A370V

Category 4 — Stable Fold, Function DisruptedUncertain significanceTransmembrane · predictedSource card

Alanine → Valine at position 370 · Lumenal loop 1 · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A370 — hydrogen bond to F374

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DynaMut2 mutant · A370V

Mutant V370 — hydrogen bond contact to D367 lost

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Bond changes · DynaMut2 interaction analysis

1 lost2 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Q366	Q366	Preserved
Hydrogen bond	D367	D367	Preserved
Hydrogen bond	N373	N373	Preserved
Hydrogen bond	F374	F374	Preserved
Polar contact	Q366	Q366	Preserved
Polar contact	D367	D367	Preserved
Polar contact	E372	E372	Preserved
Polar contact	N373	N373	Preserved
Polar contact	F374	F374	Preserved
Carbonyl	D367	—	Lost
Carbonyl	—	N373	Gained
Van der Waals	—	I259	Gained
Van der Waals	S368	S368	Preserved
Van der Waals	E372	E372	Preserved
Hydrophobic	I259	I259	Preserved
Hydrophobic	F397	F397	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

-0.81kcal/mol

Destabilising — mild

AlphaMissense

0.481

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statusno assertion criteria provided

Associated conditionsDevelopmental cataract

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.1109C>T

ClinVar accessionVCV001065598

Last evaluated2021/05/01 00:00

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

Full Variant Card

WFS1 Wolframin — A370V Variant Card

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

Alanine → Valine at position 370. Lumenal loop 1. ClinVar Uncertain significance, AlphaMissense 0.481, DynaMut2 ΔΔG -0.81 kcal/mol (destabilising).

Identity

Field	Value
Variant	A370V (p.Alanine370Valine)
DNA change	c.1109C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001065598
Amino acid change	Alanine (A) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 370	78.00 — well-folded
Domain	Lumenal loop 1
Position context	C-terminal lumenal domain · position 370 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 370 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	0.4812
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.81 (Destabilising)
Job ID	178094700796
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094700796

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	no assertion criteria provided
Last evaluated	2021/05/01 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	A370V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Developmental cataract

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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.81 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.81 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.481. 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
A370V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 370 with ball-and-stick + neighbors within 5Å)
A370V_variant_card.md — this card (source of truth)
A370V_variant_card.html — styled printable card
A370V_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)
A370V_wildtype_interactions.pse / A370V_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 A370V 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 A370V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.