African Swine Fever Virus (ASFV) was originally described in Africa almost 100 years ago and is now spreading uncontrolled across Europe and Asia and threatening to destroy the domestic pork industry. Neither effective antiviral drugs nor a protective vaccine are currently available. Efforts to understand the basis for viral pathogenicity and the development of attenuated potential vaccine strains are complicated by the large and complex ASFV genome.We report here a novel method of documenting viral diversity based on profile Hidden Markov Model domains on a genome scale. The method can be used to infer genomic relationships independent of genome alignments and also reveal ASFV genome sequence differences that alter the presence of functional protein domains in the virus. We show that the method can quickly identify differences and shared patterns between virulent and attenuated ASFV strains and will be a useful tool for developing much-needed vaccines and antiviral agents to help control this virus. The tool is rapid to run and easy to implement, readily available as a simple Docker image.ASFV infections are responsible for increasing swine mortality in several parts of the world (2).Outside of Africa, the virus has been previously reported in Portugal, and in Haiti in sporadic outbreaks, probably as an import from West Africa (3)(4). Since the virus's first European appearance in Georgia in 2007, the virus has spread in wild boar populations in Europe (reviewed in (5)), with currently 3,608 cases reported in wild boar and 1,413 cases in swine as of 1 June, 2019. Disturbingly high prevalence of ASFV has been found in Chinese dried pig blood used as porcine feed additives with all 21 tested samples testing positive by PCR as well as the generation of a full ASFV genome sequence (6). Furthermore, ASFV sequences have been identified in Chinese pork imported into Korea (7). These recent European and Asian incursions and outbreaks involve p72-Genotype II ASFV and appear not to involve the soft tick stage as originally observed in some parts in Africa. At the time of writing, neither antiviral drugs/agents nor an effective vaccine are available to stop the epidemic. The ASFV virion is enveloped, spherical or pleomorphic in shape with a diameter of 175-215 nm. The virus has a linear, dsDNA genome of 170-195 kb with complementary terminal sequences. The ASFV genome encodes >150 open reading frames (ORFs) (8). In addition to known viral structural and replication proteins, there are a large number of ORFS with undefined functions. These include the multi-gene families (MGFs) that show frequent duplication, deletion or inversion across the virus family (8). Multiple examples of attenuated ASFV strains encoding changes in MGF content, indicate that MGFs have a role in ASFV virulence (