A VCF file (Variant Call Format) is the standard output of whole genome sequencing. If you have one, it contains every pharmacogenetic variant in your genome. Gene2Rx accepts VCF files from any WGS provider (Nebula Genomics, Dante Labs, Sequencing.com, Nucleus Genomics, DNA Complete, Veritas, or any clinical lab), parses the pharmacogenetic variants, and produces a report covering 103 medications using CPIC and FDA published guidelines. This guide covers the technical details of VCF-based pharmacogenetics: reference genome handling, star-allele resolution, what WGS adds over consumer genotyping, and how to get the most out of your VCF.
A pharmacogenetic report from VCF data is an informational analysis, not a clinical test replacement. Always discuss results with your prescribing clinician before changing any medication.
VCF (Variant Call Format) is the standard bioinformatics file format for storing genetic variants. A WGS VCF contains every position in your genome where you differ from the reference: single-nucleotide variants, small insertions and deletions, and often structural variants like copy-number changes. For pharmacogenetics, the key content is the variant calls at positions defined in CPIC and PharmGKB variant tables: CYP2D6, CYP2C19, CYP2C9, SLCO1B1, VKORC1, DPYD, TPMT, UGT1A1, HLA-B, and related genes.
VCF files specify which reference genome build their variant positions are called against. GRCh37 (also called hg19) and GRCh38 (hg38) are the two common builds. Gene2Rx handles both. You do not need to lift over the VCF to a specific build before uploading. The pipeline detects the build from the VCF header or infers it from variant positions, then maps the pharmacogenetic loci correctly regardless of which build your VCF uses.
Consumer genotyping arrays (23andMe, AncestryDNA) call variants at a fixed set of positions using probe-based detection. That works for most common pharmacogenetic variants. But it misses anything the array wasn't designed to detect, including rare loss-of-function variants in DPYD, TPMT, and CYP2D6, and it cannot reliably resolve CYP2D6 copy-number changes (duplications and deletions) that determine ultrarapid vs poor metabolizer phenotype. WGS reads every base, so a WGS VCF has no blind spots for pharmacogenetic interpretation.
CYP2D6 is genotyped in clinical pharmacogenetics using star allele nomenclature: *1/*1, *1/*4, *4/*5, *1xN, etc. A star allele is a combination of variants, and some include copy-number information. Gene2Rx's pipeline resolves star alleles from VCF data by matching variant patterns against the CPIC-maintained star-allele definitions and inferring copy-number status from read depth data when present. For the most accurate CYP2D6 calls, use a WGS VCF with realignment-quality depth (typically 30x coverage) rather than a sparse exome VCF.
The clinically critical pharmacogenes in any VCF-based analysis. These are the genes CPIC and the FDA have published dosing guidelines for; every reputable pharmacogenetic pipeline covers them.
Star alleles including copy-number variants. Best resolved from WGS. Affects antidepressants (SSRIs like paroxetine, TCAs), opioids (codeine, tramadol, hydrocodone), antipsychotics (aripiprazole, brexpiprazole), beta-blockers (metoprolol), tamoxifen, and ADHD medications (atomoxetine, amphetamine).
Primary star alleles *2, *3, *17. Affects SSRIs (citalopram, escitalopram, sertraline), PPIs (omeprazole, pantoprazole), and the antiplatelet clopidogrel. Well-called from WGS VCFs.
Main variants *2, *3. Critical for warfarin dosing alongside VKORC1. Also affects some NSAIDs and phenytoin.
Promoter variant rs9923231 (also called -1639G>A) is the main clinical marker. Warfarin sensitivity is largely explained by the combination of CYP2C9 and VKORC1 genotypes.
The *5 variant (rs4149056) is the clinically important marker for statin muscle pain risk. Well-captured in all WGS VCFs.
Fluoropyrimidine chemotherapy safety. CPIC guidelines specify four key variants including some that are rare enough to require WGS for reliable detection.
Thiopurine drug safety. Loss-of-function variants are rare but can be lethal at standard drug doses. WGS coverage is important for detecting them reliably.
HLA-B*57:01 (abacavir) and HLA-B*15:02 (carbamazepine in at-risk populations). HLA star-allele calling from WGS requires specialized interpretation; Gene2Rx handles this.
A full VCF-based pharmacogenetic analysis gives you metabolizer phenotypes for every clinically actionable pharmacogene, which together inform prescribing decisions for over 100 medications across every major therapeutic class.
If you have a VCF file from any WGS source (consumer service, research study, or clinical sequencing), running a pharmacogenetic analysis is one of the highest-value uses of that data. It's a one-time analysis with lifelong relevance, informing every medication decision. Patients who have struggled with antidepressant response, side effects, or are preparing for chemotherapy benefit most directly.
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Plain .vcf and bgzip-compressed .vcf.gz files. Both GRCh37 (hg19) and GRCh38 (hg38) reference genomes are supported; the pipeline detects the build and maps pharmacogenetic loci correctly regardless.
No. Upload the raw VCF as delivered by your WGS provider. The Gene2Rx pipeline extracts only the variants it needs for pharmacogenetic interpretation; you don't need to subset the file.
30x whole genome coverage (the standard for most consumer WGS services) is more than enough for reliable pharmacogenetic interpretation. Lower coverage can work but confidence on rare variants decreases. Exome-only VCFs work for most pharmacogenes but may miss some regulatory variants and intronic positions; coverage varies by exome capture kit.
Yes. Gene2Rx accepts VCFs from any source. The file format is standardized; the pipeline does not care which lab produced it.
The clinical guidelines are the same (CPIC, FDA). The difference is data quality. WGS VCFs contain every variant in your genome, so rare alleles and copy-number variants in CYP2D6 are resolvable. Consumer genotyping arrays (23andMe, AncestryDNA) cover only the variants they were designed to detect. For most people, consumer-array-based pharmacogenetics works well. For patients with non-European ancestry, rare variants, or complex CYP2D6 needs, WGS is meaningfully better.
Find out how your DNA may influence your response to Sertraline and other medications with a Gene2Rx pharmacogenetics report.
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