I845F

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

Isoleucine → Phenylalanine at position 845 · C-terminal ER-lumenal (calcium binding, calmodulin, chaperone) · WFS1 (Wolframin)

Interactive 3D Structure

Wild-type reference

Wild-type I845 — hydrogen bond to V861

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DynaMut2 mutant · I845F

Mutant F845 — polar contact contact to E824 lost

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Bond changes · DynaMut2 interaction analysis

1 lost4 gained13 preserved

Interaction type	Wild-type partner	Mutant partner	Status
Hydrogen bond	E824	E824	Preserved
Hydrogen bond	H860	H860	Preserved
Hydrogen bond	V861	V861	Preserved
Polar contact	E824	—	Lost
Polar contact	H860	H860	Preserved
Polar contact	V861	V861	Preserved
Carbonyl	E824	E824	Preserved
Van der Waals	—	I823	Gained
Van der Waals	—	H860	Gained
Van der Waals	V861	V861	Preserved
Hydrophobic	—	I777	Gained
Hydrophobic	F810	F810	Preserved
Hydrophobic	V813	V813	Preserved
Hydrophobic	L814	L814	Preserved
Hydrophobic	L817	L817	Preserved
Hydrophobic	I823	I823	Preserved
Hydrophobic	—	F825	Gained
Hydrophobic	L842	L842	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

-0.87kcal/mol

Destabilising — mild

AlphaMissense

0.534

ambiguous

AlphaFold pLDDT

model confidence

Schema

Cat 4

Category 4 — Stable Fold, Function Disrupted

Clinical Evidence

ClinVar classificationUncertain significance

Review statuscriteria provided, single submitter

Associated conditions—

Population frequency (gnomAD v4)Ultra-rare · AF 0.000068%

cDNA changec.2533A>T

ClinVar accessionVCV002715511

Last evaluated2023/06/15 00:00

Observed at very low frequency in gnomAD.

Full Variant Card

WFS1 Wolframin — I845F Variant Card

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

Isoleucine → Phenylalanine at position 845. C-terminal ER-lumenal (calcium binding. ClinVar Uncertain significance, AlphaMissense 0.534, DynaMut2 ΔΔG -0.87 kcal/mol (destabilising).

Identity

Field	Value
Variant	I845F (p.Isoleucine845Phenylalanine)
DNA change	c.2533A>T
Gene · Protein	WFS1 · Wolframin (890 aa)
UniProt	O76024 · WFS1_HUMAN
ClinVar accession	VCV002715511
Amino acid change	Isoleucine (I) → Phenylalanine (F)

Structural Context

Field	Value
AlphaFold model	AF-O76024-F1, v6
pLDDT at residue 845	89.25 — well-folded
Domain	C-terminal ER-lumenal (calcium binding, calmodulin, chaperone)
Position context	C-terminal lumenal domain · position 845 projects into the ER lumen
IDR flag	No — pLDDT above 50 threshold

UniProt features at this position:

(none catalogued)

Position 845 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 large aromatic hydrophobic (phenylalanine). The chemistry shift implies altered local packing, hydrogen-bonding, and/or electrostatics at this site.

Computational Predictions

AlphaMissense

Field	Value
am_pathogenicity	0.5338
am_class	ambiguous
Interpretation	Likely benign (threshold 0.564)

DynaMut2

Field	Value
ΔΔG (kcal/mol)	-0.87 (Destabilising)
Job ID	178094721142
Result URL	https://biosig.lab.uq.edu.au/dynamut2/results_prediction/178094721142

Clinical Evidence

Field	Value
Classification	Uncertain significance
Review status	criteria provided, single submitter
Last evaluated	2023/06/15 00:00
Inheritance	Inheritance pattern not specified in ClinVar entry; WFS1 has both AD and AR presentations.
WFS1 variant landscape	I845F 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 4 — Stable Fold, Function Disrupted

<strong>Category 4 — Stable Fold, Function Disrupted</strong><br/><br/>|ΔΔG|=0.87 negligible. Likely site-specific functional disruption — docking strategy.

Why this card matters. Wolframin's fold survives this substitution (|ΔΔG|=0.87 kcal/mol). The pathogenic signal is real — AlphaMissense places it at 0.534. 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
I845F_molstar_viewer.html — interactive 3D viewer (auto-highlights position 845 with ball-and-stick + neighbors within 5Å)
I845F_variant_card.md — this card (source of truth)
I845F_variant_card.html — styled printable card
I845F_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)
I845F_wildtype_interactions.pse / I845F_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 I845F 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 I845F PDF card ↓Strategies are AI-generated predictions, not validated therapeutics.