Clonal hematopoiesis of indeterminate potential (CHIP) driven by somatic mutations in TET2 and DNMT3A is present in >10% of adults over 60 and confers substantial risk for hematologic malignancy and cardiovascular disease, yet the majority of patients with CHIP do not progress to disease. Analyzing 1,020,538 individuals across three biobanks (UK Biobank, All of Us, BioVU), we show that a discrete subset of enzymatically disruptive mutations — TET2 loss-of-function variants and the DNMT3A R882 hotspot — account for the majority of clinical risk in these genes and exhibit the strongest clonal fitness advantage. Because DNMT3A and TET2 encode enzymes that modulate DNA methylation, we reasoned that peripheral blood methylation patterns should reflect the functional impact of individual mutations, enabling a direct readout of enzymatic dysfunction in CHIP patients. We developed and validated methylation-based activity scores for TET2 and DNMT3A as patient specific biomarkers that quantify enzymatic activity. These scores capture functional heterogeneity across mutation subtypes, predict disease risk comparably to clinical risk scores such as the Clonal Hematopoiesis Risk Score and the AHA PREVENT cardiovascular risk model. Integrating the activity score with the clinical models substantially improves prediction of incident cytopenia, myeloid neoplasm, and major adverse cardiovascular events. These findings establish that TET2 and DNMT3A CHIP pathogenicity is proportional to the degree of enzymatic disruption conferred by specific variants, and nominate methylation-based activity scores as a functional biomarker for individualized CHIP risk stratification and monitoring therapeutic response.

M.R.S. has received honoraria from Bristol Myers Squibb, CTI, Forma, Geron, GlaxoSmithKline, Karyopharm, Ryvu, and Taiho; research funding from ALXOncology, Astex, Incyte, Takeda, and TG Therapeutics; holds equity in Empath Biosciences, Karyopharm, and Ryvu; and travel reimbursement from Astex. All other authors declare no competing interests.

This study was funded by the following National Institutes of Health grants: UG3 AG097155 (A.G.B., M.R.S.), K08 HL171833 (J.B.H.), R01 AG088657 (A.G.B.), F30 AG099331 (Y.P.), and T32 GM145734 (J.C.V.A.). Additionally, this work was supported by a Burroughs Wellcome Fund Career Award for Medical Scientists (A.G.B.), a Pew-Stewart Scholar for Cancer Research award (A.G.B.), supported by the Pew Charitable Trusts and the Alexander and Margaret Stewart Trust (A.G.B.), a Hevolution/AFAR New Investigator Award in Aging Biology and Geroscience Research (A.G.B.), and Arthritis National Research Foundation grant 1288083 (R.W.C.). The sequencing of 250,000 WGS individuals from BioVU has been funded by the Alliance for Genomic Discovery consisting of NashBio, Illumina and industry partners Amgen, AbbVie, AstraZeneca, Bayer, BMS, GSK, Merck, and Novo.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

Individual-level sequence data and CHIP calls have been deposited with UK Biobank and are freely available to approved researchers, as done with other genetic datasets to date under data fields (30105, 30106, 30107). The genotypes and phenotypes of UKB and AoU participants are available by application to the UKB (https://www.ukbiobank.ac.uk/register-apply/) and AoU (https://allofus.nih.gov/), respectively. For Vanderbilt BioVU, clonal hematopoiesis of indeterminate potential sequencing calls are available through controlled access to qualified researchers. Due to Vanderbilt BioVU cohort restrictions, access will require a data use agreement with Vanderbilt University Medical Center, which can be facilitated by the corresponding author, Dr. Bick. Methylation data for BioVU is available via dbGaP at accession number phs004433.v1.p1. CHIP calls and methylation data for CHIVE is available upon request. Framingham Heart Study methylation data is available publicly for researchers at dbGaP accession number phs000974.v1.p1.