plof

pLoF stands for predicted loss-of-function. In genetics, a pLoF variant is a genetic alteration predicted to disrupt a gene’s ability to produce a functional protein. The term is commonly used in sequencing analyses to flag variants in coding regions that are expected to severely reduce or abolish gene function.

Typical pLoF types include stop-gained (nonsense) variants that introduce a premature stop codon, frameshift variants that alter the reading frame, and splice-site variants that disrupt normal RNA splicing at donor or acceptor sites. Some annotation schemes also treat start-lost variants, which remove the translation initiation signal, as pLoF. Depending on the annotation pipeline, other large deletions or certain complex variants may be categorized as pLoF as well.

Interpretation of pLoF variants is nuanced. Not all pLoF calls result in true loss of function in vivo. Some genes tolerate loss of one copy (haploinsufficiency varies by gene), and transcripts with alternative isoforms may escape degradation or produce functional protein. Therefore, a pLoF designation often requires further evidence, such as transcript expression data, functional studies, or population-based constraint metrics.

Data resources and metrics commonly used with pLoF include gnomAD and similar datasets, which provide high-confidence pLoF annotations and gene-level constraint measures. The pLI score, for example, indicates intolerance to loss of function, while observed-to-expected pLoF ratios quantify constraint across genes.

Applications of pLoF annotations include prioritizing candidate disease genes, interpreting rare variants in clinical genetics, and informing studies of gene function and disease mechanisms. Limitations include dependence on transcript models, tissue-specific expression, and potential annotation errors, underscoring that pLoF is a predictive category requiring careful validation.