G581D

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Glycine → Aspartic acid at position 581 · Transmembrane helix 9 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type G581 — hydrogen bond to F585

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DynaMut2 mutant · G581D

Mutant D581 — polar contact contact to L577 lost

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Bond changes · DynaMut2 interaction analysis

0 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L577	L577	Preserved
Hydrogen bond	—	A578	Gained
Hydrogen bond	F585	F585	Preserved
Polar contact	L577	L577	Preserved
Polar contact	A578	A578	Preserved
Polar contact	L579	L579	Preserved
Polar contact	F585	F585	Preserved
Van der Waals	—	L577	Gained
Van der Waals	L579	L579	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

-0.53kcal/mol

Destabilising — mild

AlphaMissense

0.743

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)Ultra-rare · AF 0.00012%

cDNA changec.1742G>A

ClinVar accessionVCV003687973

Last evaluated2024/04/25 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — G581D Variant Card

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

Glycine → Aspartic acid at position 581. Transmembrane helix 9. ClinVar Uncertain significance, AlphaMissense 0.743, DynaMut2 ΔΔG -0.53 kcal/mol (destabilising).

Identity

Field	Value
Variant	G581D (p.Glycine581Aspartic acid)
DNA change	c.1742G>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003687973
Amino acid change	Glycine (G) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 581	85.50 — well-folded
Domain	Transmembrane helix 9
Position context	Inside Transmembrane helix 9 · position 581 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 581 sits in a transmembrane helix (Transmembrane helix 9). 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 small/flexible (glycine — backbone flexibility, no sidechain); the mutant is negatively charged (aspartate — carboxylate). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.7427
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.53 (Destabilising)
Job ID	178092121533
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092121533

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2024/04/25 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	G581D 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 0.743 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 0.743. 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
G581D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 581 with ball-and-stick + neighbors within 5Å)
G581D_variant_card.md — this card (source of truth)
G581D_variant_card.html — styled printable card
G581D_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)
G581D_wildtype_interactions.pse / G581D_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 G581D 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 G581D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.