Although individually uncommon, rare diseases (RD) affect an estimated 300 million people worldwide. Establishing a public health approach to RD requires counting diseases and affected patients. However, RD are under-represented in medical terminologies, with only a small fraction of RD possessing specific and unambiguous codes, and those codes not being explicitly designated as rare.

To tackle the challenge of RD codification and interoperability, Orphanet has developed a nomenclature of RD that provides unique and time-stable disease identifiers (ORPHAcodes) and meets the gold standards for implementation in health information systems and systematic research collections. The Orphanet Nomenclature of RD is multilingual and versioned; its development and updates rely on standardized procedures, manual curation and expert validation, reflecting advancements in RD knowledge and clinical practice.

This work provides an overview of the Orphanet Nomenclature and classification system for RD, detailing its production, update and mapping methodology. As of July 2025, the Orphanet Nomenclature contains a total of 6,527 RD, multiclassified into 29 classifications, each corresponding to a medical domain, accurately representing the complex multisystemic nature of RD. Extensive qualified mappings ensure semantic interoperability across multiple terminologies. Overall, 97.4% of RD are mapped to at least one ICD-10 code (with only 6.3% exhibiting an exact equivalence), 71.7% are mapped to at least one ICD-11 code (15.3% with an exact equivalence) and 93.8% are mapped to SNOMED CT (all with an exact equivalence). Genetic diseases represent 72.2% of all RD, and 63.4% are mapped to at least one phenotypic OMIM number.

By addressing the underrepresentation of RD in medical terminologies, ORPHAcodes facilitate accurate patient identification, advance research and healthcare interoperability, and help in shaping public health policies. The recognition of the Orphanet Nomenclature as the most appropriate terminology for RD clinical coding in Europe underscores its critical role in the global RD ecosystem.

The authors have declared no competing interest.

Yes

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

N/A

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data supporting this study are publicly available. Orphanet provides open access to rare disease nomenclature, classification, genetic data, and mappings to other terminologies (https://www.orpha.net). Structured datasets for large-scale analysis are distributed via the Orphadata Science platform (https://sciences.orphadata.com/) and archived in a dedicated GitHub repository (https://github.com/Orphanet/Orphadata_aggregated). Additional resources include the Orphanet Rare Disease Ontology (ORDO, https://www.orphadata.com/ordo/) and the ORPHAcodes platform (https://www.orphacode.org/). All formats are maintained and updated annually or bi-annually to ensure accuracy and accessibility. For this study, the following datasets and versions were used: - Rare diseases and alignments with terminologies and databases datasets (<iso>_product1.xml) in English, Czech, Dutch, French, German, Italian, Polish, Portuguese and Spanish version 1.3.42 / 4.1.8 [2025-03-03] released 24 Jun 2025: https://sciences.orphadata.com/alignments/ - Orphanet-SNOMED-CT mapping file (ORPHA-SNOMEDCT_Mapping_File_production.xlsx) July 2024 version, released 15 Oct 2024: https://www.orphacode.org/pack-nomenclature/ - Linearization of rare diseases English dataset (en_product7.xml) version 1.3.42 / 4.1.8 [2025-03-03] released 24 Jun 2025: https://sciences.orphadata.com/linearisation/ - Genes associated with rare diseases English dataset (en_product6.xml) version 1.3.42 / 4.1.8 [2025-03-03] released 24 Jun 2025: https://sciences.orphadata.com/genes/ - Classifications of rare diseases English datasets (en_product3_<x>.xml) version 1.3.42 / 4.1.8 [2025-03-03] released 24 Jun 2025: https://sciences.orphadata.com/classifications/