I777S

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

Isoleucine → Serine 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

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DynaMut2 mutant · I777S

Mutant S777 — polar contact to V803 lost (9 contacts lost)

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Bond changes · DynaMut2 interaction analysis

9 lost2 gained4 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	—	F704	Gained
Polar contact	—	Y706	Gained
Polar contact	V803	—	Lost
Polar contact	L804	L804	Preserved
Carbonyl	V803	—	Lost
Hydrophobic	F704	—	Lost
Hydrophobic	V707	—	Lost
Hydrophobic	V779	—	Lost
Hydrophobic	L804	—	Lost
Hydrophobic	A806	—	Lost
Hydrophobic	L814	—	Lost
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

-2.99kcal/mol

Destabilising — large

AlphaMissense

0.984

likely pathogenic

AlphaFold pLDDT

model confidence

Schema

Cat 2

Category 2 — Moderately Destabilizing

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Absent from gnomAD v4

cDNA changec.2330T>G

ClinVar accessionVCV001317056

Last evaluated2023/01/05 00:00

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

Full Variant Card

WFS1 Wolframin — I777S Variant Card

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

Isoleucine → Serine at position 777. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.984, DynaMut2 ΔΔG -2.99 kcal/mol (destabilising).

Identity

Field	Value
Variant	I777S (p.Isoleucine777Serine)
DNA change	c.2330T>G
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV001317056
Amino acid change	Isoleucine (I) → Serine (S)

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 (serine — hydroxyl). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.9837
am_class	likely pathogenic
Interpretation	Likely pathogenic (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-2.99 (Destabilising)
Job ID	178092091864
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178092091864

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/01/05 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	I777S 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 2 — Moderately Destabilizing

<strong>Category 2 — Moderately Destabilizing</strong><br/><br/>|ΔΔG|=2.99 in the 2–4 range. Pharmacological chaperone candidate.

Files in this folder

AF-O76024-F1-model_v6.pdb — AlphaFold structure
I777S_molstar_viewer.html — interactive 3D viewer (auto-highlights position 777 with ball-and-stick + neighbors within 5Å)
I777S_variant_card.md — this card (source of truth)
I777S_variant_card.html — styled printable card
I777S_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)
I777S_wildtype_interactions.pse / I777S_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 I777S 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 I777S PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.