Pharmacogenetic (PGx) testing is increasingly central to precision medicine. By analyzing how a patient’s genetic makeup influences drug metabolism, efficacy, and adverse reaction risk, PGx testing enables better therapeutic decisions. Yet reimbursement remains a major barrier—especially when labs and TPAs misapply CPT codes or overlook payer documentation rules. Understanding both the CPT-code framework and payer coverage policies is essential.
Below we walk through:
- Key CPT codes used for PGx testing
- CMS/MolDX billing guidance (Article A57384) and how it impacts claims
- Reimbursement considerations and best practices for labs and TPAs
- Emerging issues in PGx coding
- A summary table for quick reference
Understanding PGx Testing and CPT Coding
PGx (pharmacogenetic or pharmacogenomic) testing evaluates genetic variants that influence how patients respond to medications. For example, enzymes such as CYP2D6, CYP2C19, CYP2C9, VKORC1, and others determine metabolism rates for antidepressants, opioids, antiplatelets, anticoagulants, and more. The clinical value of PGx testing is growing, with more FDA-approved drugs carrying PGx biomarker labels and clinical guidelines (e.g., CPIC) recommending genetic testing before therapy decisions.
For laboratories and TPAs, correct CPT coding is vital. Without the right code, adequate documentation, or alignment with payer policy, claims may be denied or reimbursed at lower rates. That’s where CMS guidance comes in—it provides a framework for coverage decisions, documentation requirements, and billing rules, especially in Medicare.
CMS/MolDX Guidance on Pharmacogenomics Testing (Article A57384)
CMS contractor Noridian’s “Billing and Coding: MolDX: Pharmacogenomics Testing (A57384)” is a key resource. It sets forth coverage and coding instructions that many labs must follow when billing PGx tests under Medicare.
Key takeaways:
Documentation Requirement: The performing provider must have and retain records of the drug(s) under consideration or in use by the ordering physician that require the PGx test.
- Billing Instructions:
- Use the appropriate CPT or PLA (proprietary laboratory analysis) code.
- Submit 1 unit of service (UOS).
- Enter the relevant DEX Z-Code® identifier adjacent to the CPT code in narrative/comment field (for Part B & Part A) to help identify the test.
- For Part B paper claims, the drug(s) must be listed in Item 19; for electronic claims (837P) in loop 2400 or SV101-7.
- Only one PGx test per date of service is allowable; it should be the most likely test to identify alleles/variants for the drug(s) in question.
- ICD-10 Linkage: When the PGx panel is for a specific intended use (for example, major depressive disorder/neuropsychiatric cases), relevant ICD-10 codes must be included.
- Code Use: If no established CPT exists for a gene being tested, the unlisted code 81479 may be used.
These rules emphasise that PGx testing reimbursement under Medicare isn’t simply about coding—it’s about clinical linkage, documentation of the drug(s), appropriate ICD-10 use, and coding discipline.
Core CPT Codes for Targeted PGx Genotyping
Many PGx tests focus on one or a few genes with well-known drug interactions. These are billed using analyte-specific CPT codes:
- CPT 81227 – CYP2D6 gene analysis. CYP2D6 metabolizes ~25% of common drugs (antidepressants, opioids, beta-blockers).
Example: A patient receiving tricyclic antidepressants may be genotyped to determine poor vs ultra-rapid metabolism. - CPT 81226 – CYP2C19 gene analysis. Important for clopidogrel, PPIs, anticonvulsants.
Example: Testing if a patient will respond to standard clopidogrel dosage or require alternate antiplatelet therapy. - CPT 81227 + CPT 81355 – when analyzing CYP2C9 (via 81227) and VKORC1 (via 81355) together for warfarin dosing.
Example: Patient starting warfarin therapy gets both genes tested to refine initial dose. - CPT 81240 / 81241 – Factor V Leiden (81240) and Factor II (Prothrombin) G20210A (81241) mutations for thrombophilia risk.
Example: Recurrent pulmonary embolism patient gets both genes genotyped to guide long-term anticoagulation.
Note: When multiple genes are tested in one sample, stacking codes appropriately is critical—both to capture full value and to match payer expectations.
CPT Codes for Expanded PGx Sequencing Panels
Many labs offer multi-gene PGx panels covering 10, 20, 50 or even 90+ genes; these require different CPT codes.
- CPT 81120 – Pharmacogenomic testing covering 10-30 genes.
- CPT 81121 – 31-60 genes.
- CPT 81162 – 61-90 genes.
- CPT 81163 – 91 or more genes.
These codes are used for panels that go beyond the common cytochrome P450 genes to include transporters (e.g., SLCO1B1), HLA alleles, receptor genes, etc.
Example: A 45-gene PGx panel assessing CYPs, HLA, SLCO1B1 in transplant or immunosuppressant settings.
Also critical: when PGx results come from broader genomic tests:
- CPT 81415 / 81416 – Whole exome sequencing/germline.
- CPT 81425 – Whole genome sequencing of germline DNA.
Example: A TPMT variant affecting thiopurine toxicity identified during a whole-exome test for a non-PGx indication.
Although not always billed exclusively as PGx, labs must recognize that PGx findings derived from WES/WGS may require different coding and documentation.
Additional CPT & Proprietary Codes Relevant to PGx
Beyond the major codes, labs will encounter additional analyte-specific or unique codes:
- CPT 81225 – CYP1A2 gene analysis (variants *1C, *1F, *1K)
- CPT 81231 – CYP3A4 gene analysis (variants *2, *22)
- CPT 0119U – Drug metabolism targeted sequence analysis (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1, rs12777823)
- CPT 0142U – Warfarin drug response targeted sequence (CYP2C9, CYP4F2, VKORC1, rs12777823)
These codes typically correspond to clinically actionable panels but may require extra documentation and careful payer review.
Billing & Reimbursement Considerations
The CPT coding framework is only part of the challenge. Labs and TPAs must navigate real-world barriers to reimbursement.
Coverage Limitations
- Many payers limit PGx coverage to situations where a drug has a recognized PGx biomarker label or guideline support (e.g., warfarin/CYP2C9 & VKORC1).
- “Pre-emptive” PGx panel testing (before therapy decisions) is often not covered unless the lab can document a therapy decision or drug change.
- CMS guidance highlights that the drug(s) under consideration or in use must be documented to justify PGx testing.
Documentation & Medical Necessity
- Labs must document the drug(s) being considered, and clearly link the PGx test to those drugs.
- CMS requires that only one PGx test per date of service be billed, the one most likely to identify the needed allele(s).
- ICD-10 codes must align with the intended use of the test (e.g., MDD, schizophrenia when panel is for psychiatric med guidance).
Stacking vs. Panel Codes
- Some payers deny claims when labs stack multiple analyte-specific CPT codes instead of using a bundled panel code.
- Conversely, other payers may prefer stacking—so labs must check payer policy.
- CMS guidance allows the use of unlisted code 81479 if no dedicated CPT exists.
Out-of-State / Laboratory Location Issues
- Many PGx tests are performed at national labs while ordering providers are local, causing credentialing, jurisdictional and billing challenges.
- Labs and TPAs must ensure they follow state/local Medicare contractor rules and ensure proper provider/lab relationships.
Patient Financial Responsibility
- Due to limited coverage, many PGx tests result in high out-of-pocket costs for patients.
- Labs should provide transparent cost estimates, offer prior authorization, and counsel patients proactively.
Emerging Issues in PGx CPT Coding
The PGx landscape is evolving rapidly. Labs should monitor the following areas:
- Code updates: New CPT codes and PLA codes are introduced regularly (e.g., the CMS article lists many revisions).
- Next-generation sequencing panels: As NGS broadens PGx panels, new code categories and payer standards will emerge.
- ICD-10 linkage: Payers are increasingly requiring tighter ICD-10 coding to support medical necessity for panels with specific uses (e.g., MDD or neuropsychiatric).
- Heightened scrutiny: Payers are reviewing PGx claims more closely—documentation, test purpose, drug linkage and prior authorization are under greater focus.
- GLP/CPIC evidence: As clinical evidence builds for more gene-drug pairs, payer policies may shift—but labs must stay ahead.
Summary Table: Key CPT Codes & Use Cases
| CPT Code | Gene/Test | Use Case |
| 81226 | CYP2C19 | Clopidogrel, PPIs, anticonvulsants |
| 81227 | CYP2D6 / CYP2C9 | Tricyclics, opioids, warfarin (with VKORC1) |
| 81355 | VKORC1 | Warfarin sensitivity |
| 81240 / 81241 | Factor V / Factor II | Thrombophilia risk |
| 81120 | PGx panel 10–30 genes | Multi-gene PGx panels |
| 81121 | PGx panel 31–60 genes | Larger PGx panels |
| 81162 / 81163 | PGx panel 61+ / 91+ genes | Very large PGx panels |
| 81415 / 81416 / 81425 | WES / WGS | Broader genomic tests with PGx findings |
| 81225 / 81231 | CYP1A2 / CYP3A4 | Variant analysis for metabolism |
| 0119U / 0142U | Drug metabolism / warfarin sequence panels | Specialized PGx panels |
Bonus: CMS guidance allows unlisted code 81479 when no dedicated code exists.
Conclusion
Pharmacogenetic testing offers enormous promise—enabling personalized medicine, improved outcomes, and cost savings from avoidable adverse effects. However, for labs and TPAs to capitalize on that promise, correct CPT coding and alignment with payer policy are non-negotiable.
The widely referenced CMS/MolDX article (A57384) underscores the importance of linking PGx tests to specific drugs, documenting the drug/testing rationale, selecting one test per date of service, using proper CPT/PLA codes, and attaching required identifiers such as DEX Z-Codes® and ICD-10 codes.
By mastering the core CPT codes (81226, 81227, 81120, etc.), making sure documentation supports medical necessity, and staying abreast of evolving payer and CPT landscape, labs and TPAs position themselves for far better reimbursement outcomes. As evidence for PGx grows, coverage is likely to expand—but today, coding discipline, strategic documentation, and proactive payer engagement make all the difference.
