A677G

Category 4 — Stable Fold, Function DisruptedUncertain significanceLumenal · predictedσ-1 candidateSource card

Alanine → Glycine 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 · A677G

Mutant G677 — hydrogen bond to G674 lost (3 contacts lost)

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Bond changes · DynaMut2 interaction analysis

3 lost2 gained5 preserved

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

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

-1.20kcal/mol

Destabilising — moderate

AlphaMissense

0.372

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain risk allele

Review statuscriteria provided, single submitter

Associated conditionsWolfram syndrome 1

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2030C>G

ClinVar accessionVCV002429739

Last evaluated1/01/01 00:00

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

Full Variant Card

WFS1 Wolframin — A677G Variant Card

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

Alanine → Glycine at position 677. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain risk allele, AlphaMissense 0.372, DynaMut2 ΔΔG -1.20 kcal/mol (destabilising).

Identity

Field	Value
Variant	A677G (p.Alanine677Glycine)
DNA change	c.2030C>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002429739
Amino acid change	Alanine (A) → Glycine (G)

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/flexible (glycine — backbone flexibility, no sidechain). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.3719
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-1.2 (Destabilising)
Job ID	178094717728
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094717728

Clinical Evidence

Field	Value
Classification	Uncertain risk allele
Review status	criteria provided, single submitter
Last evaluated	1/01/01 00:00
Inheritance	Autosomal recessive Wolfram syndrome 1 phenotype documented.
WFS1 variant landscape	A677G is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Wolfram syndrome 1

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|=1.20 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=1.20 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.372. 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
A677G_molstar_viewer.html — interactive 3D viewer (auto-highlights position 677 with ball-and-stick + neighbors within 5Å)
A677G_variant_card.md — this card (source of truth)
A677G_variant_card.html — styled printable card
A677G_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)
A677G_wildtype_interactions.pse / A677G_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 A677G 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 A677G PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.