The clinical success of CRISPR therapies is dependent on the safety and efficacy ofCas proteins. The Cas9 from Francisella novicida (FnCas9) has negligible affinity formismatched substrates enabling it to discriminate off-targets in DNA with very highprecision even at the level of binding. However, its cellular targeting efficiency is low,limiting its use in therapeutic applications. Here, we rationally engineer the protein todevelop engineered(enFnCas9) variants with enhanced activity and expand its cellularediting activity to genomic loci previously inaccessible. Notably, some of the variantsrelease the protospacer adjacent motif (PAM) constraint from NGG to NGR/NRGmaking them rank just below SpCas9-RY and SpCas9-NG in their accessibility acrosshuman genomic sites. The enFnCas9 proteins, similar to Cas12a and Cas12f, harborhigh intrinsic specificity and can diagnose single nucleotide variants accurately.Importantly, they provide superior outcomes in terms of editing efficiency, knock-inrates, and off-target specificity over other engineered high-fidelity versions of SpCas9(SpCas9-HF1 and eSpCas9). Broad targeting range coupled with remarkablespecificity of DNA interrogation underscores the utility of these variants for safe andefficient therapeutic gene correction across multiple cell lines and target loci.