E385Q

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

Glutamic acid → Glutamine at position 385 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type E385 — ionic bond to K178

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DynaMut2 mutant · E385Q

Mutant Q385 — ionic bond to K178 lost (4 contacts lost)

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Bond changes · DynaMut2 interaction analysis

4 lost2 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Ionic bond	K178	—	Lost
Hydrogen bond	K178	—	Lost
Hydrogen bond	L381	L381	Preserved
Hydrogen bond	L382	L382	Preserved
Hydrogen bond	L388	L388	Preserved
Polar contact	K178	—	Lost
Polar contact	L381	L381	Preserved
Polar contact	N387	N387	Preserved
Polar contact	L388	L388	Preserved
Carbonyl	L382	L382	Preserved
Van der Waals	—	A175	Gained
Van der Waals	K178	K178	Preserved
Hydrophobic	A175	—	Lost
Hydrophobic	A179	A179	Preserved
Hydrophobic	—	N387	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

-0.70kcal/mol

Destabilising — mild

AlphaMissense

0.517

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 conditionsWolfram syndrome 1; Cataract 41; Wolfram-like syndrome; Autosomal dominant nonsyndromic hearing loss 6; Type 2 diabetes mellitus

Population frequency (gnomAD v4)Ultra-rare · AF 0.00027%

cDNA changec.1153G>C

ClinVar accessionVCV002080981

Last evaluated2024/05/21 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — E385Q Variant Card

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

Glutamic acid → Glutamine at position 385. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.517, DynaMut2 ΔΔG -0.70 kcal/mol (destabilising).

Identity

Field	Value
Variant	E385Q (p.Glutamic acid385Glutamine)
DNA change	c.1153G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002080981
Amino acid change	Glutamic acid (E) → Glutamine (Q)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 385	85.44 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 385 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 385 sits in a transmembrane helix (Transmembrane helix 3). Wolframin has eleven such helices anchoring it in the ER membrane; substitutions inside the bilayer-embedded segments can disrupt helix packing, lipid contacts, and the overall ER topology of the protein. The wild-type residue is negatively charged (glutamate — carboxylate); the mutant is polar amide (glutamine — H-bond donor/acceptor). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5167
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.7 (Destabilising)
Job ID	178094709949
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094709949

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, multiple submitters, no conflicts
Last evaluated	2024/05/21 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	E385Q is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1
Cataract 41
Wolfram-like syndrome
Autosomal dominant nonsyndromic hearing loss 6
Type 2 diabetes mellitus

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|=0.70 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.70 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.517. 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
E385Q_molstar_viewer.html — interactive 3D viewer (auto-highlights position 385 with ball-and-stick + neighbors within 5Å)
E385Q_variant_card.md — this card (source of truth)
E385Q_variant_card.html — styled printable card
E385Q_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)
E385Q_wildtype_interactions.pse / E385Q_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 E385Q 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 E385Q PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.