Background Transthyretin amyloid cardiomyopathy (ATTR‐CM) is an underdiagnosed cause of heart failure (HF) among patients ≥60 years of age. Although the V122I (valine to isoleucine substitution at position 122 of the transthyretin protein) variant associated with hereditary ATTR‐CM is present in 3.4% of self‐identified Black individuals in the United States (or 1.5 million people), the phenotypic penetrance is not known. Methods and Results The SCAN‐MP (Screening for Cardiac Amyloidosis With Nuclear Imaging in Minority Populations) study is a currently accruing prospective multisite study designed to determine the prevalence of ATTR‐CM using technetium‐99m‐pyrophosphate imaging in older (≥60 years of age) self‐identified Black and Hispanic individuals with HF. Calculations of the penetrance and prevalence of the V122I allele, along with analyses of functional, biochemical, and echocardiographic parameters, were performed for the first 278 Black participants in SCAN‐MP. The prevalence of ATTR‐CM was 6.8% (95% CI, 4.2–10.5; n=19 cases), of whom 63% were ATTR wild‐type. The prevalence of V122I was 6.5% (n=18 carriers), of whom 7 had ATTR‐CM, yielding a phenotypic penetrance of 39% (95% CI, 17–64). V122I carriers with ATTR‐CM evidenced more advanced HF than carriers without ATTR‐CM. Prealbumin concentration was lowest among V122I carriers with ATTR‐CM (12.9 mg/dL) versus carriers without ATTR‐CM (21.0 mg/dL) and HF controls (25.0 mg/dL, P <0.0001). Conclusions Among older Black individuals with HF and increased left ventricular wall thickness, of those with ATTR‐CM, 63% had wild‐type, and of those with V122I, the phenotypic penetrance of ATTR‐CM was 39% (95% CI, 17–64), suggesting that genotype alone is insufficient for diagnosis. Prealbumin concentration may be useful to identify V122I carriers with ATTR‐CM. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03812172.