SLC19A1

protein-coding

solute carrier family 19 member 1, the group of Minor histocompatibility antigens|Solute carrier family 19

Gene summary

The membrane protein encoded by this gene is a transporter of folate and is involved in the regulation of intracellular concentrations of folate. Three transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

MANE transcript

NM_194255.4

Inheritance

ClinVar variants

P:1U:129B:90

Top phenotype

Megaloblastic anemia, folate-responsive; Immunodeficiency 114, folate-responsive

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr21:45,493,572-45,573,365

External References & Databases

Ensembl (ENSG00000173638)

Transcript & Mutation Effects

hg38 • Region Span ~79.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

megaloblastic anemia, folate-responsiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0011141

Submitter: PanelApp Australia

combined immunodeficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0015131

Submitter: PanelApp Australia

immunodeficiency 114, folate-responsiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0957955

Submitter: ClinGen

*SLC19A1* (previously known as *RFC1*) encodes the reduced folate carrier (RFC) protein, the primary transporter for folates into cells. *SLC19A1* was first reported in relation to autosomal recessive immunodeficiency 114, folate-responsive in 2020 (Svaton et al., PMID: 32276275). The disease is characterized by poor growth, oral ulcers, mucosal bleeding, recurrent respiratory tract infections, impaired T-cell proliferation, and decreased red blood cell folate levels. Three variants (two missense, and one deletion) that have been reported in four probands in three publications (PMIDs: 36517554, 36745868, 32276275) are included in this curation. The first patient (PMID: 32276275) with a homozygous missense variant showed signs of anemia and hyperhomocysteinemia, while denying having any bleeding, limb numbness, any other neurologic symptoms, or symptoms of glossitis. Two other patients with different homozygous missense mutations also reported oral bleeding, respiratory distress, and abnormal T-cell count (PMID: 36517554). Another patient with a homozygous deletion variant reported diarrhea, recurrent fevers, and gradually developed curly gray hair (PMID: 36745868). This gene-disease relationship is also supported by animal models and rescues (PMID: 11266438). No homozygous RFC1-null pups were identified, indicating that the mutation was embryonic lethal, until a dose of 1 mg of folic acid per day was administrated to RFC1 +/−dams. While there is no established null human probands, there is also no evidence to contradict that null variants in *SLC19A1* for humans would also cause a lethality. In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen PIRD GCEP on the meeting date 16th September 2025 (SOP Version 11).

Clinical Genomic Database (CGD)

Megaloblastic anemia, folate-responsive; Immunodeficiency 114, folate-responsiveAR

Manifestation: Allergy/Immunology/Infectious; Biochemical; Hematologic

Intervention: Allergy/Immunology/Infectious; Biochemical

Rationale: Immunodeficiency 114, folate-responsive can involve immunologic and infections manifestations, and awareness can enable early and aggressive treatment of infections and sequelae, including early treatment with folinic acid, which has been reported as beneficial; Megaloblastic anemia, folate-responsive can manifest with anemia, and managemement (with oral folate) has been reported as being beneficial; Immunodeficiency 114, folate-responsive

Refs: 32276275; 36517554; 36745868

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to SLC19A1 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 155

not specifiedTotal: 95

SLC19A1-related disorderTotal: 9

Megaloblastic anemia, folate-responsiveTotal: 2

Immunodeficiency 114, folate-responsiveTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_194255.4. 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	67 clinvar	10 clinvar	78
missense	1 clinvar		123 clinvar	9 clinvar	4 clinvar	137
nonsense						0
start loss			1 clinvar			1
frameshift			4 clinvar			4
splice donor/acceptor (+/-2bp)						0
Total	1	0	129	76	14	220

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 82 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_194255.4	RefSeq	NP_919231.1	5	MANE Select
ENST00000311124.9	Ensembl	ENSP00000308895.4	5	MANE Select
NM_001205206.4	RefSeq	NP_001192135.1	5	Standard
NM_001205207.3	RefSeq	NP_001192136.1	5	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)
Folate Metabolism
Ethanol effects on histone modifications
Vitamin B1 (thiamin) metabolism

Biological Process

folic acid transport
folic acid metabolic process
methotrexate transport
transmembrane transport
folate transmembrane transport

Molecular Function

folic acid binding
folic acid transmembrane transporter activity
folate:anion antiporter activity
methotrexate transmembrane transporter activity

Cellular Component

plasma membrane
integral component of plasma membrane
basolateral plasma membrane
apical plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000311124
Coding exons: 5
Length: 50840
Individuals with no LoFs: 125616
Homozygous LoFs: 0
Heterozygous LoFs: 56
Defined: 125672
p: 0.000223

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.606	350	383	0.913	0.0000282	3676
Missense (PolyPhen)		103	132.77	0.7758		1355
Synonymous	-0.284	200	195	1.03	0.0000153	1339
Loss of Function	1.11	10	14.6	0.686	7.89e-7	146

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00020	0.00018	rare
Latino/Admixed American	0.00029	0.00026	rare
Ashkenazi Jewish	0.00052	0.00050	rare
East Asian	0.000069	0.000054	rare
Finnish	0.00010	0.000092	rare
European (Non-Finnish)	0.00023	0.00020	rare
South Asian	0.00039	0.00039	rare
Other	0.00019	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Transporter for the intake of folate. Uptake of folate in human placental choriocarcinoma cells occurs by a novel mechanism called potocytosis which functionally couples three components, namely the folate receptor, the folate transporter, and a V-type H(+)-pump.;

Recessive Scores

pRec: 0.319

Intolerance Scores

LoFtool: 0.187
RVIS EVS: -0.29
RVIS percentile EVS: 33.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.125

Gene Damage Prediction

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