Abstract Background Hereditary transthyretin-mediated (hATTR) amyloidosis is a progressive, life-threatening disease caused by mutations in the transthyretin (TTR) gene. hATTR amyloidosis phenotypes can vary by patient and mutation. The V122I (Val122Ile; p.V142I) variant is one of the most common pathogenic TTR mutations, is primarily found in people of West African descent and has historically been associated with cardiomyopathy (CM). Purpose To characterize the cumulative incidence of diagnoses frequently seen with hATTR amyloidosis in V122I carriers and non-carriers in the UK Biobank (UKBB) and the Penn Medicine BioBank (PMBB). Methods UKBB and PMBB are prospective studies with ∼500,000 and ∼60,000 subjects, respectively. Clinical presentations frequently seen with hATTR amyloidosis were assessed using ICD10 diagnosis codes: G62–polyneuropathy (PN), I50 or I098–heart failure (HF), G560–carpal tunnel syndrome (CTS), I42–CM, and E85–amyloidosis. The cumulative incidence of diagnoses was estimated using Kaplan-Meier curves. Time to first hATTR amyloidosis-related diagnosis was compared between V122I carriers and non-carriers using Cox proportional hazards regression, controlling for age, sex, smoking, and genetic ancestry. Results Of the 6,062 unrelated black participants in the UKBB, 243 were V122I carriers. Only 0.8% of V122I carriers had a formal diagnosis of hATTR amyloidosis. V122I carriers were significantly more likely to have a PN diagnosis than non-carriers (p=6.35x10–5), a finding which was replicated in the PMBB. Of the ICD10 codes assessed, Cox proportional hazards regression revealed a significant association between V122I genotype and time to first diagnosis (p=2.6x10–5), with 11.1% of V122I carriers having at least one diagnosis during follow-up versus 4.9% of non-carriers. The calculated population attributable risk showed an excess risk of 16.7% for a PN diagnosis, 6.5% for HF, 4.1% for CTS, and 2.4% for CM in V122I carriers. The cumulative incidence of any hATTR amyloidosis-related diagnosis among V122I carriers by age 65 was 11.9% (95% CI=3.1–19.8%). The incidence increased to 37.4% (95% CI=20.5–50.7%) by age 75, which was significantly higher than non-carriers (13.8%, 95% CI=11.6–16%). Additionally, an assessment of the cumulative incidence of each diagnosis separately revealed that PN became more prevalent at younger ages, while HF and CM became more prevalent at older ages. Conclusions V122I carriers were significantly more likely to receive diagnoses frequently seen with hATTR amyloidosis than non-carriers. Although these diagnoses may not all be attributed to amyloidosis, the small fraction of patients diagnosed with hATTR amyloidosis suggests a potential underdiagnosis of disease. The V122I mutation has historically been associated with a cardiac phenotype, yet these data also suggest an increased incidence of PN. Increased vigilance for the mixed phenotype may lead to earlier diagnoses and treatment of V122I carriers. Funding Acknowledgement Type of funding source: Private company. Main funding source(s): Alnylam Pharmaceuticals