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HCLS AI Factory — Intelligence Report

Patient: GEN-2026-0087 | Pipeline Run: HCLS-VCP-2026-0087 | Mode: Full (Stages 1→2→3)

License: Apache 2.0 | Date: February 2026

Report Header

Field Value
Patient ID GEN-2026-0087
Run ID HCLS-VCP-2026-0087
Pipeline Version HLS-Pipeline v1.0.0
Pipeline Mode Full (Genomics → RAG/Chat → Drug Discovery)
Hardware NVIDIA DGX Spark (GB10 GPU, 128 GB unified)
Total Pipeline Duration 4 hours 12 minutes
Report Generated February 2026
Status COMPLETE — 100 novel drug candidates ranked

1. Genomics Summary (Stage 1)

Input Data

Parameter Value
Sample HG002 (NA24385, GIAB Ashkenazi male)
Sequencing Illumina, 30× WGS, 2×250 bp paired-end
FASTQ Size 198.7 GB (R1: 99.4 GB, R2: 99.3 GB)
Reference Genome GRCh38 (3.1 GB)

Parabricks Execution

Step Tool Duration GPU Utilization Peak Memory
Alignment BWA-MEM2 (fq2bam) 34 min 82% 38 GB
Variant Calling Google DeepVariant 22 min 91% 54 GB
Total Stage 1 56 min

VCF Output

Metric Count
Total Variants Called 11,724,891
PASS Quality (QUAL>30) 3,487,216
SNPs 4,198,433
Indels 1,012,548
Multi-allelic Sites 148,762
Coding Region Variants 35,616
Transition/Transversion Ratio 2.07

Quality Assessment: PASS — Ts/Tv ratio within expected range (2.0-2.1), variant counts consistent with 30× WGS of Ashkenazi ancestry sample.

2. Annotation & Target Identification (Stage 2)

Annotation Funnel

Stage Variants Filter Applied
Raw VCF 11,724,891 —
Quality Filter 3,487,216 QUAL > 30
ClinVar Annotated 35,616 Clinical significance match
AlphaMissense Scored 6,831 AI pathogenicity prediction
HIGH Impact + Pathogenic 2,412 Actionable subset
Druggable Gene Targets 847 Knowledge base match

Top 5 Target Hypotheses (Claude RAG Analysis)

Rank Gene Variant ClinVar AlphaMissense Therapeutic Area Druggability
1 VCP rs188935092 (chr9:35065263 G>A) Pathogenic 0.87 Neurology 0.92
2 EGFR rs121913229 (chr7:55259515 T>G) Pathogenic 0.79 Oncology 0.95
3 BRCA1 rs80357914 (chr17:43091434 G>A) Pathogenic 0.72 Oncology 0.78
4 PCSK9 rs11591147 (chr1:55505647 T>G) Pathogenic 0.68 Cardiovascular 0.88
5 CFTR rs75527207 (chr7:117559590 G>A) Pathogenic 0.81 Respiratory 0.71

Primary Target Selection: VCP

Parameter Value
Gene VCP (Valosin-Containing Protein / p97)
UniProt P55072
Function AAA+ ATPase, ubiquitin-proteasome pathway
Diseases Frontotemporal Dementia (FTD), ALS, IBMPFD
Variant rs188935092 — missense, HIGH impact
ClinVar Classification Pathogenic (reviewed by expert panel)
AlphaMissense Score 0.87 (pathogenic, >0.564 threshold)
Druggability Score 0.92 (D2 ATPase domain, ~450 ų pocket)
Known Inhibitors CB-5083 (Phase I), NMS-873
Confidence HIGH — multiple independent evidence sources

Evidence Chain

  1. Genomic: rs188935092 detected at chr9:35065263 (G>A), heterozygous, QUAL=892
  2. Clinical: ClinVar classifies as Pathogenic for FTD/ALS/IBMPFD (expert panel review)
  3. AI Prediction: AlphaMissense score 0.87 (pathogenic threshold >0.564)
  4. Functional: VEP annotates as missense_variant, HIGH impact, D2 ATPase domain
  5. Druggability: Known drug target — CB-5083 reached Phase I clinical trial
  6. Structural: 4 PDB structures available including inhibitor-bound 5FTK

Milvus Vector Search Statistics

Parameter Value
Total Embeddings Indexed 3,487,216
Embedding Model BGE-small-en-v1.5 (384-dim)
Index Type IVF_FLAT (nlist=1024)
Search nprobe 16
Query Expansion Neurology therapeutic area keywords
Top-k Retrieved 20 variant contexts
Search Latency 12 ms

3. Drug Discovery Results (Stage 3)

Structure Evidence

PDB ID Resolution Method Description Score
5FTK 2.3 Å X-ray VCP D2 + CB-5083 inhibitor 13.2 (selected)
7K56 2.5 Å Cryo-EM VCP complex 10.8
8OOI 2.9 Å Cryo-EM WT VCP hexamer 8.9
9DIL 3.2 Å Cryo-EM Mutant VCP 7.4

Selected Structure: 5FTK — inhibitor-bound (CB-5083), X-ray at 2.3 Å resolution. Binding site in D2 ATPase domain, key residues: ALA464, GLY479, ASP320, GLY215.

Molecule Generation (MolMIM)

Parameter Value
Seed Compound CB-5083 (ATP-competitive VCP inhibitor)
NIM Endpoint MolMIM (port 8001)
Molecules Generated 100
Chemically Valid 98 (2 rejected by RDKit valence check)
Generation Time 2 min 14 sec

Drug-Likeness Profile

Metric Pass Fail Pass Rate
Lipinski Rule of Five 87 11 88.8%
QED > 0.67 (drug-like) 72 26 73.5%
QED > 0.49 (moderate+) 91 7 92.9%
TPSA < 140 Ų 94 4 95.9%

Molecular Docking (DiffDock)

Parameter Value
NIM Endpoint DiffDock (port 8002)
Protein Target 5FTK (VCP D2 domain)
Candidates Docked 98 (all valid molecules)
Docking Time 8 min 42 sec
Mean Dock Score -7.4 kcal/mol
Best Dock Score -11.4 kcal/mol
Scores < -8.0 (excellent) 34 candidates
Scores < -6.0 (good+) 78 candidates

Composite Scoring

Formula: 30% Generation + 40% Docking + 30% QED

Docking normalization: max(0, min(1, (10 + dock_score) / 20))

Top 10 Ranked Candidates

Rank Composite Gen Score Dock (kcal/mol) QED MW (Da) LogP Lipinski
1 0.89 0.92 -11.4 0.81 423.5 3.2 PASS
2 0.86 0.88 -10.8 0.79 441.2 3.7 PASS
3 0.84 0.85 -10.2 0.82 398.7 2.9 PASS
4 0.82 0.91 -9.8 0.74 467.1 4.1 PASS
5 0.81 0.83 -9.5 0.78 412.3 3.4 PASS
6 0.79 0.87 -9.1 0.71 455.8 3.8 PASS
7 0.78 0.80 -8.9 0.76 389.2 2.7 PASS
8 0.76 0.84 -8.7 0.69 478.4 4.3 PASS
9 0.75 0.79 -8.5 0.73 401.6 3.1 PASS
10 0.74 0.82 -8.2 0.68 448.9 3.9 PASS

CB-5083 Seed Comparison

Metric CB-5083 (Seed) Top Candidate Improvement
Dock Score -8.1 kcal/mol -11.4 kcal/mol +41% binding affinity
QED 0.62 0.81 +31% drug-likeness
MW 487.2 Da 423.5 Da -13% (better oral absorption)
Composite 0.64 0.89 +39% overall

4. Pipeline Performance

Stage Timing

Stage Duration GPU Util (avg) Peak Memory
1 — Genomics (fq2bam) 34 min 82% 38 GB
1 — Genomics (DeepVariant) 22 min 91% 54 GB
2 — Annotation 18 min 15% (CPU-bound) 12 GB
2 — Milvus Indexing 24 min 35% 22 GB
2 — RAG/Chat (interactive) 45 min 5% 8 GB
3 — Structure Retrieval 2 min 0% (network I/O) 2 GB
3 — MolMIM Generation 2 min 14 sec 78% 18 GB
3 — DiffDock Docking 8 min 42 sec 85% 24 GB
3 — Scoring + Reporting 1 min 30 sec 0% (CPU) 4 GB
Total ~4 hr 12 min

Service Health at Report Generation

Service Port Status
Landing Page 8080 HEALTHY
Genomics Portal 5000 HEALTHY
Milvus 19530 HEALTHY
RAG API 5001 HEALTHY
Streamlit Chat 8501 HEALTHY
MolMIM NIM 8001 HEALTHY
DiffDock NIM 8002 HEALTHY
Discovery UI 8505 HEALTHY
Grafana 3000 HEALTHY
Prometheus 9099 HEALTHY

5. Clinical Interpretation

Summary

Patient GEN-2026-0087 carries a heterozygous pathogenic missense variant (rs188935092) in the VCP gene. This variant is associated with Frontotemporal Dementia (FTD), ALS, and Inclusion Body Myopathy with Paget Disease and Frontotemporal Dementia (IBMPFD). The variant is classified as Pathogenic by ClinVar expert panel review and scores 0.87 on the AlphaMissense pathogenicity scale.

Drug Discovery Outcome

The AI-driven drug discovery pipeline identified 100 novel VCP inhibitor candidates with the top candidate showing a 39% improvement in composite score over the CB-5083 seed compound. All top 10 candidates pass Lipinski's Rule of Five and show favorable QED scores (>0.67), suggesting oral drug-likeness.

  1. Genetic counseling for FTD/ALS risk assessment
  2. Experimental validation of top 5 candidates in VCP ATPase activity assays
  3. ADMET profiling for lead optimization
  4. Cross-modal follow-up with Imaging Intelligence Agent for neurological assessment

6. Provenance

Item Value
Pipeline HLS-Pipeline v1.0.0 (Nextflow DSL2)
Parabricks nvcr.io/nvidia/clara/clara-parabricks:4.6.0-1
DeepVariant Google DeepVariant (via Parabricks, >99% accuracy)
Reference GRCh38 (3.1 GB)
ClinVar February 2026 release (4.1M variants)
AlphaMissense v1.0 (71,697,560 predictions)
VEP Ensembl VEP (GRCh38)
Milvus v2.4 (IVF_FLAT, nlist=1024, COSINE)
Embedding Model BGE-small-en-v1.5 (384-dim)
LLM claude-sonnet-4-20250514 (temperature=0.3)
MolMIM nvcr.io/nvidia/clara/bionemo-molmim:1.0
DiffDock nvcr.io/nvidia/clara/diffdock:1.0
Hardware NVIDIA DGX Spark (GB10, 128 GB unified)
Scoring 30% gen + 40% dock + 30% QED

This is a demonstration intelligence report generated by the HCLS AI Factory. All patient data is synthetic. The report illustrates the platform's end-to-end capability from genomic variant calling through drug candidate ranking.

HCLS AI Factory — Apache 2.0 | February 2026