We are excited to announce the first article by the ClinGen Hemoglobinopathy Variant Curation Expert Panel (https://www.clinicalgenome.org/affiliation/50052/), published in Human Mutation (DOI:10.1002/humu.24280), that discusses the process, challenges and considerations of specifying the ACMG/AMP guidelines for variants related to hemoglobinopathies. The ACMG/AMP guidelines comprise a series of generic criteria for the standardized interpretation and reporting of sequence variants across laboratories. Owing to the varying degrees of subjectivity and uncertainty allowed by these guidelines, the Clinical Genome Resource (ClinGen) assembles Variant Curation Expert Panels (VCEPs) to develop specifications for the ACMG/AMP framework. The ClinGen Hemoglobinopathy VCEP was created collaboratively between the ITHANET Portal (https://www.ithanet.eu/) and the Global Globin Network of the Human Variome Project (http://www.humanvariomeproject.org/gg2020/) for specifying the ACMG/AMP variant curation framework to evaluate all available evidence relevant to hemoglobinopathies and the globin genes, with the aim to standardize the curation and interpretation of variants in different conditions. The Hemoglobinopathy VCEP specifications were approved by ClinGen in April 2021 (Step 2 approval), which initiated the process of further validation and adaptation with known globin gene variants in a pilot study (toward Step 3 approval). The observations by the Hemoglobinopathy VCEP outlined in this article can help highlight the challenges generally encountered during variant curation and interpretation and during the specification of ACMG/AMP guidelines for future VCEPs.