SLC5A4

Summary

SLC5A4 (solute carrier family 5 member 4, HGNC:11039) is a protein-coding gene on chromosome 22q12.3, encoding Probable glucose sensor protein SLC5A4 (Q9NY91). Does not function as sodium/D-glucose symporter.

Predicted to enable low-affinity D-glucose:sodium symporter activity. Predicted to be involved in D-glucose transmembrane transport and sodium ion transport. Predicted to act upstream of or within proton transmembrane transport. Predicted to be located in membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 6527 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 114 total
• MANE Select transcript: NM_014227

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11039
Approved symbol	SLC5A4
Name	solute carrier family 5 member 4
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Aliases	SAAT1, SGLT3, DJ90G24.4
Ensembl gene	ENSG00000100191
Ensembl biotype	protein_coding
OMIM	618633
Entrez	6527

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000266086

RefSeq mRNA: 1 — MANE Select: NM_014227 NM_014227

CCDS: CCDS13903

Canonical transcript exons

ENST00000266086 — 15 exons

Exon	Start	End
ENSE00000653378	32218464	32218725
ENSE00000653379	32220920	32221022
ENSE00000653380	32224267	32224482
ENSE00000653382	32225655	32225823
ENSE00000653390	32247411	32247515
ENSE00000653391	32248743	32248802
ENSE00000879965	32234873	32235093
ENSE00000879966	32251770	32251874
ENSE00000911204	32230968	32231075
ENSE00000911206	32254142	32254213
ENSE00000911207	32255195	32255347
ENSE00001626704	32229194	32229344
ENSE00001688297	32238985	32239090
ENSE00001787189	32237244	32237324
ENSE00001801487	32232899	32233034

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 77.24.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1248 / max 133.0594, expressed in 7 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193740	0.1248	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
duodenum	UBERON:0002114	77.24	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.33	silver quality
buccal mucosa cell	CL:0002336	76.01	silver quality
endometrium epithelium	UBERON:0004811	73.66	gold quality
metanephric glomerulus	UBERON:0004736	72.12	gold quality
paraflocculus	UBERON:0005351	69.46	gold quality
frontal pole	UBERON:0002795	68.81	gold quality
middle frontal gyrus	UBERON:0002702	68.37	gold quality
islet of Langerhans	UBERON:0000006	66.17	gold quality
smooth muscle tissue	UBERON:0001135	63.23	gold quality
small intestine	UBERON:0002108	62.93	gold quality
upper lobe of left lung	UBERON:0008952	61.81	gold quality
body of uterus	UBERON:0009853	61.72	gold quality
small intestine Peyer’s patch	UBERON:0003454	61.22	gold quality
sural nerve	UBERON:0015488	60.94	silver quality
right lung	UBERON:0002167	60.76	gold quality
left lobe of thyroid gland	UBERON:0001120	60.04	gold quality
upper lobe of lung	UBERON:0008948	59.75	gold quality
thyroid gland	UBERON:0002046	59.68	gold quality
right lobe of thyroid gland	UBERON:0001119	59.63	gold quality
endocervix	UBERON:0000458	57.81	gold quality
ectocervix	UBERON:0012249	56.75	gold quality
gall bladder	UBERON:0002110	56.73	gold quality
cerebellar vermis	UBERON:0004720	56.67	gold quality
omental fat pad	UBERON:0010414	56.61	gold quality
peritoneum	UBERON:0002358	56.56	gold quality
left uterine tube	UBERON:0001303	56.17	gold quality
cortex of kidney	UBERON:0001225	56.16	gold quality
adipose tissue of abdominal region	UBERON:0007808	55.73	gold quality
pancreas	UBERON:0001264	55.70	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.06
E-GEOD-99795	no	6.02

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 8)

• determination that SGLT3 is not a Na+/glucose cotransporter but instead a glucose sensor in the plasma membrane of cholinergic neurons, skeletal muscle, and other tissues (PMID:13130073)
• substrate specificity study of imino sugars with hSGLT3; results for hSGLT3 are compared with those for alpha-glucosidases and human SGLT type 1 (PMID:17110502)
• Suggest SGLT3 may be a possible candidate for changes in membrane potential of skeletal muscle during periods of glucose-supplemented exercise. (PMID:18198291)
• hSGLT3 functions as a sugar sensor in vivo and mutating a single amino acid converts this sugar sensor into a sugar transporter similar to SGLT1. (PMID:20421923)
• the expression and functional role of SGLT3 in the human kidney (PMID:22766068)
• Data suggest SGLT3 in neurons of portal vein wall plays role in sensing blood glucose level and in satiety response; dietary protein indirectly affects satiety response via up-regulation of intestinal gluconeogenesis and thus blood glucose. [REVIEW] (PMID:25200297)
• Whole-exome sequencing (WES) of several extended pedigrees with high density of attention-deficit/hyperactivity disorder (ADHD) identified a triplet ATG deletion in SLC5A4 leading to a single amino acid loss (DeltaM500) in the hSGLT3 protein imperfectly co-segregating with the clinical phenotype of ADHD. [DeltaM500] in hSGLT3 inhibits membrane targeting and thus largely disrupts glucose-induced sodium conductance. (PMID:30286162)
• Intestinal sodium/glucose cotransporter 3 expression is epithelial and downregulated in obesity. (PMID:33385407)

Cross-species orthologs

16 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc5a8l	ENSDARG00000003697
mus_musculus	Slc5a4a	ENSMUSG00000020229
rattus_norvegicus	Slc5a4	ENSRNOG00000049734
drosophila_melanogaster	CG2187	FBGN0017448
drosophila_melanogaster	rumpel	FBGN0029950
drosophila_melanogaster	SLC5A11	FBGN0031998
drosophila_melanogaster	bumpel	FBGN0037895
drosophila_melanogaster	ChT	FBGN0038641
drosophila_melanogaster	salt	FBGN0039872
drosophila_melanogaster	Smvt	FBGN0039873
drosophila_melanogaster	CG31262	FBGN0051262
drosophila_melanogaster	CG31668	FBGN0051668
drosophila_melanogaster	CG33124	FBGN0053124
drosophila_melanogaster	kumpel	FBGN0250757
caenorhabditis_elegans		WBGENE00000501
caenorhabditis_elegans		WBGENE00014092

Paralogs (12): SLC5A1 (ENSG00000100170), SLC5A5 (ENSG00000105641), SLC5A7 (ENSG00000115665), SLC5A9 (ENSG00000117834), SLC5A6 (ENSG00000138074), SLC5A2 (ENSG00000140675), SLC5A12 (ENSG00000148942), SLC5A10 (ENSG00000154025), SLC5A11 (ENSG00000158865), SLC5A3 (ENSG00000198743), SLC5A8 (ENSG00000256870), (ENSG00000293606)

Protein

Protein identifiers

Probable glucose sensor protein SLC5A4 — Q9NY91 (reviewed: Q9NY91)

Alternative names: Solute carrier family 5 member 4

All UniProt accessions (1): Q9NY91

UniProt curated annotations — full annotation on UniProt →

Function. Does not function as sodium/D-glucose symporter. However, may function as a D-glucose sensor by generating a D-glucose-induced depolarization which is pH-independent, Na(+)-dependent at neutral pH and probably H(+)-dependent at acidic pH.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in skeletal muscle, where it may localize to the neuromuscular junction (at protein level). Expressed in small intestine where it may localize to cholinergic neurons of the submucosal plexus and myenteric plexus (at protein level). Detected in kidney (at protein level).

Activity regulation. Inhibited by phlorizin.

Miscellaneous. Although it belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family, lacks Na(+)/glucose symporter activity.

Similarity. Belongs to the sodium:solute symporter (SSF) (TC 2.A.21) family.

RefSeq proteins (1): NP_055042* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001734	Na/solute_symporter	Family
IPR018212	Na/solute_symporter_CS	Conserved_site
IPR038377	Na/Glc_symporter_sf	Homologous_superfamily

Pfam: PF00474

UniProt features (32 total): topological domain 11, transmembrane region 11, sequence conflict 3, sequence variant 2, chain 1, region of interest 1, compositionally biased region 1, glycosylation site 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NY91-F1	85.31	0.51

Functional residue map

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

Glycosylation sites (1): 248

Mutagenesis-validated functional residues (1):

Position	Phenotype
457	confers sugar transport activity not found in the wild-type protein. increased sensitivity to inhibitor phlorizin.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-189200	Cellular hexose transport
R-HSA-382551	Transport of small molecules
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 83 (showing top): GOBP_CARBOHYDRATE_TRANSPORT, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, HNF1_Q6, GOBP_MONOATOMIC_CATION_TRANSPORT, HNF1_C, HNF1_01, GOBP_RENAL_ABSORPTION, GOBP_IMPORT_INTO_CELL, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_SODIUM_ION_TRANSPORT, MODULE_342, GOBP_RENAL_SYSTEM_PROCESS, MODULE_69, GOMF_METAL_ION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_MONOATOMIC_CATION_TRANSMEMBRANE_TRANSPORTER_ACTIVITY

GO Biological Process (4): sodium ion transport (GO:0006814), monoatomic ion transport (GO:0006811), sodium ion transmembrane transport (GO:0035725), transmembrane transport (GO:0055085)

GO Molecular Function (3): solute:sodium symporter activity (GO:0015370), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
SLC-mediated transmembrane transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	2
metal ion transport	1
sodium ion transport	1
monoatomic cation transmembrane transport	1
cellular process	1
sodium ion transmembrane transporter activity	1
solute:monoatomic cation symporter activity	1
binding	1
transporter activity	1
transmembrane transport	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

955 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC5A4	Q92681	Q92681	924
SLC5A4	SLC2A2	P11168	628
SLC5A4	TAS1R2	Q8TE23	606
SLC5A4	TAS1R3	Q7RTX0	580
SLC5A4	SLC2A5	P22732	538
SLC5A4	SLC2A11	Q9BYW1	536
SLC5A4	SLC2A7	Q6PXP3	512
SLC5A4	H7C1H1	H7C1H1	511
SLC5A4	SLC2A12	Q8TD20	495
SLC5A4	SLC2A8	Q9NY64	490
SLC5A4	SLC2A14	Q8TDB8	445
SLC5A4	SLC2A6	Q9UGQ3	436
SLC5A4	SLC2A13	Q96QE2	413
SLC5A4	SLC35E4	Q6ICL7	382
SLC5A4	GNAT3	A8MTJ3	375
SLC5A4	ALDH18A1	P54886	375

IntAct

16 interactions, top by confidence:

A	B	Type	Score
KASH5	SLC5A4	psi-mi:“MI:0915”(physical association)	0.560
TMEM237	SLC5A4	psi-mi:“MI:0915”(physical association)	0.560
MS4A3	SLC5A4	psi-mi:“MI:0915”(physical association)	0.560
GOLM1	SLC5A4	psi-mi:“MI:0915”(physical association)	0.560
OPRPN	SLC5A4	psi-mi:“MI:0915”(physical association)	0.400
SLC5A4	GPR89A	psi-mi:“MI:0914”(association)	0.350
SLC5A4	CLGN	psi-mi:“MI:0914”(association)	0.350
SLC5A4	KASH5	psi-mi:“MI:0915”(physical association)	0.000
SLC5A4	TMEM237	psi-mi:“MI:0915”(physical association)	0.000
SLC5A4	MS4A3	psi-mi:“MI:0915”(physical association)	0.000
SLC5A4	GOLM1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): GOLM1 (Two-hybrid), MS4A3 (Two-hybrid), TMEM237 (Two-hybrid), CCDC155 (Two-hybrid), PIGM (Affinity Capture-MS), YIPF3 (Affinity Capture-MS), TMEM39B (Affinity Capture-MS), OMA1 (Affinity Capture-MS), CERS6 (Affinity Capture-MS), FITM2 (Affinity Capture-MS), GOLGA5 (Affinity Capture-MS), ERMP1 (Affinity Capture-MS), GPR89A (Affinity Capture-MS), ICAM4 (Affinity Capture-MS), FADS1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1D8PDB5, A0A1D8PNR5, A1A654, C8V329, D3ZIS0, F4KD71, F9X9V3, I1RAK8, K3UII4, L7WU90, O14035, O74248, O74537, O80592, O94469, P05316, P17064, P22152, P31636, P32837, P33413, P38090, P38196, P38724, P38731, P39980, P40039, P53099, Q04895, Q05998, Q08485, Q08579, Q09887, Q10279, Q12119, Q21434, Q42400, Q4WGE2, Q7XBS0, Q874L4

Diamond homologs: A0PJK1, A8I1B9, A8WHP3, D3ZIS0, P11170, P13866, P26429, P26430, P31636, P31637, P31639, P53790, P53791, P53792, P53793, P53794, P96169, Q28610, Q28728, Q2M3M2, Q3ZC26, Q5FY69, Q5SWY8, Q6R4Q5, Q8C3K6, Q8K0E3, Q8VDT1, Q8WWX8, Q91ZP4, Q923I7, Q9ET37, Q9JKZ2, Q9NY91, Q9Z1F2, P31448

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1853 predictions. Top by Δscore:

Variant	Effect	Δscore
22:32218726:C:CC	acceptor_gain	1.0000
22:32220916:TTACC:T	donor_loss	1.0000
22:32220919:C:A	donor_loss	1.0000
22:32220919:CCTT:C	donor_gain	1.0000
22:32220946:T:TA	donor_gain	1.0000
22:32221018:TACAG:T	acceptor_gain	1.0000
22:32221019:ACAG:A	acceptor_gain	1.0000
22:32221020:CAG:C	acceptor_gain	1.0000
22:32221020:CAGC:C	acceptor_gain	1.0000
22:32221021:AG:A	acceptor_gain	1.0000
22:32221022:GC:G	acceptor_loss	1.0000
22:32221023:C:CC	acceptor_gain	1.0000
22:32221023:C:T	acceptor_loss	1.0000
22:32221028:C:CT	acceptor_gain	1.0000
22:32221029:A:T	acceptor_gain	1.0000
22:32221035:C:CT	acceptor_gain	1.0000
22:32221035:C:T	acceptor_gain	1.0000
22:32224405:C:CA	donor_gain	1.0000
22:32225650:CTCA:C	donor_loss	1.0000
22:32225651:TCA:T	donor_loss	1.0000
22:32225652:CAC:C	donor_loss	1.0000
22:32225653:A:AT	donor_loss	1.0000
22:32225820:TATC:T	acceptor_gain	1.0000
22:32225821:ATCC:A	acceptor_loss	1.0000
22:32225822:TC:T	acceptor_gain	1.0000
22:32225823:CC:C	acceptor_gain	1.0000
22:32225823:CCTG:C	acceptor_loss	1.0000
22:32225824:C:CC	acceptor_gain	1.0000
22:32225825:T:A	acceptor_loss	1.0000
22:32229190:TCA:T	donor_loss	1.0000

AlphaMissense

4297 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:32225793:G:C	S437R	0.991
22:32225793:G:T	S437R	0.991
22:32225795:T:G	S437R	0.991
22:32229298:G:C	S392R	0.991
22:32229298:G:T	S392R	0.991
22:32229300:T:G	S392R	0.991
22:32232913:C:G	R336P	0.990
22:32232915:G:C	S335R	0.990
22:32232915:G:T	S335R	0.990
22:32232917:T:G	S335R	0.990
22:32229268:G:C	S402R	0.988
22:32229268:G:T	S402R	0.988
22:32229270:T:G	S402R	0.988
22:32231015:C:G	C361S	0.986
22:32231016:A:T	C361S	0.986
22:32229274:G:C	S400R	0.985
22:32229274:G:T	S400R	0.985
22:32229276:T:G	S400R	0.985
22:32231045:C:G	C351S	0.980
22:32231046:A:T	C351S	0.980
22:32234932:A:G	W276R	0.980
22:32234932:A:T	W276R	0.980
22:32229336:C:G	G380R	0.978
22:32231016:A:G	C361R	0.978
22:32232926:C:A	G332W	0.977
22:32233021:C:G	R300P	0.977
22:32229194:C:G	R427P	0.976
22:32231063:C:G	C345S	0.976
22:32231064:A:T	C345S	0.976
22:32255248:C:G	D28H	0.976

dbSNP variants (sampled 300 via entrez): RS1000001733 (22:32304417 C>T), RS1000076488 (22:32352011 T>A), RS1000081190 (22:32259597 C>T), RS1000084762 (22:32292501 T>C), RS1000098395 (22:32300262 T>C), RS1000118163 (22:32265733 G>A,C), RS1000120746 (22:32350983 C>T), RS1000150776 (22:32347171 G>A), RS1000184165 (22:32318454 G>A,T), RS1000188467 (22:32288697 C>T), RS1000201332 (22:32354326 T>A,C), RS1000248961 (22:32234411 T>G), RS1000277414 (22:32349183 C>T), RS1000288578 (22:32276022 G>A), RS1000295788 (22:32333806 C>T)

Disease associations

OMIM: gene MIM:618633 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003773_10	Loneliness (multivariate analysis)	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007865	loneliness measurement

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 — Hexose transporter family

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	3
sodium arsenite	affects methylation	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
abrine	increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methapyrilene	increases methylation	1
Valproic Acid	increases methylation	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TN99	HAP1 SLC5A4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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