A677V

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

Alanine → Valine at position 677 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type A677 — hydrogen bond to G674

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DynaMut2 mutant · A677V

Mutant V677 — hydrogen bond contact to A671 lost

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Bond changes · DynaMut2 interaction analysis

1 lost6 gained7 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	A671	A671	Preserved
Hydrogen bond	—	L672	Gained
Hydrogen bond	G674	G674	Preserved
Hydrogen bond	T681	T681	Preserved
Polar contact	—	A671	Gained
Polar contact	L672	L672	Preserved
Polar contact	G674	G674	Preserved
Polar contact	—	K679	Gained
Polar contact	—	E680	Gained
Polar contact	T681	T681	Preserved
Van der Waals	—	L672	Gained
Van der Waals	—	G674	Gained
Van der Waals	K679	—	Lost
Hydrophobic	T686	T686	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

-0.82kcal/mol

Destabilising — mild

AlphaMissense

0.600

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 conditionsWFS1-Related Spectrum Disorders; Autosomal dominant nonsyndromic hearing loss 6

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2030C>T

ClinVar accessionVCV000906641

Last evaluated2018/01/12 00:00

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

Full Variant Card

WFS1 Wolframin — A677V Variant Card

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

Alanine → Valine at position 677. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.600, DynaMut2 ΔΔG -0.82 kcal/mol (destabilising).

Identity

Field	Value
Variant	A677V (p.Alanine677Valine)
DNA change	c.2030C>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV000906641
Amino acid change	Alanine (A) → Valine (V)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 677	81.19 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 677 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 677 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	0.5995
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.82 (Destabilising)
Job ID	178092132364
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092132364

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2018/01/12 00:00
Inheritance	Autosomal dominant pattern indicated by associated DFNA6/14/38 (WFS1 hearing loss 6).
WFS1 variant landscape	A677V is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

WFS1-Related Spectrum Disorders
Autosomal dominant nonsyndromic hearing loss 6

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|=0.82 < 2 kcal/mol (fold intact) + AlphaMissense 0.600 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|=0.82 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.600. 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
A677V_molstar_viewer.html — interactive 3D viewer (auto-highlights position 677 with ball-and-stick + neighbors within 5Å)
A677V_variant_card.md — this card (source of truth)
A677V_variant_card.html — styled printable card
A677V_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)
A677V_wildtype_interactions.pse / A677V_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 A677V 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 A677V PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.