IonTriage™ | Clinical VUS Mechanistic Triage & Channelopathy Precision Therapeutics

⚡ Instant Clinical Benchmark Presets (All 15 Curated Genes) 1-Click Triage

Select any gene to load a verified pathogenic benchmark variant & auto-evaluate

🔍 Patient Variant Query

Target Gene

Protein Variant (HGVS)

gnomAD Allele Frequency (AF)

Family Pedigree & De Novo Status

Patient HPO Terms / Clinical Phenotypes

📈 Telemetry & Dynamic Stress Calibrator (v1.6.0)

Heart Rate (bpm)

Baseline QT (ms)

Core Temp (°C)

Serum K⁺ (mEq/L)

TWA (µV)

Exercise Peak HR

Exercise Recovery QTc (ms)

Nocturnal Bradycardia / Sleep Episode

🌍 Multi-Ancestry Stratification & Form 3926 eIND (v1.7.0)

Patient Continental Ancestry

Ancestry-Specific AF (Optional Override)

Auto-Generate Turnkey Form FDA 3926 eIND Dossier

Patient Initials

Physician Name

🧬 Pediatric Trio Phasing & De Novo Calling (v2.0.0)

VCF Multi-Sample Format Line FORMAT followed by Proband Father Mother sample fields

Second Hit / In-Trans Variant

Phasing Mode

📚 Electrophysiology Literature Miner & Corpus (v2.0.0)

Custom Literature Corpus / Abstract Snippets

💡 Curated Benchmark Cases

📊 173 Real ClinVar Patient Variants Evaluated with 3D AlphaFold Metrics

Exhaustive screening cohort of real human missense Variants of Uncertain Significance (VUS) retrieved from NCBI ClinVar across CFTR, SCN1A, SCN2A, SCN5A, KCNQ1, and KCNH2. Click "Analyze" on any row to immediately load the variant into the diagnostic engine.

ClinVar ID	Gene	Variant	pLDDT	Pore Dist	PCRI	Category	Predicted Effect	Action

🧠 N-of-1 Patient Digital Twin & Action Potential Simulator

Simulate a virtual cellular clone of an individual patient's electrophysiology incorporating real-time physiological biometrics (age, weight, serum potassium) to optimize multi-drug titration and predict seizure/arrhythmia suppression index with safety margin indices.

Patient ID / Label

Target Gene & Variant

Patient Age (Years)

Weight (kg)

Serum K⁺ (mEq/L)

🧬 Allele-Specific Oligonucleotide (ASO) Synthesis Designer

Automated design of 5-10-5 2'-O-MOE gapmer antisense oligonucleotides engineered with central mismatch catalytic discrimination for dominant lethal Gain-of-Function channelopathy variants.

🏢 Biopharma Clinical Trial Cohort Enrichment & Drug Rescue Screener

Stratify heterogeneous rare-disease patient cohorts by 3D binding cavity stereochemistry and gating reversibility. Transform inconclusive trials (HR=0.82, p=0.18) into breakthrough designated trials (HR=0.38, p<0.001) while filtering high-risk paradoxical death contraindications.

Trial Study Asset

Investigational Drug

🧬 Compound Heterozygote & Multi-Allelic Studio

Autosomal recessive channelopathies and transporter disorders (such as CFTR Cystic Fibrosis and KCNQ1 Jervell and Lange-Nielsen Syndrome) are caused by compound heterozygosity. Model trans-allelic combinations and in-cis intronic modifiers (5T / 7T / 9T) to determine composite residual channel conductance, phenotypic severity, and targeted drug indications.

Clinical Benchmark Presets:

Target Gene

Allele 1 Variant (HGVS)

In-Cis Modifier 1 (Optional)

Allele 2 Variant (HGVS)

In-Cis Modifier 2 (e.g. 5T / 7T / 9T)

✂️ Splicing Studio & Poison Exon Targeting

Cryptic deep-intronic pseudoexons, canonical splice site disruptions, and naturally occurring poison exons (such as SCN1A poison exon 20N) trigger nonsense-mediated decay (NMD) and haploinsufficiency channelopathies. Model splice site perturbations and targeted antisense oligonucleotide (ASO) exon skipping rescue.

Clinical Splicing Presets:

Target Gene

cDNA / Splicing Variant (HGVS.c or Target)

📄 Clinical Prior-Authorization Appeal & Theratyping Dossier

Generate formal prior-authorization appeal letters directly formatted for submission to insurance medical directors to overturn drug coverage denials.

Patient Full Name

Patient Date of Birth

Medical Record # (MRN)

Attending Physician

NPI Number

State Medical License

Medical Center / Hospital Affiliation

🧪 Cohort Batch Triage Screener

Paste a cohort of variants (one per line, format: GENE VARIANT [GNOMAD_AF] or tab-delimited) to screen an entire cohort simultaneously.

Gene	Variant	Classification	Grantham	BLOSUM62	Contraindication Alert	Primary Targeted Intervention

📖 Biophysical & Electrophysiological Guidance Manual

1. Selectivity Filter Architecture (DEKA & Tetrameric Filters)

Voltage-gated sodium channels (Nav1.1, Nav1.2, Nav1.5) rely on a conserved asymmetric ring of four amino acid residues (Asp-Glu-Lys-Ala, DEKA) across domains I-IV to achieve strict sodium selectivity. In contrast, tetrameric potassium channels (Kv7.1, hERG) utilize symmetric pore loops (TxGYG / GFG motifs). Any charge reversal or steric occlusion directly within these pore coordinates collapses ion permeation, causing complete loss-of-function.

2. Fast-Inactivation IFM Gate & Phenotypic Bifurcation

The cytoplasmic linker between domains III and IV contains an invariant hydrophobic triad (Ile-Phe-Met, IFM) that acts as a hinged lid occluding the intracellular pore mouth during sustained depolarization. Mutations in the IFM motif delay or prevent channel inactivation, creating persistent late sodium current (INa,L). In SCN1A this drives Familial Hemiplegic Migraine 3 (FHM3); in SCN2A it causes Early-Infantile Epileptic Encephalopathy (<3 months); in SCN5A it causes Long QT Syndrome Type 3 (LQT3).

3. Critical Contraindications

SCN1A Loss-of-Function (Dravet Syndrome): Sodium channel blockers (Phenytoin, Carbamazepine, Lamotrigine) precipitate intractable status epilepticus and dramatically heighten Sudden Unexpected Death in Epilepsy (SUDEP).
SCN5A Loss-of-Function (Brugada Syndrome): Class Ic antiarrhythmics (Flecainide, Propafenone) trigger fatal re-entrant ventricular fibrillation.
SCN2A Late-Onset (>3 months / ASD): Sodium channel blockers aggravate cognitive, behavioral, and communication deficits.

1. Selectivity Filter Architecture (DEKA & Tetrameric Filters)

2. Fast-Inactivation IFM Gate & Phenotypic Bifurcation

3. Critical Contraindications

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