D389H

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Aspartic acid → Histidine at position 389 · Transmembrane helix 3 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type D389 — hydrogen bond to E391

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DynaMut2 mutant · D389H

Mutant H389 — hydrogen bond to Q392 lost (5 contacts lost)

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Bond changes · DynaMut2 interaction analysis

5 lost2 gained5 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L172	L172	Preserved
Hydrogen bond	E391	—	Lost
Hydrogen bond	Q392	—	Lost
Hydrogen bond	A393	A393	Preserved
Polar contact	—	L172	Gained
Polar contact	N387	N387	Preserved
Polar contact	E391	—	Lost
Polar contact	Q392	—	Lost
Polar contact	A393	A393	Preserved
Van der Waals	—	E391	Gained
Van der Waals	Q392	—	Lost
Hydrophobic	Q392	Q392	Preserved

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

0.62kcal/mol

Stabilising — mild

AlphaMissense

0.826

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 conditionsWolfram-like syndrome

Population frequency (gnomAD v4)Ultra-rare · AF 0.00066%

cDNA changec.1165G>C

ClinVar accessionVCV001333946

Last evaluated2019/01/28 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — D389H Variant Card

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

Aspartic acid → Histidine at position 389. Transmembrane helix 3. ClinVar Uncertain significance, AlphaMissense 0.826, DynaMut2 ΔΔG +0.62 kcal/mol (stabilising).

Identity

Field	Value
Variant	D389H (p.Aspartic acid389Histidine)
DNA change	c.1165G>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001333946
Amino acid change	Aspartic acid (D) → Histidine (H)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 389	82.50 — well-folded
Domain	Transmembrane helix 3
Position context	Inside Transmembrane helix 3 · position 389 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 389 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 (aspartate — carboxylate); the mutant is titratable basic (histidine — imidazole). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8264
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.62 (Stabilising)
Job ID	178092113604
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092113604

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2019/01/28 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	D389H is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram-like syndrome

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|=0.62 < 2 kcal/mol (fold intact) + AlphaMissense 0.826 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|=0.62 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.826. 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
D389H_molstar_viewer.html — interactive 3D viewer (auto-highlights position 389 with ball-and-stick + neighbors within 5Å)
D389H_variant_card.md — this card (source of truth)
D389H_variant_card.html — styled printable card
D389H_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)
D389H_wildtype_interactions.pse / D389H_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 D389H 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 D389H PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.