# Rh blood group system
The Rh blood group system is a family of red blood cell surface antigens defined by the RHD and RHCE genes, which encode transmembrane proteins carrying the D, C, c, E, and e antigens; after ABO, it is the most clinically significant blood group system in transfusion medicine.[1](https://www.nature.com/nature-index/topics/l4/molecular-genetics-of-rh-blood-group-variants) • [2](https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-group-system)
| Key fact | Detail |
|---|---|
| ISBT designation | System 004, symbol RH, genes RHD and RHCE, chromosome 1p36.11, CD240[3](https://www.isbtweb.org/asset/3BBBD515-1BF4-4EF4-80E9858F10C2B1AB/) |
| Discovery | 1939/40, by Karl Landsteiner, Alex Wiener, Philip Levine, and R.E. Stetson; soon recognized as the cause of the majority of transfusion reactions[4](https://www.aabb.org/blood-biotherapies/blood/transfusion-medicine/transfusion-medicine-resources/transfusion-medicine-history) |
| Five major antigens | D, C, E, c, and e; D is the most clinically important antigen in the system[5](https://www.dghs.mohfw.gov.in/uploads/assets/QxrLHZs7kH7VIBtakQ3Xxt7xjy4rfUdzffPWNnam.pdf) • [2](https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-group-system) |
| D frequency | 85% of Caucasians, 92% of Blacks, and 99% of Asians carry D[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK2261/pdf/Bookshelf_NBK2261.pdf) |
| Allele count | 55 Rh antigens, over 400 RHD alleles, and over 150 RHCE alleles recognized by the ISBT[7](https://aob.amegroups.org/article/view/6532/html) |
| Prevention | Rh immune globulin introduced commercially in 1967 to prevent Rh disease in newborns of Rh-negative women[4](https://www.aabb.org/blood-biotherapies/blood/transfusion-medicine/transfusion-medicine-resources/transfusion-medicine-history) |
## Discovery and early history
The first clinical report came in 1939, when Philip Levine and R.E. Stetson described a pregnant woman who developed postpartum hemorrhage and was transfused with her husband's blood. Levine and Stetson tested her serum against multiple ABO-matched donors and found agglutination with 80% of the donor samples, indicating an antibody to something other than the ABO antigens.[8](https://www.ncbi.nlm.nih.gov/books/NBK594252/) In 1939/40 the Rh blood group system was formally identified by [Karl Landsteiner](https://www.edgepedia.org/karl-landsteiner), Alex Wiener, Philip Levine, and R.E. Stetson, and was soon recognized as the cause of the majority of transfusion reactions; the AABB history places the identification of the Rh factor next to the discovery of ABO as one of the most important breakthroughs in blood banking.[4](https://www.aabb.org/blood-biotherapies/blood/transfusion-medicine/transfusion-medicine-resources/transfusion-medicine-history)
**The name Rhesus.** Landsteiner and Wiener discovered the first Rhesus antiserum during experiments using blood-group agglutination to study evolutionary relationships among primates, and then worked toward an explanation of the inheritance of the Rh+ and Rh− antigens.[9](https://www.cambridge.org/core/journals/british-journal-for-the-history-of-science/article/writing-printing-speaking-rhesus-bloodgroup-genetics-and-nomenclatures-in-the-midtwentieth-century/F31AFFECEC27A490A622DE4BEFDD1D7A) In 1940 Landsteiner and Wiener reported the identification of the Rh factor and its influence on the consequences of transfusions between people of different groups.[10](https://www.ojp.gov/pdffiles1/Digitization/46413NCJRS.pdf)
## Genetics and proteins
Molecular studies showed that the system rests on two homologous genes, RHD and RHCE, at the RH locus on chromosome 1.[11](https://www.isbtweb.org/asset/9C74B9EA-CF18-45BD-806A0D783632CF6E/) RHD encodes the D protein, while RHCE encodes the protein carrying the C/c and E/e antigens.[12](https://pubmed.ncbi.nlm.nih.gov/7888828/) The RhCE protein carries the C/c antigen in its second extracellular loop and the E/e antigen in its fourth, plus additional antigens such as Cw and Cx.[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK2261/pdf/Bookshelf_NBK2261.pdf) At the amino acid level, a serine-to-proline substitution at position 103 determines C versus c specificity, and a proline-to-alanine substitution at position 226 determines E versus e.[2](https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-group-system)
**Membrane assembly.** Unlike most cell surface molecules, the Rh proteins are not glycosylated, but they are closely associated with a red cell membrane glycoprotein called RhAG.[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK2261/pdf/Bookshelf_NBK2261.pdf) Expression of either Rh protein requires RhAG for proper assembly on the red cell membrane, so defects in RHAG cause the loss of both RhD and RhCE proteins.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC3042511/)
**Variant mechanisms.** Rh-variant phenotypes arise through at least four mechanisms: rearrangements of the tandemly arranged RHCE and/or RHD genes, point mutations causing amino acid changes, nonsense mutations, and nucleotide deletions producing a frameshift and premature stop codon.[14](https://ashpublications.org/blood/article/95/2/375/138582/The-Rh-blood-group-system-a-review) Gene conversion appears to be the principal mechanism responsible for polymorphism in the RH system.[12](https://pubmed.ncbi.nlm.nih.gov/7888828/) A weak D type is a variant RhD protein with substitutions in the transmembrane or intracellular segments that expresses a reduced amount of D antigen, generally fewer than 5,000 D antigens per red cell.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC3042511/)
## Antigens, frequencies, and nomenclature
The five principal antigens are D, C, E, c, and e, and they are highly immunogenic, meaning they can induce antibody production when recognized as foreign by a person who lacks them.[5](https://www.dghs.mohfw.gov.in/uploads/assets/QxrLHZs7kH7VIBtakQ3Xxt7xjy4rfUdzffPWNnam.pdf) • [15](https://www.lemonde.fr/realites-biomedicales/article/2025/04/30/quand-une-personne-possede-deux-populations-de-globules-rouges-genetiquement-differentes_6601969_6579630.html) Population frequencies vary widely: D is present in 85% of Caucasians, 92% of Blacks, and 99% of Asians; C in 68%, 27%, and 93%; E in 29%, 22%, and 39%; c in 80%, 96%, and 47%; and e in 98%, 98%, and 96% of these groups respectively.[6](https://www.ncbi.nlm.nih.gov/sites/books/NBK2261/pdf/Bookshelf_NBK2261.pdf)
Four nomenclatures have been used for the system: Fisher-Race, Wiener, Rosenfield, and ISBT.[5](https://www.dghs.mohfw.gov.in/uploads/assets/QxrLHZs7kH7VIBtakQ3Xxt7xjy4rfUdzffPWNnam.pdf) In 1962 Richard E. Rosenfield introduced a numerical terminology in which blood lacking the D antigen is noted as Rh:−1; this system lent itself to computerization and became the basis of the ISBT terminology for all blood groups.[11](https://www.isbtweb.org/asset/9C74B9EA-CF18-45BD-806A0D783632CF6E/) The count of recognized antigens has grown with molecular methods: a 2020 review counted 55 Rh antigens, over 400 RHD alleles, and over 150 RHCE alleles recognized by the ISBT, and a 2026 update reported four new antigens, PARG, CEVF, CEWA, and CETW (RH60 to RH63), attributing the many newly reported RHCE alleles to increased adoption of DNA-based testing in immunohematology laboratories.[7](https://aob.amegroups.org/article/view/6532/html) • [16](https://pubmed.ncbi.nlm.nih.gov/42490338/)
## Clinical significance
Rh antibodies can cause severe transfusion reactions and in this respect are second only to the ABO system.[17](https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2824.2008.00188.x) The D antigen is the most clinically important antigen within the system.[2](https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-group-system) Rh immune globulin, introduced commercially in 1967, prevents [Rh disease](https://www.edgepedia.org/rh-disease) in the newborns of Rh-negative women.[4](https://www.aabb.org/blood-biotherapies/blood/transfusion-medicine/transfusion-medicine-resources/transfusion-medicine-history)
**Variant alleles in practice.** Cross-reactive RHCE alleles such as RHCE*ceHAR and RHCE*ceCF may type as D positive with some monoclonal anti-D reagents, and hybrid alleles and allele dropout complicate DNA-based typing; the 2026 RHCE review also discusses the association between RHCE alleles and specific RHD alleles as common haplotypes.[16](https://pubmed.ncbi.nlm.nih.gov/42490338/) Red cell genotyping is used to identify patients or donors with variant Rh alleles.[18](https://pubmed.ncbi.nlm.nih.gov/38910442/) For patients with sickle cell disease and thalassemia, the International Collaboration for Transfusion Medicine Guidelines recommends selecting ABO, Rh (D, C, c, E, e), and K matched red cells even in the absence of alloantibodies.[19](https://aob.amegroups.org/article/view/11898/html)
**Rh null and acquired changes.** In Rh null phenotypes, compatible allogeneic blood is scarce, and Rh null alloimmunization in pregnancy can be extremely difficult to manage in the setting of hemolytic disease of the fetus and newborn.[13](https://pmc.ncbi.nlm.nih.gov/articles/PMC3042511/) Rh type can also change acquired: loss of heterozygosity on chromosome 1 affecting RHD and RHCE produces Rh mosaicism, with mixed populations of D positive and D negative red cells, a phenomenon reported to affect at least one person in 500 over age 60, and a documented leukemia case involved a somatic deletion in the D-encoding gene shifting a patient from Rh positive to Rh negative.[15](https://www.lemonde.fr/realites-biomedicales/article/2025/04/30/quand-une-personne-possede-deux-populations-de-globules-rouges-genetiquement-differentes_6601969_6579630.html)
## References
1. [Molecular Genetics of Rh Blood Group Variants, Nature Index](https://www.nature.com/nature-index/topics/l4/molecular-genetics-of-rh-blood-group-variants)
2. [Blood Group System – an overview, ScienceDirect Topics](https://www.sciencedirect.com/topics/medicine-and-dentistry/blood-group-system)
3. [Table of blood group systems v12.0, ISBT (31 May 2025)](https://www.isbtweb.org/asset/3BBBD515-1BF4-4EF4-80E9858F10C2B1AB/)
4. [Transfusion Medicine History, AABB](https://www.aabb.org/blood-biotherapies/blood/transfusion-medicine/transfusion-medicine-resources/transfusion-medicine-history)
5. [5. Rh blood group system, DGHS (India) training material](https://www.dghs.mohfw.gov.in/uploads/assets/QxrLHZs7kH7VIBtakQ3Xxt7xjy4rfUdzffPWNnam.pdf)
6. [Blood Groups and Red Cell Antigens, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/sites/books/NBK2261/pdf/Bookshelf_NBK2261.pdf)
7. [Floch et al., Molecular genetics of the Rh blood group system: alleles and antibodies – a narrative review, Annals of Blood](https://aob.amegroups.org/article/view/6532/html)
8. [Rh Blood Group System, StatPearls, NCBI Bookshelf](https://www.ncbi.nlm.nih.gov/books/NBK594252/)
9. [Writing, printing, speaking: Rhesus blood-group genetics and nomenclatures in the mid-twentieth century, BJHS, Cambridge Core](https://www.cambridge.org/core/journals/british-journal-for-the-history-of-science/article/writing-printing-speaking-rhesus-bloodgroup-genetics-and-nomenclatures-in-the-midtwentieth-century/F31AFFECEC27A490A622DE4BEFDD1D7A)
10. [Major achievements in blood group research, NCJRS document](https://www.ojp.gov/pdffiles1/Digitization/46413NCJRS.pdf)
11. [Blood group systems 133, ISBT](https://www.isbtweb.org/asset/9C74B9EA-CF18-45BD-806A0D783632CF6E/)
12. [Defining the Rh blood group antigens. Biochemistry and molecular genetics, PubMed](https://pubmed.ncbi.nlm.nih.gov/7888828/)
13. [Molecular genetics and clinical applications for RH, PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC3042511/)
14. [The Rh blood group system: a review, Blood (ASH)](https://ashpublications.org/blood/article/95/2/375/138582/The-Rh-blood-group-system-a-review)
15. [Quand une personne possède deux populations de globules rouges génétiquement différentes, Le Monde](https://www.lemonde.fr/realites-biomedicales/article/2025/04/30/quand-une-personne-possede-deux-populations-de-globules-rouges-genetiquement-differentes_6601969_6579630.html)
16. [The Rh blood group system: RHCE update, Immunohematology (PubMed)](https://pubmed.ncbi.nlm.nih.gov/42490338/)
17. [Blood group systems, Smart, ISBT Science Series (Wiley)](https://onlinelibrary.wiley.com/doi/10.1111/j.1751-2824.2008.00188.x)
18. [When and why is red blood cell genotyping applicable in transfusion medicine: a systematic review, PubMed](https://pubmed.ncbi.nlm.nih.gov/38910442/)
19. [Transfusion with blood group genotype matching: advances, limitations, and challenges, Annals of Blood](https://aob.amegroups.org/article/view/11898/html)
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*Topic: Encyclopedia › Life and health › Human health and medicine › Human structure and function › Cardiovascular and lymphatic systems › Blood groups and transfusion medicine*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license