rs375228668: Y-Chromosome Ancestry and Haplogroup E-M35
The genetic variant rs375228668, historically designated as M35.1 in phylogenetics, is a single nucleotide polymorphism located on the non-recombining portion of the human Y chromosome. It serves as the defining ancestral branch marker for paternal haplogroup E1b1b1 (E-M35). This lineage represents an important evolutionary node tracing deep paternal migrations across North Africa, East Africa, the Near East, and Southern Europe.
What each genotype means
Haplogroup E1b1b Lineage Marker
You carry the derived C allele at rs375228668 (traditionally designated M35.1 in phylogenetics), which defines the major Y-chromosome lineage haplogroup E1b1b (also called E-M215/E-M35). This non-recombining paternal marker carries no known direct medical or disease consequences and is interpreted solely as an ancestral heritage trait. It signifies unbroken direct-line paternal descent from populations that expanded through North Africa, the Horn of Africa, the Near East, and parts of southern Europe.
Carried by approximately 40% to over 70% of males in North and East African populations, as well as notable minorities across Southern Europe and the Middle East, but uncommon elsewhere globally.
Ancestral Paternal Lineage
You carry the ancestral G allele at rs375228668, indicating an absence of the defining M35.1 mutation for haplogroup E1b1b. This genotype carries no known functional impact or medical risk and represents the widespread ancestral state across most other human paternal haplogroups outside of the E1b1b branch. It indicates your direct male lineage traces back to a different branch of the human Y-chromosome phylogenetic tree.
Present in the vast majority of males globally outside of North Africa, East Africa, and Mediterranean paternal clades.
Genomic Location and Variant Classification
The single nucleotide polymorphism rs375228668 is situated on the non-recombining portion of the male-specific Y chromosome (MSY), near position 19,579,817 on the GRCh38 human reference genome assembly. While some annotations locate it in an intergenic region or flanking the male pseudogene TXLNGY, the marker is categorized as non-functional regarding gene expression and metabolic phenotypes. In phylogenetic terminology maintained by organizations such as the International Society of Genetic Genealogy (ISOGG), this variant is classic marker M35.1. Its primary biological and demographic significance lies not in disease biology or clinical dysfunction, but as a stable lineage-defining polymorphism passed strictly down patrilineal trees without meiotic recombination.
Role in Defining Y-DNA Haplogroup E-M35
In human population genetics, rs375228668 marks the divergence that separates basal clade E1b1b from the derived haplogroup E1b1b1 (commonly labeled E-M35). Extensive population sequencing—such as detailed phylogeographic studies published in journals like Genome Biology and Evolution—has shown that E-M35 bifurcates into major regional sub-branches, including E-V68 and E-Z827. Derived mutations downstream of E-M35, including sub-branches like E-M78, E-V13, and E-M81, illuminate regional expansions that accompanied major pastoralist and agricultural dispersals in the late Pleistocene and early Holocene across northeastern and northwestern Africa.
Geographic and Population Distribution
Because rs375228668 is located on the male-specific non-recombining Y chromosome, it occurs exclusively in individuals with a paternal Y chromosome. The derived lineage characterized by this transition reaches its greatest genetic diversity and prevalence across Northeast Africa, the Horn of Africa, and Northwest Africa (Maghreb), where branches like E-M81 are predominant among Berber-speaking populations. In addition, subclades such as E-V13 occur at notable frequencies in Southeastern Europe and the Balkans, reflecting Neolithic and maritime Mediterranean connections with the Near East. In global reference datasets like gnomAD and the 1000 Genomes Project, carriers are heavily localized according to patrilineal biogeography.
Clinical Significance and Interpreting Test Results
Direct-to-consumer and genealogical genotyping panels frequently test rs375228668 to assign patrilineal haplogroups. The evidence linking this variant to health-related traits, drug metabolism, or clinical conditions is non-existent; it is considered purely an ancestry informative marker. Carrying a derived or ancestral base at rs375228668 confers no known health risks, elevated disease probabilities, or cellular disadvantages. Individuals reviewing personal raw genetic data should view this variant solely through the lens of evolutionary anthropology, as it conveys historical patrilineal migratory connections rather than medical or diagnostic findings.
How common is this variant?
Because rs375228668 is situated on the Y chromosome, it is restricted to paternal lineages and absent in females. Paternal haplogroup E-M35 frequencies peak across North and East Africa (often exceeding 40-70% in specific regional cohorts) and persist at moderate to low frequencies in Mediterranean Europe and the Near East.
Frequently asked questions
Does having the rs375228668 variant increase my risk for any disease?
No. The rs375228668 variant is an ancestral single nucleotide polymorphism used exclusively for genealogical classification. It has no documented association with health conditions, cellular defects, or hereditary diseases in medical databases such as ClinVar.
Why does a consumer DNA test report two alleles for a Y-chromosome variant?
Biological males have only one Y chromosome, meaning Y-linked SNPs are technically hemizygous (carrying one copy). Many commercial microarrays process all loci through standard diploid software algorithms, artificially duplicating the single detected allele (such as displaying CC or GG instead of a single letter).
Can women have a genotype recorded at rs375228668?
Because rs375228668 is located on the non-recombining region of the Y chromosome, individuals with XX biological chromosomes do not carry this locus. In consumer raw data, females will typically show 'no call', a missing result (--), or undetermined status at this position.
What is the difference between rs375228668 and marker M35.1?
They refer to the exact same physical DNA variant on the Y chromosome. The term 'rs375228668' is the standard accession identifier assigned by the dbSNP database, whereas 'M35.1' is the classic nomenclature developed by anthropological geneticists to identify the branch defining haplogroup E-M35.
Sources & further reading
Educational information only, last refreshed 9/10/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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