SLC46A1

protein-coding

solute carrier family 46 member 1, the group of Solute carrier family 46

Gene summary

This gene encodes a transmembrane proton-coupled folate transporter protein that facilitates the movement of folate and antifolate substrates across cell membranes, optimally in acidic pH environments. This protein is also expressed in the brain and choroid plexus where it transports folates into the central nervous system. This protein further functions as a heme transporter in duodenal enterocytes, and potentially in other tissues like liver and kidney. Its localization to the apical membrane or cytoplasm of intestinal cells is modulated by dietary iron levels. Mutations in this gene are associated with autosomal recessive hereditary folate malabsorption disease. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Aug 2013]

MANE transcript

NM_080669.6

Inheritance

ClinVar variants

P:32U:149B:119

Top phenotype

Folate malabsorption, hereditary

gnomAD constraint

pLI —, LoF o/e 0.37

Max pathogenic AF

—

Genomic locus

chr17:28,394,642-28,407,197

External References & Databases

Ensembl (ENSG00000076351)

Transcript & Mutation Effects

hg38 • Region Span ~12.6 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

hereditary folate malabsorptionSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: Orphanet

hereditary folate malabsorptionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: Ambry Genetics

hereditary folate malabsorptionDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: ClinGen

SLC46A1 was first reported in relation to autosomal recessive hereditary folate malabsorption (HFM) in 2006 (Qiu et al., PMID: 17129779). HFM is characterized by impaired intestinal folate absorption and reduced transport of folate into the central nervous system, resulting in systemic and cerebrospinal fluid folate deficiency. Clinical manifestations include megaloblastic anemia, recurrent infections, hypogammaglobulinemia, failure to thrive, and neurologic impairment. Findings are usually reversible with parenteral folate administration. The immunologic phenotype is thought to result from impairment of DNA synthesis and lymphocyte proliferation. Heterozygous carriers do not manifest clinical symptoms. Seventeen unique variants (8 missense, 9 null) identified in fifteen probands from nine publications (PMIDs: 17129779, 17446347, 20005757, 20795774, 21333572, 23816405, 24534056, 29390264, 33146883) were included in this curation. Additional supporting cases have been reported in the literature, including segregation data (PMID: 20005757); however, the maximum score for genetic evidence (12 points) has been reached. The disease mechanism is loss of function of the proton-coupled folate transporter (PCFT), resulting in impaired folate absorption and transport. Multiple patient-derived variants have been shown experimentally to abolish or markedly reduce folate transport activity (PMIDs: 17129779, 21602279, 17446347). Additional experimental evidence supports this gene–disease relationship. SLC46A1 knockout mice develop severe pancytopenia with macrocytic anemia and impaired erythroid maturation due to systemic folate deficiency, recapitulating key features of human disease (PMID: 21346251). Qiu et al. demonstrated that PCFT is highly active at acidic pH, localizes to the plasma membrane, and is highly expressed in the duodenum, consistent with folate absorption in the proximal small intestine. They also show that patient-derived mutant proteins exhibit markedly reduced or absent folate transport activity compared with wild-type PCFT (PMID: 17129779). In summary, there is definitive evidence supporting the relationship between SLC46A1 and autosomal recessive hereditary folate malabsorption. This relationship has been replicated in both research and clinical diagnostic settings and has been consistently upheld over time. This classification was approved by the ClinGen SCID-CID GCEP on July 16, 2026 (SOP Version 12).

hereditary folate malabsorptionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: PanelApp Australia

hereditary folate malabsorptionDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: G2P

hereditary folate malabsorptionSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009238

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Folate malabsorption, hereditaryAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Gastrointestinal; Hematologic; Neurologic

Intervention: Biochemical

Rationale: Individuals may present in infancy with anemia, diarrhea, infections/immune deficiency, and cognitiive impairment, and treatment (eg, with folate/folinic acid supplementation) can be effective

Refs: 5450108; 3987728; 2381546; 11804211; 11807405; 7129779; 17641272; 18559978; 17446347; 21333572; 21489556

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC46A1 variants in ClinVar

7 Conditions Cataloged

not providedTotal: 277

Congenital defect of folate absorptionTotal: 51

Inborn genetic diseasesTotal: 45

not specifiedTotal: 36

SLC46A1-related disorderTotal: 13

Intellectual disabilityTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_080669.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar	104 clinvar		105
missense	5 clinvar	4 clinvar	146 clinvar	15 clinvar		170
nonsense	2 clinvar	2 clinvar				4
start loss		1 clinvar				1
frameshift	12 clinvar	3 clinvar	1 clinvar			16
splice donor/acceptor (+/-2bp)	1 clinvar	2 clinvar	1 clinvar			4
Total	20	12	149	119	0	300

Highest pathogenic variant AF is 0.00007126038

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 18 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_080669.6	RefSeq	NP_542400.2	5	MANE Select
ENST00000612814.5	Ensembl	ENSP00000480703.1	5	MANE Select
NM_001242366.3	RefSeq	NP_001229295.1	4	Standard
ENST00000581516.1	Ensembl	ENSP00000462942.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Methotrexate Pathway, Pharmacokinetics
Vitamin digestion and absorption - Homo sapiens (human)
Mineral absorption - Homo sapiens (human)
Folate malabsorption, hereditary
Methylenetetrahydrofolate Reductase Deficiency (MTHFRD)

Biological Process

cellular iron ion homeostasis
folic acid transport
heme transport
folic acid metabolic process
methotrexate transport

Molecular Function

folic acid binding
folic acid transmembrane transporter activity
proton transmembrane transporter activity
heme transporter activity
methotrexate transmembrane transporter activity

Cellular Component

cytoplasm
plasma membrane
cell surface
integral component of membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000440501
Coding exons: 6
Length: 12555
Individuals with no LoFs: 3989
Homozygous LoFs: 120652
Heterozygous LoFs: 1
Defined: 124642
p: 0.821

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.24	201	257	0.782	0.0000143	2877
Missense (PolyPhen)		86	117.76	0.73029		1314
Synonymous	1.82	93	118	0.787	0.00000676	1020
Loss of Function	2.14	5	13.5	0.371	6.66e-7	156

Population LoF Frequency

Population	CAF	p-value	Status
African	1.0	0.77	notable
Latino/Admixed American	1.0	0.84	notable
Ashkenazi Jewish	1.0	0.87	notable
East Asian	1.0	0.84	notable
Finnish	1.0	0.86	notable
European (Non-Finnish)	1.0	0.81	notable
South Asian	1.0	0.83	notable
Other	1.0	0.82	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Has been shown to act both as an intestinal proton- coupled high-affinity folate transporter and as an intestinal heme transporter which mediates heme uptake from the gut lumen into duodenal epithelial cells. The iron is then released from heme and may be transported into the bloodstream. Dietary heme iron is an important nutritional source of iron. Shows a higher affinity for folate than heme. {ECO:0000269|PubMed:17129779, ECO:0000269|PubMed:17156779, ECO:0000269|PubMed:17446347, ECO:0000269|PubMed:17475902}.;

Recessive Scores

pRec: 0.156

Essentials

Essential (CRISPR2): N
Indispensability pred.: N
Indispensability score: 0.245

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium