A406D

Category 3/4 — Most DruggableUncertain significanceTransmembrane · predictedSource card

Alanine → Aspartic acid at position 406 · Transmembrane helix 4 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A406 — hydrogen bond to L402

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DynaMut2 mutant · A406D

Mutant D406 — hydrogen bond contact to E403 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained8 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	L402	L402	Preserved
Hydrogen bond	E403	E403	Preserved
Hydrogen bond	L410	L410	Preserved
Polar contact	L402	L402	Preserved
Polar contact	E403	E403	Preserved
Polar contact	F408	—	Lost
Polar contact	L409	L409	Preserved
Polar contact	L410	L410	Preserved
Van der Waals	—	E403	Gained
Van der Waals	F408	F408	Preserved
Van der Waals	—	L410	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

-0.98kcal/mol

Destabilising — mild

AlphaMissense

0.902

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.1217C>A

ClinVar accessionVCV003061672

Last evaluated2026/01/14 00:00

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

Full Variant Card

WFS1 Wolframin — A406D Variant Card

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

Alanine → Aspartic acid at position 406. Transmembrane helix 4. ClinVar Uncertain significance, AlphaMissense 0.902, DynaMut2 ΔΔG -0.98 kcal/mol (destabilising).

Identity

Field	Value
Variant	A406D (p.Alanine406Aspartic acid)
DNA change	c.1217C>A
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV003061672
Amino acid change	Alanine (A) → Aspartic acid (D)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 406	88.38 — well-folded
Domain	Transmembrane helix 4
Position context	Inside Transmembrane helix 4 · position 406 is bilayer-embedded
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 406 sits in a transmembrane helix (Transmembrane helix 4). 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/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	0.9023
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.98 (Destabilising)
Job ID	178092107109
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092107109

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2026/01/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A406D 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|=0.98 < 2 kcal/mol (fold intact) + AlphaMissense 0.902 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|=0.98 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.902. 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
A406D_molstar_viewer.html — interactive 3D viewer (auto-highlights position 406 with ball-and-stick + neighbors within 5Å)
A406D_variant_card.md — this card (source of truth)
A406D_variant_card.html — styled printable card
A406D_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)
A406D_wildtype_interactions.pse / A406D_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 A406D 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 A406D PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.