SLC52A3

Summary

SLC52A3 (solute carrier family 52 member 3, HGNC:16187) is a protein-coding gene on chromosome 20p13, encoding Solute carrier family 52, riboflavin transporter, member 3 (Q9NQ40). Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism.

This gene encodes a riboflavin transporter protein that is strongly expressed in the intestine and likely plays a role in intestinal absorption of riboflavin. The protein is predicted to have eleven transmembrane domains and a cell surface localization signal in the C-terminus. Mutations at this locus have been associated with Brown-Vialetto-Van Laere syndrome and Fazio-Londe disease.

Source: NCBI Gene 113278 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Brown-Vialetto-van Laere syndrome 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 500 total — 21 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 51
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_033409

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16187
Approved symbol	SLC52A3
Name	solute carrier family 52 member 3
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	bA371L19.1, hRFT2, RFVT3, RFT2
Ensembl gene	ENSG00000101276
Ensembl biotype	protein_coding
OMIM	613350
Entrez	113278

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 21 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000217254, ENST00000381944, ENST00000473664, ENST00000488495, ENST00000645534, ENST00000674666, ENST00000675066, ENST00000675466, ENST00000676154, ENST00000906489, ENST00000906490, ENST00000906491, ENST00000906492, ENST00000906493, ENST00000906494, ENST00000906495, ENST00000937376, ENST00000937377, ENST00000937378, ENST00000942447, ENST00000942448, ENST00000942449

RefSeq mRNA: 3 — MANE Select: NM_033409 NM_001370085, NM_001370086, NM_033409

CCDS: CCDS13007

Canonical transcript exons

ENST00000645534 — 5 exons

Exon	Start	End
ENSE00000655119	763498	764003
ENSE00001042524	760080	761238
ENSE00003505354	761701	761824
ENSE00003817438	768297	768500
ENSE00003900116	765208	765825

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 92.50.

FANTOM5 (CAGE): breadth broad, TPM avg 1.0599 / max 54.2742, expressed in 359 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
185990	0.8550	294
185991	0.1797	71
185989	0.0253	13

Top tissues by expression

236 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	92.50	gold quality
mucosa of transverse colon	UBERON:0004991	92.49	gold quality
left testis	UBERON:0004533	92.11	gold quality
testis	UBERON:0000473	90.42	gold quality
ileal mucosa	UBERON:0000331	88.10	gold quality
kidney epithelium	UBERON:0004819	86.88	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.66	gold quality
left ventricle myocardium	UBERON:0006566	85.63	gold quality
jejunal mucosa	UBERON:0000399	85.11	gold quality
upper arm skin	UBERON:0004263	82.91	gold quality
duodenum	UBERON:0002114	81.35	gold quality
metanephros cortex	UBERON:0010533	79.59	gold quality
apex of heart	UBERON:0002098	78.70	gold quality
heart right ventricle	UBERON:0002080	78.67	gold quality
deltoid	UBERON:0001476	78.40	silver quality
jejunum	UBERON:0002115	77.73	gold quality
biceps brachii	UBERON:0001507	77.66	gold quality
tibialis anterior	UBERON:0001385	77.54	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	77.22	gold quality
adult mammalian kidney	UBERON:0000082	77.14	gold quality
myocardium	UBERON:0002349	76.95	gold quality
quadriceps femoris	UBERON:0001377	76.87	gold quality
rectum	UBERON:0001052	76.77	gold quality
pancreatic ductal cell	CL:0002079	76.49	silver quality
metanephros	UBERON:0000081	76.44	gold quality
palpebral conjunctiva	UBERON:0001812	76.21	gold quality
small intestine	UBERON:0002108	76.09	gold quality
adult organism	UBERON:0007023	75.98	gold quality
vastus lateralis	UBERON:0001379	75.84	gold quality
small intestine Peyer’s patch	UBERON:0003454	75.60	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting SLC52A3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4269	99.55	69.89	1373
HSA-MIR-4677-3P	99.49	67.91	1246
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-1294	98.91	69.26	1030
HSA-MIR-9986	98.91	69.28	1024
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-1288-5P	98.85	67.01	734
HSA-MIR-3194-3P	98.83	66.22	1167
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-423-5P	98.69	67.48	1522

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Discusses cloning of rat riboflavin transporter 2 and identification of a comparable protein in human. (PMID:19122205)
• identified a candidate gene, C20orf54, in a consanguineous family with Brown-Vialetto-Van Laere syndrome with multiple affected individuals and subsequently demonstrated that mutations in this gene were the cause of disease in other, unrelated families (PMID:20206331)
• results indicate that riboflavin transporter 2(RFT2) is a transporter involved in the epithelial uptake of riboflavin in the small intestine for its nutritional utilization (PMID:20724488)
• Susceptibility loci at C20orf54 for esophageal squamous cell carcinoma. (PMID:20729853)
• These results demonstrate a potential role for specific cysteine residues in the cell surface expression of riboflavin transporter 2 in human intestinal epithelial cells. (PMID:21512156)
• Mutations of riboflavin transporter-2 gene is associated with Brown-Vialetto-Van Laere syndrome. (PMID:22273710)
• Single nucleotide polymorphism in C20orf54 gene is associated with esophageal squamous cell carcinoma. (PMID:22471455)
• RFT2 protein functional single nucleotide polymorphism might be associated with the development of esophageal squamous cell carcinoma. (PMID:22533825)
• Identification of novel mutations that affect amino acid changes in Brown-Vialetto-Van Laere syndrome patients. (PMID:22718020)
• Defective expression of RFT2 is associated with the development of gastric carcinoma and may result in decreased plasma riboflavin levels in GC. (PMID:22791947)
• Defective expression of C20orf54 is associated with the development of Kazak esophageal squamous cell carcinoma and this may represent a mechanism underlying the decreased plasma riboflavin levels in ESCC. (PMID:23275236)
• Intestinal riboflavin uptake process undergoes differentiation-dependent upregulation and suggest that this is mediated (at least in part) via transcriptional mechanisms of SLC52A1 and SLC52A3. (PMID:23413253)
• summary of recent findings on the cloning, nomenclature, functional characterization and genetic diseases of RFVT1/SLC52A1, RFVT2/SLC52A2 and RFVT3/SLC52A3 [review] (PMID:23506902)
• data suggest that MMND is a distinct clinical subgroup of childhood onset MND patients where the known genetic defects are so far negative. (PMID:24139842)
• the single-nucleotide polymorphism rs13042395 in C20orf54 showed a significantly lower risk of esophageal squamous cell carcinoma in the younger age group but no significant association in the older group in a Korean population. (PMID:24152165)
• C20orf54 expression were significantly up-regulated in CSCC. (PMID:24260322)
• These results strongly suggest that RFVT3 would functionally be involved in riboflavin absorption in the apical membranes of intestinal epithelial cells (PMID:24264046)
• Increase in methylation of CpG 2 and CpG 3 in hRFT2gene promoter region is associated with the genesis of cervical squamous cell carcinoma. (PMID:24761851)
• Results suggest that RFT2 contributes to esophageal squamous cell carcinoma tumorigenesis and may serve as a potential therapeutic target. (PMID:25045844)
• Binding of Sp1 to the minimal SLC52A3 promoter. (PMID:25394472)
• A close association exists between functional SNP rs3746804 in C20orf54 and susceptibility to esophageal squamous cell carcinoma (PMID:25427582)
• C20orf54 rs13042395 polymorphism was significantly associated with decreased ESCC and GCA risk especially for the subjects with under-weight or normal. (PMID:26154995)
• RFT2 plays an important role in gastric carcinogenesis by modulating riboflavin absorption (PMID:26722538)
• our knowledge, this is the first report to indicate that Rfvt3 contributes to placental riboflavin transport, and that disruption of Slc52a3 gene caused neonatal mortality with hyperlipidemia and hypoglycemia owing to riboflavin deficiency. (PMID:27272163)
• Single nucleotide polymorphism rs13042395 in the SLC52A3 TT genotype carriers were likely to have reduced lymph node metastasis and longer relapse-free survival time. (PMID:27472962)
• This study found that RFT2 was overexpressed in glioma samples compared with normal brain tissue. (PMID:27584688)
• SLC52A3 rs13042395 C>T polymorphism was associated with decreased cancer risk in the normal body mass index group, whereas no association was present in obesity group. (PMID:27600099)
• This study also identified a number of residues in the hRFVT-3 polypeptide that are important for its function/cell surface expression. (PMID:28637675)
• RFVT3 is a target for posttranscriptional regulation by miR-423-5p in intestinal epithelial cells, and this regulation has functional consequences on intestinal riboflavin (RF) uptake process. (PMID:28912250)
• Fourteen mutations in SLC52a3 were associated with Brown-Vialetto-Van Laere syndrome. (PMID:29053833)
• The riboflavin transporter-3 (SLC52A3) 5’-flanking regions contain NF-kappaB p65/Rel-B-binding sites, which are crucial for mediating SLC52A3 transcriptional activity in esophageal squamous cell carcinoma (ESCC) cells. (PMID:29428966)
• RFVT3 gene and protein expression levels were higher in DLD-1 and HT-29 compared to Caco2 cells. In tumor tissues of patients with CRC, RFVT3 gene expression levels were increased, while protein expression was reduced, with a small reduction in riboflavin amount. (PMID:29715086)
• In the in vitro model, exposing Caco-2 cells to tumor necrosis factor-alpha (TNF-alpha) led to a significant inhibition in RF uptake, an effect that was abrogated upon knocking down TNF receptor 1 (TNFR1). The inhibition in RF uptake was associated with a significant reduction in the expression of hRFVT-3 and -1 protein and mRNA levels, as well as in the activity of the SLC52A3 and SLC52A1 promoters (PMID:30156861)
• Justification for screening SLC52A3 included notable clinical similarities between Brown-Vialetto-Van Laere syndrome (PMID:30553531)
• An Association and Meta-Analysis of Esophageal Squamous Cell Carcinoma Risk Associated with PLCE1 rs2274223, C20orf54 rs13042395 and RUNX1 rs2014300 Polymorphisms. (PMID:30666517)
• Reports on 109 patients with a genetically confirmed diagnosis of riboflavin transporter deficiency are summarized in order to highlight commonly presenting clinical features and possible differences between patients with pathogenic SLC52A2 (RTD2) or SLC52A3 (RTD3) mutations. [review] (PMID:30793323)
• Functional variation of SLC52A3 rs13042395 predicts survival of Chinese gastric cancer patients. (PMID:32888389)
• BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes. (PMID:33189404)
• Promotion of rs3746804 (p. L267P) polymorphism to intracellular SLC52A3a trafficking and riboflavin transportation in esophageal cancer cells. (PMID:34223992)
• Three cases of adult-onset Brown-Vialetto-Van Laere syndrome: Novel variants in SLC52A3 gene and MRI abnormalities. (PMID:34384672)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc52a3-1	ENSDARG00000042737
mus_musculus	Slc52a3	ENSMUSG00000027463
rattus_norvegicus	Slc52a3	ENSRNOG00000005132
drosophila_melanogaster	Rift	FBGN0039882
caenorhabditis_elegans		WBGENE00021626
caenorhabditis_elegans		WBGENE00044637

Paralogs (2): SLC52A1 (ENSG00000132517), SLC52A2 (ENSG00000185803)

Protein

Protein identifiers

Solute carrier family 52, riboflavin transporter, member 3 — Q9NQ40 (reviewed: Q9NQ40)

Alternative names: Riboflavin transporter 2

All UniProt accessions (5): Q9NQ40, A0A6Q8PFG7, A0A6Q8PFQ2, A0A6Q8PHL2, A0A6Q8PHL7

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane transporter mediating the uptake by cells of the water soluble vitamin B2/riboflavin that plays a key role in biochemical oxidation-reduction reactions of the carbohydrate, lipid, and amino acid metabolism. Humans are unable to synthesize vitamin B2/riboflavin and must obtain it via intestinal absorption.

Subcellular location. Apical cell membrane. Cell membrane Cell membrane. Nucleus membrane. Cytoplasm Cytoplasm.

Tissue specificity. Predominantly expressed in testis. Highly expressed in small intestine and prostate.

Disease relevance. Brown-Vialetto-Van Laere syndrome 1 (BVVLS1) [MIM:211530] A rare neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, which develop over a relatively short period of time in a previously healthy individual. Sensorineural hearing loss may precede the neurological signs. The course is invariably progressive, but the rate of decline is variable within and between families. With disease evolution, long tract signs, lower motor neuron signs, cerebellar ataxia and lower cranial nerve (III-VI) palsies develop, giving rise to a complex picture resembling amyotrophic lateral sclerosis. Diaphragmatic weakness and respiratory compromise are some of the most distressing features, leading to recurrent chest infections and respiratory failure, which are often the cause of patients’ demise. The disease is caused by variants affecting the gene represented in this entry. Fazio-Londe disease (FALOND) [MIM:211500] A rare neurological disease characterized by progressive weakness of the muscles innervated by cranial nerves of the lower brain stem. It may present in childhood with severe neurological deterioration with hypotonia, respiratory insufficiency leading to premature death, or later in life with bulbar weakness which progresses to involve motor neurons throughout the neuroaxis. Clinical manifestations include dysarthria, dysphagia, facial weakness, tongue weakness, and fasciculations of the tongue and facial muscles. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activity is strongly inhibited by riboflavin analogs, such as lumiflavin, flavin mononucleotide (FMN), flavin adenine dinucleotide (FAD), by methylene blue, and to a lesser extent by amiloride. Riboflavin transport is Na(+)-independent at low pH but significantly reduced by Na(+) depletion under neutral pH conditions.

Similarity. Belongs to the riboflavin transporter family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NQ40-1	1, SLC52A3a	yes
Q9NQ40-2	2, SLC52A3b

RefSeq proteins (3): NP_001357014, NP_001357015, NP_212134* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009357	Riboflavin_transptr	Family

Pfam: PF06237

Catalyzed reactions (Rhea), 1 shown:

• riboflavin(in) = riboflavin(out) (RHEA:35015)

UniProt features (60 total): sequence variant 23, topological domain 12, transmembrane region 11, mutagenesis site 5, glycosylation site 2, splice variant 2, sequence conflict 2, chain 1, modified residue 1, disulfide bond 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8XSN	ELECTRON MICROSCOPY	3.29

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQ40-F1	80.60	0.55

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 251

Disulfide bonds (1): 386–463

Glycosylation sites (2): 94, 168

Mutagenesis-validated functional residues (5):

Position	Phenotype
326	no effect on cell surface localization.
386	abolishes cell surface localization.
455	no effect on cell surface localization.
463	abolishes cell surface localization.
467	abolishes cell surface localization.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-196843	Vitamin B2 (riboflavin) metabolism
R-HSA-1430728	Metabolism
R-HSA-196849	Metabolism of water-soluble vitamins and cofactors
R-HSA-196854	Metabolism of vitamins and cofactors

MSigDB gene sets: 203 (showing top): GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_ORGANIC_ANION_TRANSPORT, GOBP_CELLULAR_RESPONSE_TO_HEAT, GOBP_VITAMIN_TRANSPORT, GOBP_RESPONSE_TO_ABIOTIC_STIMULUS, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_SENSORY_PERCEPTION, GOCC_NUCLEAR_ENVELOPE, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, NUYTTEN_EZH2_TARGETS_DN, GOCC_APICAL_PART_OF_CELL, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOCC_PLASMA_MEMBRANE_REGION, GOCC_NUCLEAR_MEMBRANE, GOBP_RESPONSE_TO_HEAT

GO Biological Process (5): riboflavin metabolic process (GO:0006771), sensory perception of sound (GO:0007605), riboflavin transport (GO:0032218), cellular response to heat (GO:0034605), flavin adenine dinucleotide biosynthetic process (GO:0072388)

GO Molecular Function (2): riboflavin transmembrane transporter activity (GO:0032217), protein binding (GO:0005515)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), nuclear membrane (GO:0031965), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Metabolism of water-soluble vitamins and cofactors	1
Metabolism of vitamins and cofactors	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
flavin-containing compound metabolic process	1
sensory perception of mechanical stimulus	1
vitamin transport	1
nitrogen compound transport	1
response to heat	1
cellular response to stress	1
nucleotide biosynthetic process	1
flavin-containing compound biosynthetic process	1
flavin adenine dinucleotide metabolic process	1
riboflavin transport	1
vitamin transmembrane transporter activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
nucleus	1
nuclear envelope	1
organelle membrane	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC52A3	PLCE1	Q9P212	855
SLC52A3	DLEC1	Q9Y238	722
SLC52A3	FLAD1	Q8NFF5	669
SLC52A3	SLC25A32	Q9H2D1	592
SLC52A3	ATP8A2	Q9NTI2	576
SLC52A3	ETFDH	Q16134	559
SLC52A3	ADH1B	P00325	496
SLC52A3	RFK	Q969G6	493
SLC52A3	AADACL2	Q6P093	487
SLC52A3	OTOF	Q9HC10	460
SLC52A3	ETFB	P38117	447
SLC52A3	TMC1	Q8TDI8	438
SLC52A3	ALDH2	P05091	436
SLC52A3	RNF6	Q9Y252	435
SLC52A3	S100A14	Q9HCY8	429

IntAct

11 interactions, top by confidence:

A	B	Type	Score
SLC52A3	DNM2	psi-mi:“MI:0915”(physical association)	0.560
SLC52A3	TOR1A	psi-mi:“MI:0915”(physical association)	0.560
ATXN3	SLC52A3	psi-mi:“MI:0915”(physical association)	0.560
SLC52A3	TMEM120B	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): SLC52A3 (Synthetic Lethality), SLC52A3 (Affinity Capture-RNA), SLC52A3 (Protein-peptide), ABCB6 (Affinity Capture-MS), CCPG1 (Affinity Capture-MS), CYC1 (Affinity Capture-MS), CYP2J2 (Affinity Capture-MS), FZD2 (Affinity Capture-MS), FZD8 (Affinity Capture-MS), GBA (Affinity Capture-MS), NDFIP2 (Affinity Capture-MS), SLC44A2 (Affinity Capture-MS), TMEM120B (Affinity Capture-MS), TMEM147 (Affinity Capture-MS), TMEM186 (Affinity Capture-MS)

ESM2 similar proteins: A1A4N1, A2AWR3, A2VE54, B0S5Y3, B2RXV4, B5X4H8, C1BKZ7, D2HSA6, O00400, O54698, O54699, O75387, P28573, Q08B29, Q0VCM6, Q14542, Q28E13, Q4FZU9, Q4HX89, Q5E9R1, Q5RF58, Q60825, Q61672, Q62687, Q6AYY8, Q6BZ39, Q6BZW3, Q6GMG6, Q6PGE7, Q710D3, Q758C3, Q80WK7, Q84XI3, Q86WB7, Q8CGA3, Q8N370, Q8VXY7, Q944P0, Q94AA1, Q99808

Diamond homologs: B0S5Y3, B5MEV3, B5X4H8, C1BKZ7, D2HSA6, G4SDH4, Q3LFN0, Q4FZU9, Q5E9R1, Q6GMG6, Q863Y7, Q863Y8, Q9D6X5, Q9D8F3, Q9HAB3, Q9NQ40, Q9NWF4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

500 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	11
Uncertain significance	225
Likely benign	176
Benign	29

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070902	NM_033409.4(SLC52A3):c.550G>T (p.Glu184Ter)	Pathogenic
1074049	NM_033409.4(SLC52A3):c.85del (p.Leu29fs)	Pathogenic
140	NM_033409.4(SLC52A3):c.211G>T (p.Glu71Ter)	Pathogenic
142	NM_033409.4(SLC52A3):c.670T>C (p.Phe224Leu)	Pathogenic
1425010	NM_033409.4(SLC52A3):c.481_484dup (p.Gly162fs)	Pathogenic
145	NM_033409.4(SLC52A3):c.82C>A (p.Pro28Thr)	Pathogenic
1760485	NM_033409.4(SLC52A3):c.775C>T (p.Gln259Ter)	Pathogenic
210011	NM_033409.4(SLC52A3):c.49T>C (p.Trp17Arg)	Pathogenic
210018	NM_033409.4(SLC52A3):c.639C>G (p.Tyr213Ter)	Pathogenic
210025	NM_033409.4(SLC52A3):c.1198-2A>C	Pathogenic
2154127	NM_033409.4(SLC52A3):c.408C>G (p.Tyr136Ter)	Pathogenic
2785607	NM_033409.4(SLC52A3):c.293G>A (p.Trp98Ter)	Pathogenic
2815117	NM_033409.4(SLC52A3):c.51G>A (p.Trp17Ter)	Pathogenic
2815140	NM_033409.4(SLC52A3):c.790_791del (p.Ser264fs)	Pathogenic
2920552	NM_033409.4(SLC52A3):c.853C>T (p.Gln285Ter)	Pathogenic
3248316	NC_000020.10:g.(?745957)(749607_?)del	Pathogenic
4710522	NM_033409.4(SLC52A3):c.745G>T (p.Glu249Ter)	Pathogenic
4712184	NM_033409.4(SLC52A3):c.317dup (p.Ala107fs)	Pathogenic
4820614	NM_033409.4(SLC52A3):c.858del (p.Tyr287fs)	Pathogenic
640455	NC_000020.11:g.(?761006)(765794_?)del	Pathogenic
800969	NM_033409.4(SLC52A3):c.71G>A (p.Trp24Ter)	Pathogenic
139	NM_033409.4(SLC52A3):c.1325_1326del (p.Leu442fs)	Likely pathogenic
1709238	NM_033409.4(SLC52A3):c.742del (p.Trp248fs)	Likely pathogenic
1748142	NM_033409.4(SLC52A3):c.1203dup (p.Ser402fs)	Likely pathogenic
2427133	NC_000020.10:g.(?744142)(745909_?)del	Likely pathogenic
2583157	NM_033409.4(SLC52A3):c.374C>T (p.Thr125Ile)	Likely pathogenic
2683896	NM_033409.4(SLC52A3):c.704T>C (p.Leu235Pro)	Likely pathogenic
3340167	NM_033409.4(SLC52A3):c.1292G>A (p.Trp431Ter)	Likely pathogenic
3383371	NM_033409.4(SLC52A3):c.662del (p.Leu221fs)	Likely pathogenic
429375	NM_033409.4(SLC52A3):c.1334T>G (p.Leu445Arg)	Likely pathogenic

SpliceAI

797 predictions. Top by Δscore:

Variant	Effect	Δscore
20:764000:CTCC:C	acceptor_gain	1.0000
20:764001:TCCC:T	acceptor_loss	1.0000
20:764002:CC:C	acceptor_gain	1.0000
20:764003:CC:C	acceptor_gain	1.0000
20:764004:C:CA	acceptor_loss	1.0000
20:764005:T:A	acceptor_loss	1.0000
20:761235:CCAC:C	acceptor_gain	0.9900
20:761236:CACC:C	acceptor_gain	0.9900
20:761238:CCTGC:C	acceptor_loss	0.9900
20:761240:T:A	acceptor_loss	0.9900
20:761249:G:T	acceptor_gain	0.9900
20:761699:A:AC	donor_gain	0.9900
20:761700:C:CC	donor_gain	0.9900
20:761700:CA:C	donor_gain	0.9900
20:761711:T:TA	donor_gain	0.9900
20:761712:C:A	donor_gain	0.9900
20:761822:GACCT:G	acceptor_loss	0.9900
20:761824:CCTA:C	acceptor_loss	0.9900
20:761825:CTA:C	acceptor_loss	0.9900
20:761826:T:A	acceptor_loss	0.9900
20:763493:CACA:C	donor_loss	0.9900
20:763494:ACAC:A	donor_loss	0.9900
20:763495:CACCT:C	donor_loss	0.9900
20:763496:A:AG	donor_loss	0.9900
20:763497:CC:C	donor_loss	0.9900
20:763514:TGGAG:T	donor_gain	0.9900
20:763999:ACTCC:A	acceptor_gain	0.9900
20:764000:CTCCC:C	acceptor_gain	0.9900
20:764001:TCC:T	acceptor_gain	0.9900
20:764001:TCCCT:T	acceptor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000185549 (20:766450 C>G), RS1000226577 (20:777093 G>A,C), RS1000359267 (20:771897 G>T), RS1000468453 (20:777358 A>G), RS1000530052 (20:778237 A>G), RS1000536359 (20:760924 TACTC>T), RS1000564967 (20:777155 G>C), RS1000598681 (20:776675 C>A), RS1000881572 (20:767470 C>T), RS1000895791 (20:761878 C>A,T), RS1001001415 (20:772944 G>A,C), RS1001072957 (20:773134 C>T), RS1001140784 (20:767514 C>T), RS1001190041 (20:767867 G>T), RS1001251776 (20:767170 G>A)

Disease associations

OMIM: gene MIM:613350 | disease phenotypes: MIM:211530, MIM:211500, MIM:609129

GenCC curated gene-disease

Disease	Classification	Inheritance
Brown-Vialetto-van Laere syndrome 1	Definitive	Autosomal recessive
progressive bulbar palsy	Moderate	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Brown-Vialetto-van Laere syndrome 1	Definitive	AR

Mondo (5): Brown-Vialetto-van Laere syndrome 1 (MONDO:0024537), progressive bulbar palsy of childhood (MONDO:0100428), auditory neuropathy (MONDO:0021944), Madras motor neuron disease (MONDO:0015307), progressive bulbar palsy (MONDO:0008890)

Orphanet (4): RFVT2-related riboflavin transporter deficiency (Orphanet:572543), Riboflavin transporter deficiency (Orphanet:97229), Madras motor neuron disease (Orphanet:137867), Progressive bulbar paralysis of childhood (Orphanet:56965)

HPO phenotypes

51 total (30 of 51 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000544	External ophthalmoplegia
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001283	Bulbar palsy
HP:0001298	Encephalopathy
HP:0001308	Tongue fasciculations
HP:0001317	Abnormal cerebellum morphology
HP:0001324	Muscle weakness
HP:0001347	Hyperreflexia
HP:0001348	Brisk reflexes
HP:0001349	Facial diplegia
HP:0001605	Vocal cord paralysis
HP:0001621	Weak voice
HP:0002015	Dysphagia
HP:0002058	Myopathic facies
HP:0002078	Truncal ataxia
HP:0002093	Respiratory insufficiency
HP:0002094	Dyspnea
HP:0002098	Respiratory distress
HP:0002141	Gait imbalance
HP:0002205	Recurrent respiratory infections
HP:0002312	Clumsiness
HP:0002650	Scoliosis
HP:0002808	Kyphosis
HP:0002877	Nocturnal hypoventilation

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002180_3	Adverse response to chemotherapy in breast cancer (alopecia) (docetaxel)	7.000000e-06
GCST005355_1	Helping behaviour (self reported)	7.000000e-10
GCST008860_36	Prostate cancer	3.000000e-08

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010244	Bulbar Palsy, Progressive	C10.574.562.300; C10.668.467.300
C538268	Auditory neuropathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: transporter — SLC52 family of riboflavin transporters

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	5
sodium arsenite	affects acetylation, affects methylation, decreases methylation, increases abundance, increases expression	4
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	increases expression, decreases methylation	2
Tobacco Smoke Pollution	affects expression, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	increases expression	1
monomethylarsonous acid	affects acetylation, affects methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	increases methylation	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1
Testosterone	decreases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D4Q0	HCT116-SLC52A3-KO-c12	Cancer cell line	Male
CVCL_D4Q1	HCT116-SLC52A3-KO-c5	Cancer cell line	Male
CVCL_D4W3	LS180-SLC52A3-KO-c10	Cancer cell line	Female
CVCL_D4W4	LS180-SLC52A3-KO-c13	Cancer cell line	Female

Clinical trials (associated diseases)

5 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT03067857	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Therapy for Motor Neuron Disease
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT01023932	Not specified	COMPLETED	Auditory Neuropathy and Cochlear Implants
NCT05666466	Not specified	UNKNOWN	Noninvasive Diagnostic Techniques in Determination of Site of Lesion of Auditory Neuropathy Spectrum Disorder
NCT06125015	Not specified	COMPLETED	Unexpected ABR Results in Patients Suspected With Auditory Neuropathy Spectrum Disorder