acid (E) → Lysine (K)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 120	84.81 — 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 120 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	0.7119
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.53 (Stabilising)
Job ID	178092125092
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092125092

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2021/06/16 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E120K 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|=0.53 < 2 kcal/mol (fold intact) + AlphaMissense 0.712 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|=0.53 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.712. 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
E120K_molstar_viewer.html — interactive 3D viewer (auto-highlights position 120 with ball-and-stick + neighbors within 5Å)
E120K_variant_card.md — this card (source of truth)
E120K_variant_card.html — styled printable card
E120K_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)
E120K_wildtype_interactions.pse / E120K_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 E120K 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 E120K PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.