A95D

Category 3/4 — Most DruggableUncertain significanceCytoplasmic · predictedSource card

Alanine → Aspartic acid at position 95 · N-terminal cytoplasmic (intrinsically disordered) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A95 — hydrogen bond to L92

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DynaMut2 mutant · A95D

Mutant D95 — hydrogen bond to W129 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost6 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	V91	V91	Preserved
Hydrogen bond	L92	L92	Preserved
Hydrogen bond	G98	G98	Preserved
Hydrogen bond	Q103	Q103	Preserved
Hydrogen bond	W129	—	Lost
Polar contact	V91	V91	Preserved
Polar contact	L92	L92	Preserved
Polar contact	E93	E93	Preserved
Polar contact	—	A97	Gained
Polar contact	G98	G98	Preserved
Polar contact	—	A102	Gained
Polar contact	Q103	Q103	Preserved
Polar contact	—	V106	Gained
Polar contact	—	W129	Gained
Van der Waals	—	L92	Gained
Van der Waals	E93	E93	Preserved
Van der Waals	A97	—	Lost
Van der Waals	—	Q103	Gained
Hydrophobic	A102	—	Lost
Hydrophobic	Q103	Q103	Preserved
Hydrophobic	V106	V106	Preserved
Hydrophobic	W129	W129	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

-1.47kcal/mol

Destabilising — moderate

AlphaMissense

0.994

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.284C>A

ClinVar accessionVCV001473915

Last evaluated2022/08/10 00:00

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

Full Variant Card

WFS1 Wolframin — A95D Variant Card

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

Alanine → Aspartic acid at position 95. N-terminal cytoplasmic (intrinsically disordered). ClinVar Uncertain significance, AlphaMissense 0.994, DynaMut2 ΔΔG -1.47 kcal/mol (destabilising).

Identity

Field	Value
Variant	A95D (p.Alanine95Aspartic acid)
DNA change	c.284C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001473915
Amino acid change	Alanine (A) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 95	89.81 — 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 95 sits in N-terminal cytoplasmic (intrinsically disordered). The wild-type residue is small/hydrophobic (alanine — methyl 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	0.9936
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.47 (Destabilising)
Job ID	178092087522
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092087522

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2022/08/10 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A95D 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|=1.47 < 2 kcal/mol (fold intact) + AlphaMissense 0.994 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|=1.47 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.994. 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
A95D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 95 with ball-and-stick + neighbors within 5Å)
A95D_variant_card.md — this card (source of truth)
A95D_variant_card.html — styled printable card
A95D_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)
A95D_wildtype_interactions.pse / A95D_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 A95D 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 A95D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.