E199G

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Glutamic acid → Glycine at position 199 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E199 — ionic bond to K190

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DynaMut2 mutant · E199G

Mutant G199 — ionic bond to K192 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost1 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K190	—	Lost
Ionic bond	K192	—	Lost
Hydrogen bond	K190	—	Lost
Hydrogen bond	K192	—	Lost
Hydrogen bond	A196	A196	Preserved
Hydrogen bond	—	E202	Gained
Hydrogen bond	N203	N203	Preserved
Polar contact	K190	—	Lost
Polar contact	K192	—	Lost
Polar contact	A196	A196	Preserved
Polar contact	V197	V197	Preserved
Polar contact	E202	E202	Preserved
Polar contact	N203	N203	Preserved
Van der Waals	L201	L201	Preserved
Van der Waals	N203	—	Lost
Hydrophobic	V195	—	Lost
Hydrophobic	A196	—	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

-1.18kcal/mol

Destabilising — moderate

AlphaMissense

0.811

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 conditionsWFS1-related disorder

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.596A>G

ClinVar accessionVCV002631626

Last evaluated2023/07/18 00:00

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

Full Variant Card

WFS1 Wolframin — E199G Variant Card

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

Glutamic acid → Glycine at position 199. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.811, DynaMut2 ΔΔG -1.18 kcal/mol (destabilising).

Identity

Field	Value
Variant	E199G (p.Glutamic acid199Glycine)
DNA change	c.596A>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002631626
Amino acid change	Glutamic acid (E) → Glycine (G)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 199	80.75 — 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 199 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is negatively charged (glutamate — carboxylate); the mutant is small/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8115
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.18 (Destabilising)
Job ID	178092115425
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092115425

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/07/18 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	E199G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-related disorder

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|=1.18 < 2 kcal/mol (fold intact) + AlphaMissense 0.811 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|=1.18 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.811. 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
E199G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 199 with ball-and-stick + neighbors within 5Å)
E199G_variant_card.md — this card (source of truth)
E199G_variant_card.html — styled printable card
E199G_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)
E199G_wildtype_interactions.pse / E199G_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 E199G 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 E199G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.