NBPF3 rs4654748: Vitamin B6 and Your Genetics
The rs4654748 polymorphism is a single-nucleotide variant located on chromosome 1 within the NBPF3 genomic region, closely linked to the ALPL gene. Genome-wide association studies have identified it as a significant marker associated with circulating concentrations of pyridoxal 5'-phosphate, the active form of vitamin B6. Carrying the C allele is typically linked to lower circulating baseline blood levels of this essential nutrient.
What each genotype means
Lower circulating vitamin B6
This genotype is associated with lower blood concentrations of pyridoxal 5'-phosphate, the active form of vitamin B6. Research suggests this variant may influence how efficiently vitamin B6 is cleared from the bloodstream. Please discuss your dietary intake and nutritional status with a qualified healthcare provider or registered dietitian.
This genotype is common, with the C allele appearing at a frequency of approximately 0.41 in many populations.
Slightly reduced vitamin B6
Individuals with this genotype may show intermediate blood concentrations of vitamin B6 compared to those with the CC or TT genotypes. This association reflects how your genetics may influence your body's vitamin B6 levels. You should consult with a healthcare professional to determine if your dietary habits are appropriate for your individual needs.
This heterozygous genotype is frequently observed in the general population across various ancestries.
Normal vitamin B6 levels
This genotype is associated with normal circulating levels of vitamin B6 in the blood. It is considered the baseline or reference profile in studies examining this specific genetic variant. No specific dietary adjustments are indicated based solely on this genotype.
This genotype is common and represents the standard genetic profile for this variant in many populations.
Genomic Context and Biology of rs4654748
The single-nucleotide polymorphism rs4654748 is positioned on chromosome 1 within an intron of the neuroblastoma breakpoint family member 3 (NBPF3) gene. Although mapped inside NBPF3, this variant sits in tight linkage disequilibrium with the nearby alkaline phosphatase (ALPL) gene. ALPL encodes tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme directly responsible for hydrolyzing extracellular pyridoxal 5'-phosphate (PLP) into unphosphorylated pyridoxal so it can cross cellular membranes. Because of this genomic proximity, researchers propose that rs4654748 may act as a regulatory proxy affecting alkaline phosphatase expression or clearance dynamics, rather than altering the functional coding sequence of NBPF3 itself.
Scientific Research on Circulating Vitamin B6
Large-scale genome-wide association studies (GWAS), beginning with foundational work by Tanaka and colleagues in 2009, established rs4654748 as a robust locus for circulating vitamin B6 concentrations. The research identified that each copy of the minor C allele correlates with a statistically significant reduction in plasma PLP levels, approximately 1.4 ng/mL per allele. Subsequent meta-analyses and one-carbon metabolism studies have replicated this association with genome-wide significance (p < 5 × 10⁻⁸). Despite strong statistical linkage with plasma biomarker levels, the overall clinical evidence categorizing rs4654748 as a direct cause of overt clinical deficiency remains limited, because blood levels do not always reflect intracellular enzyme saturation.
Population Distribution and Allele Prevalence
The distribution of the rs4654748 variant displays distinct patterns across global populations. In individuals of European ancestry, the minor C allele occurs at a frequency of approximately 25% to 30%, making heterozygous and homozygous carriers relatively common. Global population databases such as gnomAD indicate that allele frequencies can vary significantly across other ancestral groups, with some cohorts demonstrating higher or lower baseline prevalence. Because most initial discovery cohorts comprised participants of European descent, ongoing research is necessary to evaluate the precise quantitative impact of this variant across diverse, non-European populations.
Clinical Interpretation and Limitations
It is essential to distinguish between a statistical biomarker association and a medical diagnosis. Carrying one or two copies of the C allele does not imply a clinical diagnosis of vitamin B6 deficiency or an enzymatic disease. Nutritional status depends on numerous non-genetic determinants, including overall dietary intake, kidney function, age, alcohol consumption, and systemic inflammation. Genetic testing results for rs4654748 should not be used as a standalone guide to megadose vitamin B6 supplements, as excessive intake of pyridoxine can lead to sensory neuropathy. Any dietary modifications or supplement regimens should be evaluated alongside conventional clinical laboratory panels and healthcare providers.
How common is this variant?
The minor C allele exhibits an estimated frequency of 0.25 to 0.30 in populations of European ancestry, with homozygous CC individuals representing roughly 5% to 9% of these cohorts.
Frequently asked questions
Does having the rs4654748 C allele mean I have a vitamin B6 deficiency?
No. The C allele is associated with lower average concentrations of pyridoxal 5'-phosphate in blood serum, but this is a statistical correlation rather than a clinical diagnosis. Most individuals carrying this allele maintain adequate functional intracellular levels through standard balanced nutrition.
Should I start taking high-dose vitamin B6 supplements if my genotype is CC?
You should not begin taking high-dose vitamin B6 supplements based purely on genetic data. Excessive pyridoxine supplementation can cause adverse side effects, including peripheral neuropathy. Always consult a healthcare professional or dietitian and check serum levels before taking targeted supplements.
Why is the variant mapped to NBPF3 if it relates to ALPL?
The rs4654748 polymorphism is physically positioned within an intron of the NBPF3 gene on chromosome 1, but it resides in tight linkage disequilibrium with the nearby ALPL gene. ALPL produces the enzyme that breaks down extracellular vitamin B6, leading researchers to hypothesize that rs4654748 serves as a genetic marker for ALPL regulatory activity.
Can diet overcome the genetic effect of the rs4654748 variant?
Yes. Dietary intake plays a central role in maintaining vitamin B6 sufficiency regardless of genotype. Consuming nutrient-rich whole foods—such as poultry, fish, chickpeas, potatoes, and bananas—generally provides adequate vitamin B6 to meet daily physiological requirements.
Sources & further reading
Educational information only, last refreshed 9/5/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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