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SLC46A1
solute carrier family 46 member 1
SLC46A1 is located on the long (q) arm of chromosome 17, at band 17q11.2. Arm ratio per GRCh38 - banding schematic.
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Clinical tests that include this
Overview
SLC46A1 encodes the proton-coupled folate transporter, a membrane protein that moves folate vitamins into cells. This transporter is crucial in the small intestine, where it facilitates the absorption of dietary folates across the brush border membrane of intestinal epithelial cells. The protein is also expressed in the brain, where it regulates the movement of folates between brain tissue and cerebrospinal fluid.
Pathogenic variants in SLC46A1 cause hereditary folate malabsorption, a rare autosomal recessive condition characterised by severely impaired folate uptake. Folates are essential for DNA synthesis, red blood cell production, and neurological development, so deficiency can lead to anaemia, immune dysfunction, and developmental delay. The gene is located on chromosome 17 and is included in multiple UK clinical genomics panels for metabolic and haematological disorders.
What the gene does
The proton-coupled folate transporter functions as a carrier protein embedded in the plasma membrane of intestinal and brain cells. It uses a proton gradient to drive the inward transport of folate molecules, operating optimally at acidic pH. This mechanism is particularly important in the duodenum and proximal jejunum, where PCFT mediates the majority of dietary folate absorption.
Folates absorbed through PCFT are subsequently converted to active coenzyme forms that participate in one-carbon metabolism. These coenzymes are required for purine and thymidine synthesis, making PCFT indirectly essential for DNA replication and repair. In the central nervous system, the transporter facilitates folate delivery across the choroid plexus, maintaining adequate folate concentrations in cerebrospinal fluid to support neuronal function and myelin synthesis. Disruption of PCFT activity therefore affects rapidly dividing tissues and the nervous system most severely.
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Chromosome location
SLC46A1 is located on the long arm of chromosome 17 at position 11.2, designated as 17q11.2. The gene spans approximately 15 kilobases of genomic DNA and comprises five exons. This chromosomal region is not associated with recurrent structural rearrangements, and pathogenic variants in SLC46A1 are typically single-nucleotide changes or small insertions and deletions rather than large deletions.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. The proton-coupled folate transporter is predicted to contain twelve transmembrane helices that form a channel through the lipid bilayer, a topology typical of solute carrier family members. The 459-amino-acid protein is thought to have both N-terminal and C-terminal regions located on the cytoplasmic side of the membrane, with multiple extracellular loops contributing to substrate recognition and binding.
Key variants
Pathogenic variants in SLC46A1 are distributed throughout the coding sequence and include missense changes, nonsense variants, and small frameshifts. Missense variants can alter single amino acids critical for folate binding or proton coupling, reducing transporter efficiency. Nonsense and frameshift variants typically produce truncated proteins that are non-functional or rapidly degraded. Because hereditary folate malabsorption follows an autosomal recessive inheritance pattern, affected individuals carry pathogenic variants on both copies of the gene.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in SLC46A1 cause hereditary folate malabsorption, a rare autosomal recessive disorder that presents in infancy with megaloblastic anaemia, immune deficiency, and neurological abnormalities. Untreated, the condition can lead to developmental delay, seizures, and failure to thrive. Early diagnosis and treatment with high-dose folinic acid can prevent many complications and support normal development. The severity of symptoms varies depending on the residual transporter activity, with some variants causing near-complete loss of function and others retaining partial activity.
No disease links recorded for this gene in our reference set.
Inheritance pattern
Conditions caused by pathogenic SLC46A1 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
SLC46A1 is included on multiple NHS Genomic Medicine Service gene panels, reflecting its clinical importance across several specialties. The gene holds green classification status on panels for cerebral folate deficiency, cytopenias and congenital anaemias, intellectual disability, likely inborn error of metabolism, and undiagnosed metabolic disorders. It is also listed on the primary immunodeficiency or monogenic inflammatory bowel disease panel and the Developmental Disorders Genotype-to-Phenotype Database (DDG2P). These panel memberships indicate that SLC46A1 sequencing is recommended when clinical features suggest folate metabolism disorders or unexplained anaemia with neurological involvement.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the proton-coupled folate transporter?
The proton-coupled folate transporter is a membrane protein that moves folate vitamins into cells by coupling their transport to the movement of protons. It is the primary mechanism by which the body absorbs folate from food in the small intestine and also operates in the brain to maintain folate levels in cerebrospinal fluid.
How is hereditary folate malabsorption inherited?
Hereditary folate malabsorption follows an autosomal recessive inheritance pattern. This means an affected individual must inherit a pathogenic variant in SLC46A1 from both parents. Parents who each carry one variant are typically unaffected carriers.
Can hereditary folate malabsorption be treated?
Research suggests that early treatment with high-dose folinic acid, a reduced form of folate that can bypass the defective transporter to some extent, can prevent or ameliorate many complications of hereditary folate malabsorption. Treatment is lifelong and requires specialist metabolic monitoring.