I777T

Category 2 — Moderately DestabilizingUncertain significanceLumenal · predictedσ-1 candidateSource card

Isoleucine → Threonine at position 777 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I777 — hydrogen bond to L804

Fullscreen ↗

DynaMut2 mutant · I777T

Mutant T777 — hydrophobic to L814 lost (4 contacts lost)

Fullscreen ↗

Bond changes · DynaMut2 interaction analysis

4 lost1 gained9 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	Y706	Y706	Preserved
Hydrogen bond	V803	V803	Preserved
Hydrogen bond	L804	L804	Preserved
Polar contact	V803	V803	Preserved
Polar contact	L804	L804	Preserved
Carbonyl	V803	V803	Preserved
Van der Waals	—	V803	Gained
Hydrophobic	F704	F704	Preserved
Hydrophobic	V707	V707	Preserved
Hydrophobic	V779	—	Lost
Hydrophobic	L804	—	Lost
Hydrophobic	A806	—	Lost
Hydrophobic	L814	L814	Preserved
Hydrophobic	L842	—	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

-2.51kcal/mol

Destabilising — large

AlphaMissense

0.970

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditionsInborn genetic diseases

Population frequency (gnomAD v4)Ultra-rare · AF 0.00048%

cDNA changec.2330T>C

ClinVar accessionVCV004634772

Last evaluated2025/11/20 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — I777T Variant Card

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

Isoleucine → Threonine at position 777. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.970, DynaMut2 ΔΔG -2.51 kcal/mol (destabilising).

Identity

Field	Value
Variant	I777T (p.Isoleucine777Threonine)
DNA change	c.2330T>C
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV004634772
Amino acid change	Isoleucine (I) → Threonine (T)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 777	92.31 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 777 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 777 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 medium hydrophobic (isoleucine — branched); the mutant is small polar (threonine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9699
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.51 (Destabilising)
Job ID	178092096659
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092096659

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2025/11/20 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	I777T is 1 of ~326 pathogenic-spectrum variants in WFS1 (out of 2,243 catalogued in ClinVar)

Inborn genetic diseases

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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.51 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
I777T_molstar_viewer.html — interactive 3D viewer (auto-highlights position 777 with ball-and-stick + neighbors within 5Å)
I777T_variant_card.md — this card (source of truth)
I777T_variant_card.html — styled printable card
I777T_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)
I777T_wildtype_interactions.pse / I777T_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 I777T 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 I777T PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.