A806V

Category 3/4 — Most DruggableUncertain significanceLumenal · predictedσ-1 candidateSource card

Alanine → Valine at position 806 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A806 — hydrogen bond to F775

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DynaMut2 mutant · A806V

Mutant V806 — hydrogen bond contact to K774 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	K774	—	Lost
Hydrogen bond	F775	F775	Preserved
Polar contact	F775	F775	Preserved
Van der Waals	—	F775	Gained
Van der Waals	—	F810	Gained
Hydrophobic	F775	F775	Preserved
Hydrophobic	I777	I777	Preserved
Hydrophobic	F810	F810	Preserved
Hydrophobic	L814	L814	Preserved
Hydrophobic	L842	L842	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

0.56kcal/mol

Stabilising — mild

AlphaMissense

0.862

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 0.00066%

cDNA changec.2417C>T

ClinVar accessionVCV002901882

Last evaluated2023/06/14 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — A806V Variant Card

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

Alanine → Valine at position 806. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.862, DynaMut2 ΔΔG +0.56 kcal/mol (stabilising).

Identity

Field	Value
Variant	A806V (p.Alanine806Valine)
DNA change	c.2417C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002901882
Amino acid change	Alanine (A) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 806	90.88 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 806 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 806 sits in the C-terminal lumenal domain (residues 653–869), wolframin's largest soluble region. This domain projects into the ER lumen and is implicated in calcium handling, ER stress sensing, and protein–protein interactions with ATF6 and Na+/K+ ATPase β1. The wild-type residue is small/hydrophobic (alanine — methyl sidechain); the mutant is small hydrophobic (valine — branched). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.8622
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	0.56 (Stabilising)
Job ID	178092111215
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092111215

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/06/14 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A806V 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|=0.56 < 2 kcal/mol (fold intact) + AlphaMissense 0.862 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|=0.56 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.862. 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
A806V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 806 with ball-and-stick + neighbors within 5Å)
A806V_variant_card.md — this card (source of truth)
A806V_variant_card.html — styled printable card
A806V_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)
A806V_wildtype_interactions.pse / A806V_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 A806V 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 A806V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.