CurrentCignaPolicy 0500

Pharmacogenetic Testing

Defines medical necessity and coverage stance for pharmacogenetic (pharmacogenomic) testing for Cigna-administered health benefit plans, including covered and not covered tests and coding guidance; applies to providers requesting reimbursement.

Policy Summary

PayerCigna

PolicyPharmacogenetic Testing

Policy CodePolicy 0500

Change TypeAnnual review — no clinical statement changes

Effective DateMay 16, 2026

Next Review DateFeb 15, 2027

Key ActionSubmit pharmacogenetic test requests in accordance with the applicable benefit plan and use covered diagnosis/procedure codes to avoid denial.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

ALLcriteria required for medical necessity

40+explicit non-reimbursable codes/panels

13 RCTsRCTs in antidepressant meta-analysis

n=5230warfarin meta-analysis participants

No changesannual reviews with no clinical changes

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Coverage Criteria

Medically Necessary Pharmacogenetic Testing

Covered when ALL of the following are met

Primary medical necessity criteria: The individual is a candidate for a targeted drug therapy associated with a specific gene biomarker or gene pathogenic/likely pathogenic variant.

Impact on clinical decision-making: The results of the pharmacogenetic test will directly impact clinical decision-making.

Analytical validity: The testing method is considered to be scientifically valid to identify the specific gene biomarker or gene pathogenic/likely pathogenic variant.

Laboratory must meet CLIA high-complexity standards (see laboratory requirements).

Evidence of improved outcomes or FDA requirement: EITHER identification of the specific gene or biomarker for use with a specific drug target has been demonstrated to improve clinical outcomes for the individual's condition OR identification of the gene biomarker is noted to be clinically necessary prior to initiating therapy within the FDA-approved prescribing label.

Not Medically Necessary / Not Covered

Not covered

Population screening: Pharmacogenetic screening in the general population is considered not medically necessary.

Gene expression classifiers for pharmacologic response: Gene expression classifiers and gene expression profiling for pharmacologic response (for example, whole blood mRNA classifiers) are not covered or reimbursable.

Evidence summaries relevant to coverage

Summary of evidence and guidance relevant to coverage:

PGx for major depressive disorder: Randomized trials and a 2025 meta-analysis (13 RCTs) showed PGx-guided antidepressant treatment improved response at 8 and 12 weeks and improved remission at 8 weeks versus treatment-as-usual, but limitations include heterogeneity, variable blinding, short follow-up, and potential publication bias; VA/DoD (2022) found insufficient evidence to recommend for or against PGx testing for antidepressant selection and AACAP advises against routine use in children/adolescents.

PGx for tacrolimus dosing after kidney transplant: A 2021 meta-analysis (5 RCTs, n=684) of CYP3A5 genotype-guided initial tacrolimus dosing showed increased proportion achieving therapeutic concentrations and shorter time to therapeutic range but did not demonstrate improvements in clinical endpoints such as graft survival or acute rejection.

PGx for warfarin dosing: A meta-analysis (16 RCTs, n=5230) demonstrated genotype-guided warfarin dosing reduced time to therapeutic INR, time to stable INR, increased time in therapeutic range, and reduced excessive anticoagulation and bleeding compared with conventional dosing; benefit versus clinically guided algorithms was less clear.

This policy explicitly excludes gene expression classifiers and gene expression profiling intended to predict pharmacologic response (for example, whole‑blood mRNA classifiers). The policy states there is a lack of evidence to support use of gene expression classifiers from whole blood specimens for predicting treatment response, and such assays are listed among tests that are not covered or reimbursable.

Examples of non‑covered gene expression testing are provided in the Not Covered or Reimbursable code/list sections and the policy directs readers to related coverage resources for gene expression classifiers in other clinical contexts (e.g., oncology, transplant).

The policy states that pharmacogenetic testing is not recommended for general population screening. It notes that randomized clinical trials and other high‑quality studies supporting general population screening are lacking in the published peer‑reviewed literature.

As a result, pharmacogenetic screening of asymptomatic individuals without a specific clinical indication is considered not medically necessary under this policy.

Under the policy’s not‑medically‑necessary statements, pharmacogenetic screening in the general population is considered not medically necessary. The policy separately clarifies that gene expression classifiers for pharmacologic response are not covered or reimbursable.

The Background and Gene Expression Classifiers sections explain that while gene expression analyses can be clinically useful in some settings (for example, tumor classification from biopsy specimens), there is specifically a lack of evidence to support the use of whole‑blood gene expression profiling to predict pharmacologic response, which underlies the noncoverage stance.

Professional guidance informs the policy stance on routine pharmacogenetic (PGx) testing for antidepressant selection. The 2022 VA/DoD clinical practice guideline concluded there is insufficient evidence to recommend for or against PGx testing to guide antidepressant selection or dosing.

The American Academy of Child and Adolescent Psychiatry (AACAP) specifically advises clinicians to avoid using pharmacogenetic testing to select psychotropic medications in children and adolescents and calls for additional high‑quality prospective studies to determine the clinical significance of pharmacodynamic and combinatorial PGx testing in that population.

Covered Indications

When an individual is a candidate for a targeted drug therapy tied to a specific gene biomarker/variant and results will directly impact clinical decision-making, and the test method is scientifically valid.

Candidate for targeted therapy (covered indication): When an individual is a candidate for a targeted drug therapy tied to a specific gene biomarker or pathogenic/likely pathogenic variant and the test method is scientifically valid, testing is eligible when clinical utility (analytical and clinical validity and evidence of improved outcomes) is demonstrated or testing is required by the FDA-approved prescribing label.

See clinical utility requirements and FDA-labeled biomarker guidance.

Medication selection or dosing informed by genetic test results for MDD (antidepressants), warfarin dosing, tacrolimus initial dosing, and drugs with pharmacogenomic biomarkers in labeling.

Antidepressant selection (MDD): Medication selection informed by pharmacogenetic testing for major depressive disorder has RCT evidence and a 2025 meta-analysis showing modest short-term improvements in response and early remission, but evidence limitations and professional guidance (VA/DoD 2022, AACAP) advise caution and do not support routine use in all patients.

Warfarin dosing: Genotype-guided warfarin dosing (incorporating CYP2C9, VKORC1, CYP4F2 polymorphisms) has randomized trial and meta-analytic evidence showing improved surrogate anticoagulation measures (time to therapeutic INR, TTR) and reduced excessive anticoagulation and bleeding versus conventional dosing.

Tacrolimus initial dosing: CYP3A5 genotype-guided initial tacrolimus dosing increases the proportion achieving therapeutic concentrations and shortens time to therapeutic range but has not shown clear improvements in clinical endpoints (eg, graft survival, acute rejection) in available trials.

Drugs with pharmacogenomic biomarkers in labeling: Pharmacogenetic testing is supported when an FDA-approved drug label specifies that biomarker testing is clinically necessary prior to initiating therapy.

Coding

Not Covered or ReimbursablemixedNot Covered

81230	CYP3A4 gene analysis, common variant(s)
81231	CYP3A5 gene analysis, common variants
81283	IFNL3 gene analysis, rs12979860 variant
81355	VKORC1 gene analysis, common variant(s)
81418	Drug metabolism genomic sequence analysis panel, must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis
0029U	Drug metabolism targeted sequence analysis (CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823)
0030U	Drug metabolism (warfarin response) targeted sequence analysis (CYP2C9, CYP4F2, VKORC1, rs12777823)
0031U	CYP1A2 gene analysis, common variants
0032U	COMT gene analysis, c.472G>A (rs4680) variant
0033U	HTR2A gene analysis

1–10 of 31

1/4

Panel minimum gene count (example)

Minimum panel sizeAt least 6 genes

Required genes (examples)Must include CYP2C19 and CYP2D6

CYP2D6 copy-number analysisCYP2D6 duplication/deletion (copy number variant) analysis required

Example CPT descriptorReferenced in descriptor for 81418: drug metabolism genomic sequence analysis panel must include testing of at least 6 genes including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis

Provider Actions & Billing

Prior Authorization

Benefit-plan & Coding-based Prior Authorization

Coverage depends on the member's specific benefit plan. In the absence of a controlling federal or state mandate, the customer's benefit plan document (e.g., Group Service Agreement, Evidence of Coverage, Certificate of Coverage, Summary Plan Description) governs and may supersede this policy. Reimbursement is allowed only if the requested service is submitted in accordance with the applicable Coverage Policy and accompanied by covered diagnosis and/or procedure code(s).

Confirm member-specific coverage in the customer's benefit plan document prior to testing
Submit claims only when the service and diagnosis/procedure codes are covered under the member's plan

Prior Authorization

Prior Authorization Requirement

Prior authorization may be required per the member's benefit plan. Administrative reviews of this policy indicate no changes to clinical policy statements in recent annual/focused reviews, but they do not remove any plan-level prior authorization or utilization review requirements.

Check the member's benefit plan for any prior authorization or utilization review requirements before ordering pharmacogenetic testing
If prior authorization is required by the plan, obtain approval before performing the test to avoid denial

Documentation Required

Coding and Plan-Document Documentation

When billing, providers must use the most appropriate CPT/HCPCS/ICD-10 codes effective on the date of claim submission. Claims lacking covered diagnosis or procedure codes referenced by this Coverage Policy will be denied as not covered.

Use current, appropriate procedure and diagnosis codes for the date of service
Do not submit claims with codes that are not listed as covered by the applicable Coverage Policy
If uncertain about coding, consult plan coding guidance or contact the payer prior to submission

Denial Risk

Billing & Coverage Denial Risks

Claims for services that do not meet the policy's covered indications or that are submitted without covered diagnosis/procedure codes will be denied as not covered. Denials may also occur if prior authorization (when required by the plan) was not obtained.

Denial risk if documentation does not demonstrate that testing meets the policy's medical necessity criteria
Denial risk if billed diagnosis/procedure codes are not covered under the member's plan
Denial risk if required prior authorization was not obtained

Documentation Required

Provider Documentation & Professional Practice

Follow plan documentation rules and professional practice resources when ordering and interpreting pharmacogenetic testing; consider co-ordering or consultation with genetics professionals where appropriate.

Document clinical indication and how results will impact management to support medical necessity
Follow plan-specific documentation requirements for prior authorization and claims submission
Consider co-ordering or involving genetics professionals (e.g., genetic counselors, clinical geneticists) per CPIC/ACMG/CAP guidance for test selection and interpretation

Not Covered

The policy provides an extensive list of specific codes and named panels that are not covered or reimbursable. Examples include numerous CPT and proprietary U‑codes for pharmacogenomic and psychiatry panels (for example, 81418—drug metabolism genomic sequence analysis panel requiring at least six genes including CYP2C19 and CYP2D6 with CYP2D6 duplication/deletion analysis; multiple psychiatry panel U‑codes such as 0173U, 0175U, 0345U, 0347U, 0348U, 0349U, 0350U; and larger drug metabolism panels such as 0438U, 0434U, 0437U), as well as procedure code G9143 for warfarin responsiveness testing by genetic technique.

Providers must reference the Not Covered or Reimbursable code list in the policy when determining billing and reimbursement expectations, because these specific codes and panels are identified as not payable under this policy.

The policy reiterates that pharmacogenetic testing for general population screening is not supported by current evidence and therefore is not recommended. It emphasizes that clinical trials evaluating population‑level screening are lacking in the peer‑reviewed literature.

Consequently, requests for PGx testing without a clear, specific clinical indication (that would meet the policy’s medical‑necessity criteria) are not covered.

Definitions

Pharmacogenetic testing (definition)

DefinitionGenetic analysis (eg, genotyping, variant analysis) to identify gene biomarkers or variants that influence drug response

PurposeIdentify variants that affect drug metabolism, transport, targets, efficacy, or adverse reactions

Test typesIncludes targeted genotyping, pathogenic/likely pathogenic variant analysis, and multi-gene panels

Laboratory standardClinical laboratories offering tests must meet CLIA high-complexity testing standards

Gene expression classifiers

DefinitionAssays of RNA/mRNA expression used to classify disease, provide prognosis, or tailor treatment based on gene expression patterns

Clinical use examplesCan be useful for disease classification and prognosis (eg, tumor biopsy assays)

Policy stanceThis policy states there is a lack of evidence to support use of gene expression classifiers/profiling (eg, whole blood mRNA) for predicting pharmacologic response

Related guidanceSee Related Coverage Resources for other policies addressing gene expression classifiers in transplant and oncology contexts

PGx-guided treatment

DefinitionTherapeutic selection or dosing decisions informed by pharmacogenomic test results (single-gene or multi-gene) to guide medication choice or dose

ScopeIncludes single-gene genotyping (eg, CYP2C19, CYP2D6, CYP3A5, VKORC1) and multi-gene panels and decision-support tools

Evidence considerationsEvidence and clinical utility vary by indication (eg, supportive meta-analytic evidence for warfarin dosing; mixed evidence for antidepressant PGx and combinatorial tools)

Clinical validity requirementTesting methods must be analytically valid and demonstrate clinical utility or be required per FDA prescribing information

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