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Introduction: Propionic acidemia (PA), a deficiency of propionyl-CoA carboxylase, is caused by biallelic pathogenic variants in PCCA or PCCB.The genotypic heterogeneity and compound heterozygosity make genotype-based phenotype severity predictions challenging, particularly when individuals do not harbor two loss-of-function (LOF) alleles.Improved understanding of the genotype-phenotype associations may help improve prognostication and guide selections of patients who could benefit from emerging liver-directed therapies.Methods: We are conducting a prospective natural history study of PA in the NIH Clinical Center (ClinicalTrials.govIdentifier: NCT02890342).Protocol visits were accomplished via outpatient visits or hospital admissions and included specialty evaluations, nutritional assessments, imaging studies, laboratory testing, biobanking of research.Cardiac, renal, hematological, hepatic, ophthalmologic, neurological and metabolic parameters were systematically evaluated.Patients underwent a 1-13 C-propionate oxidation breath test (POBT), a non-invasive whole-body measurement that largely reflects residual hepatic propionyl-CoA carboxylase activity, expressed as cumulative percent isotope dose metabolized at 120 min.Results: Fifty-nine individuals with PA were enrolled, including 52 evaluated in person and 7 virtually.Variants in PCCA were present in 20 individuals (34%) and in PCCB in 39 individuals (66%).The most frequent PCCB variant was c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), identified in 18/39 participants (46%).Seven individuals have undergone organ transplantation: five isolated liver transplants (median age 1.5 years; range 1-20), one isolated kidney transplant (age 42), and one combined liver-kidney transplant (age 21.5 years).Among non-transplanted participants, individuals harboring two LOF alleles had significantly lower propionate oxidation compared to those with other genotypes (p<0.001).This group also demonstrated lower full-scale IQ (p=0.006),lower composite Vineland scores (p=0.014),higher 3-hydroxypropionic acid levels (p=0.021), and higher C3 levels (p=0.028).In contrast, 2-methylcitric acid levels were not significantly different between groups (p=0.242).The PCCA missense variant c.782A>G (p.Glu261Gly) was associated with a severe clinical phenotype when present in trans with a LOF allele; two of three individuals harboring this variant underwent liver transplantation.In contrast, the PCCB missense variant c.683C>T (p.Pro228Leu), identified in two individuals, both of whom carried this variant in trans with the common LOF allele c.1218_1228delinsTAGAGCACAGGA (p.Gly407fs), correlated with a milder phenotype, higher propionate oxidation (mean POBT 120 min: 26.6%), and relatively lower metabolite levels (mean 3-hydroxypropionic acid 31.1 mol/L: normal < 12.4 mol/L); mean 2-methylcitric acid 10.2 mol/L: normal < 1 mol/L).Similar findings were observed in individuals with the PCCB c.1606A>G (p.Asn536Asp) variant, common in Amish communities.Conclusion: A wide spectrum of clinical severity was observed in this cohort, reflecting the underlying heterogeneity in PA.Predicting severity based solely on genotype may be challenging unless a patient carries two LOF alleles, and missense variants can be particularly difficult to classify.Integrating detailed clinical phenotyping, in vivo propionate oxidation, and metabolic biomarkers data provided additional context for assessing the impact of several missense variants on residual enzyme activity and disease course, particularly when more than one individual carried the same variant.This approach may assist in distinguishing milder from more severe presentations and has implications for patients considering liver-directed therapies, including transplantation and future investigational gene therapy options.Continued longitudinal follow-up will further refine these correlations and support individualized therapeutic decision-making.