SLC15A2

Summary

SLC15A2 (solute carrier family 15 member 2, HGNC:10921) is a protein-coding gene on chromosome 3q13.33, encoding Solute carrier family 15 member 2 (Q16348). Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides.

The mammalian kidney expresses a proton-coupled peptide transporter that is responsible for the absorption of small peptides, as well as beta-lactam antibiotics and other peptide-like drugs, from the tubular filtrate. This transporter, SLC15A2, belongs to the same gene family as SLC15A1 (MIM 600544), the proton-coupled peptide transporter found in the small intestine (Liu et al, 1995 [PubMed 7756356]).

Source: NCBI Gene 6565 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 123 total
• Druggable target: yes — 8 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_021082

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10921
Approved symbol	SLC15A2
Name	solute carrier family 15 member 2
Location	3q13.33
Locus type	gene with protein product
Status	Approved
Aliases	PEPT2
Ensembl gene	ENSG00000163406
Ensembl biotype	protein_coding
OMIM	602339
Entrez	6565

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000295605, ENST00000465060, ENST00000469013, ENST00000469422, ENST00000489711, ENST00000489886, ENST00000489957, ENST00000886960, ENST00000886961, ENST00000886962, ENST00000886963, ENST00000886964, ENST00000966831, ENST00000966832

RefSeq mRNA: 2 — MANE Select: NM_021082 NM_001145998, NM_021082

CCDS: CCDS3007, CCDS54631

Canonical transcript exons

ENST00000489711 — 22 exons

Exon	Start	End
ENSE00001074200	121911574	121911666
ENSE00001074209	121930840	121930950
ENSE00001074210	121923222	121923266
ENSE00001074214	121923040	121923129
ENSE00001074227	121931639	121931735
ENSE00001074231	121924351	121924383
ENSE00001074239	121939349	121939495
ENSE00001074241	121897388	121897529
ENSE00001074245	121913021	121913120
ENSE00001150442	121928421	121928555
ENSE00001150451	121927758	121927839
ENSE00001150459	121924945	121925033
ENSE00001888180	121894401	121894581
ENSE00001894212	121940831	121944188
ENSE00003463423	121922220	121922302
ENSE00003527993	121915616	121915693
ENSE00003532583	121896406	121896493
ENSE00003542425	121922775	121922861
ENSE00003590311	121929302	121929348
ENSE00003628720	121928982	121929146
ENSE00003646923	121940384	121940488
ENSE00003665064	121915227	121915317

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 97.65.

FANTOM5 (CAGE): breadth broad, TPM avg 1.5515 / max 114.8289, expressed in 253 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38204	0.7915	169
38203	0.4672	200
38205	0.1949	98
38206	0.0643	46
38202	0.0336	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nasal cavity epithelium	UBERON:0005384	97.65	gold quality
bronchial epithelial cell	CL:0002328	96.08	gold quality
epithelium of bronchus	UBERON:0002031	95.67	gold quality
bronchus	UBERON:0002185	95.49	gold quality
palpebral conjunctiva	UBERON:0001812	94.98	gold quality
nasal cavity mucosa	UBERON:0001826	94.01	gold quality
corpus epididymis	UBERON:0004359	93.62	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.48	gold quality
parotid gland	UBERON:0001831	91.48	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.43	gold quality
seminal vesicle	UBERON:0000998	89.02	gold quality
trachea	UBERON:0003126	88.78	gold quality
eye	UBERON:0000970	88.40	gold quality
epithelium of nasopharynx	UBERON:0001951	87.88	gold quality
urethra	UBERON:0000057	87.15	gold quality
entorhinal cortex	UBERON:0002728	86.85	gold quality
cranial nerve II	UBERON:0000941	86.69	gold quality
prostate gland	UBERON:0002367	86.01	gold quality
right uterine tube	UBERON:0001302	85.57	gold quality
saliva-secreting gland	UBERON:0001044	85.49	gold quality
lower lobe of lung	UBERON:0008949	85.04	gold quality
caudate nucleus	UBERON:0001873	84.89	gold quality
trabecular bone tissue	UBERON:0002483	84.76	gold quality
temporal lobe	UBERON:0001871	84.63	gold quality
minor salivary gland	UBERON:0001830	84.18	gold quality
nucleus accumbens	UBERON:0001882	84.00	gold quality
medial globus pallidus	UBERON:0002477	83.89	gold quality
bone marrow cell	CL:0002092	83.75	gold quality
amygdala	UBERON:0001876	83.67	gold quality
corpus callosum	UBERON:0002336	83.58	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.50
E-MTAB-6379	no	3.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

120 targeting SLC15A2, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-302A-3P	99.89	71.23	1777
HSA-MIR-302B-3P	99.89	71.23	1777
HSA-MIR-302C-3P	99.89	71.20	1778
HSA-MIR-302D-3P	99.89	71.25	1777
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 30)

• the two identified aminoterminal regions in mammalian peptide carriers play an important role in determining the substrate affinity and also other characteristic features of the two transporter subtypes. (PMID:11944083)
• expression, localization and functional aspects of this protein in the normal respiratory tract and in cystic fibrosis (PMID:12579467)
• Amino acid substitution at Arg57 in PEPT2 causes a complete loss of transport function. (PMID:15020234)
• polymorphisms in the gene encoding hPEPT2 can alter substrate transport and therefore could affect drug disposition in vivo (PMID:15282265)
• expression and function of the peptide transporter PepT2 (SLC15A2) in differentiated primary cultures of upper airway lung epithelia (PMID:15626774)
• functionalities of PEPT1 and PEPT2 were largely conserved in terms of glycylsarcosine uptake kinetics and inhibitor specificity (PMID:15981923)
• PEPT2-PDZK1 interaction thus plays a physiologically important role in both oligopeptide handling as well as peptide-like drug transport in the human kidney (PMID:16738539)
• does not operate as a cotransporter in tissues where there is little or no pH gradient, such as choroid plexus, lung, or mammary gland (PMID:18367661)
• PEPT2 plays a vital role in microbial recognition by nucleotide-binding oligomerization domain (NOD)-like receptor proteins (PMID:18474668)
• PEPT2 to be the dominant transporter for the reabsorption of di- and tripeptides and its pharmacological substrates in the organism, and for the removal of these substrates from the cerebrospinal fluid (PMID:18668438)
• there are no major differences in the substrate recognition pattern of hPEPT1 and rPEPT2 with regard to the ACE inhibitors tested. (PMID:18713951)
• the expression/activity of PEPT2 may be a critical factor in the modulation of opioidergic neurotransmission in vivo. (PMID:18762712)
• PEPT2 polymorphism distributions differ significantly between Chinese, Malay and Asian Indian populations. Cephalexin pharmacokinetics were not different between Chinese and Asian Indians. (PMID:18766334)
• hPEPT1 and hPEPT2 are unlikely to contribute to clinically important drug interactions in humans. (PMID:19246733)
• Higher blood lead burden in children with the PEPT2*2 mutation may suggest that this common genetic variant is a biomarker of increased vulnerability to the neurotoxic effects of lowest level lead exposure. (PMID:19723536)
• anserine is recognized by the proton-coupled peptide transporters PEPT1 and PEPT2 with medium affinity. Anserine is able to displace other substrates from the transport process. (PMID:20067523)
• Data identify Drosophila Yin and PEPT2 as evolutionarily conserved phagosome-associated transporters. (PMID:20406817)
• PepT2-mRNA is expressed in U373-MG and glial cells but showed no regulation of PepT2-mRNA expression in both cell types. (PMID:20868728)
• ALAD2 and hPEPT2*2 polymorphisms may exaggerate Pb blood burden in boys. (PMID:21327641)
• PEPT1,PEPT2, PHT1, and PHT2 are expressed in human nasal epithelium. (PMID:21366347)
• LNCaP expresses high levels of PEPT2 and PHT1. (PMID:22950754)
• JAK3 is a powerful regulator of the peptide transporters PEPT1 and PEPT2. (PMID:23934551)
• This study showed that ALAD2 and hPEPT2*2 may be valuable markers of risk, and indicate novel mechanisms of lead-induced neurotoxicity (PMID:25514583)
• OSR1 has the capacity to downregulate the peptide transporters PEPT1 and PEPT2 by decreasing the carrier protein abundance in the cell membrane (PMID:25531100)
• In vitro study displayed different response to sorafenib depending on the genotype of SLC15A2. (PMID:25965825)
• PEPT2 is functionally expressed in H441 cells, making the cell line a good in vitro model to study PEPT2 function and its regulation in human distal lung. (PMID:26168863)
• PEPT2 is expressed in keratinocytes and involved in skin oligopeptide uptake. (PMID:27216463)
• Two novel genes, SLC15A2 (rs1143671 and rs1143672) and SLCO1B3 (rs4149117 and rs7311358), are associated with the warfarin maintenance dose in a Chinese population. (PMID:29234073)
• The transporters PEPT2, PHT1, and PHT2 are responsible for the uptake of carnosine into glioblastoma cells and full function of all three transporters is required for maximum uptake. (PMID:31073693)
• Alternate expression of PEPT1 and PEPT2 in epidermal differentiation is required for NOD2 immune responses by bacteria-derived muramyl dipeptide. (PMID:31757425)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc15a2	ENSDARG00000032010
mus_musculus	Slc15a2	ENSMUSG00000022899
rattus_norvegicus	Slc15a2	ENSRNOG00000002305

Paralogs (4): SLC15A1 (ENSG00000088386), SLC15A3 (ENSG00000110446), SLC15A4 (ENSG00000139370), SLC15A5 (ENSG00000188991)

Protein

Protein identifiers

Solute carrier family 15 member 2 — Q16348 (reviewed: Q16348)

Alternative names: Kidney H(+)/peptide cotransporter, Oligopeptide transporter, kidney isoform, Peptide transporter 2

All UniProt accessions (2): C9IZ38, Q16348

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled amino-acid transporter that transports oligopeptides of 2 to 4 amino acids with a preference for dipeptides. Transports neutral and anionic dipeptides with a proton to peptide stoichiometry of 2:1 or 3:1. In kidney, involved in the absorption of circulating di- and tripeptides from the glomerular filtrate. Can also transport beta-lactam antibiotics, such as the aminocephalosporin cefadroxil, and other antiviral and anticancer drugs. Transports the dipeptide-like aminopeptidase inhibitor bestatin. Also able to transport carnosine. Involved in innate immunity by promoting the detection of microbial pathogens by NOD-like receptors (NLRs). Mediates transport of bacterial peptidoglycans across the plasma membrane or, in macrophages, the phagosome membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand.

Subunit / interactions. Interacts (via extracellular domain region) with trypsin.

Subcellular location. Apical cell membrane. Cytoplasmic vesicle. Phagosome membrane. Cell membrane.

Tissue specificity. Expressed in kidney. Not detected in intestine. Highly expressed in macrophages.

Domain organisation. The extracellular domain (ECD) region specifically binds trypsin.

Polymorphism. SLC15A2 is polymmorphic and has two main variants that differ in three amino acid positions, hPEPT21 and hPEPT22. They are distributed evenly among the population and don’t show functional differences.

Similarity. Belongs to the major facilitator superfamily. Proton-dependent oligopeptide transporter (POT/PTR) (TC 2.A.17) family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q16348-1	1	yes
Q16348-2	2

RefSeq proteins (2): NP_001139470, NP_066568* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000109	POT_fam	Family
IPR004768	Oligopep_transport	Family
IPR018456	PTR2_symporter_CS	Conserved_site
IPR029028	Alpha/beta_knot_MTases	Homologous_superfamily
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF00854

Catalyzed reactions (Rhea), 8 shown:

• glycyl-L-leucine(out) + 2 H(+)(out) = glycyl-L-leucine(in) + 2 H(+)(in) (RHEA:76167)
• glycyl-L-lysine(out) + 2 H(+)(out) = glycyl-L-lysine(in) + 2 H(+)(in) (RHEA:76171)
• glycyl-L-glutamate(out) + 3 H(+)(out) = glycyl-L-glutamate(in) + 3 H(+)(in) (RHEA:76175)
• a dipeptide(out) + 2 H(+)(out) = a dipeptide(in) + 2 H(+)(in) (RHEA:76179)
• L-alanyl-L-alanine(out) + 2 H(+)(out) = L-alanyl-L-alanine(in) + 2 H(+)(in) (RHEA:76183)
• an L-amino acid tripeptide(out) + 2 H(+)(out) = an L-amino acid tripeptide(in) + 2 H(+)(in) (RHEA:76187)
• carnosine(out) + 2 H(+)(out) = carnosine(in) + 2 H(+)(in) (RHEA:76191)
• N-acetyl-D-muramoyl-L-alanyl-D-isoglutamine(out) + 3 H(+)(out) = N-acetyl-D-muramoyl-L-alanyl-D-isoglutamine(in) + 3 H(+)(in) (RHEA:76375)

UniProt features (49 total): topological domain 13, transmembrane region 12, sequence variant 7, glycosylation site 5, modified residue 3, sequence conflict 3, region of interest 2, chain 1, compositionally biased region 1, splice variant 1, strand 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
6EZI	X-RAY DIFFRACTION	1.5
9UDC	ELECTRON MICROSCOPY	3.38
7PMY	ELECTRON MICROSCOPY	3.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16348-F1	84.17	0.45

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 (3): 9, 12, 28

Glycosylation sites (5): 435, 472, 528, 567, 587

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 227 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_CIRCULATORY_SYSTEM_PROCESS, MODULE_162, LU_IL4_SIGNALING, GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, MODULE_64, BROWNE_HCMV_INFECTION_16HR_UP, CHANDRAN_METASTASIS_DN, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, CADWELL_ATG16L1_TARGETS_DN, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, NF1_Q6_01, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP

GO Biological Process (17): protein transport (GO:0015031), peptidoglycan transport (GO:0015835), xenobiotic transport (GO:0042908), dipeptide transport (GO:0042938), renal absorption (GO:0070293), regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0070424), dipeptide import across plasma membrane (GO:0140206), tripeptide import across plasma membrane (GO:0140207), antibacterial innate immune response (GO:0140367), transport across blood-brain barrier (GO:0150104), xenobiotic detoxification by transmembrane export across the plasma membrane (GO:1990961), immune system process (GO:0002376), oligopeptide transport (GO:0006857), peptide transport (GO:0015833), innate immune response (GO:0045087), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (7): peptide:proton symporter activity (GO:0015333), tripeptide transmembrane transporter activity (GO:0042937), dipeptide transmembrane transporter activity (GO:0071916), protein binding (GO:0005515), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857), oligopeptide transmembrane transporter activity (GO:0035673)

GO Cellular Component (6): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), phagocytic vesicle membrane (GO:0030670), extracellular exosome (GO:0070062), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
nitrogen compound transport	2
dipeptide transmembrane transport	2
oligopeptide import across plasma membrane	2
oligopeptide transmembrane transporter activity	2
intracellular protein localization	1
establishment of protein localization	1
carbohydrate derivative transport	1
oligopeptide transport	1
renal system process	1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
regulation of cytoplasmic pattern recognition receptor signaling pathway	1
tripeptide transmembrane transport	1
defense response to bacterium	1
innate immune response	1
vascular transport	1
xenobiotic export from cell	1
detoxification	1
export across plasma membrane	1
biological_process	1
peptide transport	1
immune response	1
defense response to symbiont	1
cellular process	1
monoatomic cation transmembrane transport	1
solute:proton symporter activity	1
peptide transmembrane transporter activity	1
tripeptide transport	1
binding	1
secondary active transmembrane transporter activity	1
transporter activity	1
transmembrane transport	1
transmembrane transporter activity	1
oligopeptide transmembrane transport	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
endocytic vesicle membrane	1
phagocytic vesicle	1

Protein interactions and networks

STRING

1306 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC15A2	SLC22A8	Q8TCC7	670
SLC15A2	SLC22A4	Q9H015	663
SLC15A2	SLC22A5	O76082	654
SLC15A2	SLC22A6	Q4U2R8	648
SLC15A2	ACE	P12821	624
SLC15A2	SLC47A1	Q96FL8	623
SLC15A2	SLC22A2	O15244	622
SLC15A2	CARNS1	A5YM72	616
SLC15A2	SLCO2B1	O94956	592
SLC15A2	SLCO1A2	P46721	586
SLC15A2	SLC47A2	Q86VL8	572
SLC15A2	SLC22A7	Q9Y694	565
SLC15A2	SLC22A11	Q9NSA0	556
SLC15A2	ABCG2	Q9UNQ0	536
SLC15A2	SLC22A9	Q8IVM8	534
SLC15A2	SLC22A1	O15245	534

IntAct

171 interactions, top by confidence:

A	B	Type	Score
SLC15A2	KPRP	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	SMARCC1	psi-mi:“MI:0915”(physical association)	0.560
OTX1	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	TENT5B	psi-mi:“MI:0915”(physical association)	0.560
LMO4	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	ENKD1	psi-mi:“MI:0915”(physical association)	0.560
KRT34	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
VENTX	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-2	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
AQP1	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	NTAQ1	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	KLHL38	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	ANKS1A	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	C11orf87	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-3	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	CHRD	psi-mi:“MI:0915”(physical association)	0.560
PITX1	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP12-3	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	KRTAP26-1	psi-mi:“MI:0915”(physical association)	0.560
ADAM12	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	KRTAP15-1	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	PLSCR4	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	WWOX	psi-mi:“MI:0915”(physical association)	0.560
TLX3	SLC15A2	psi-mi:“MI:0915”(physical association)	0.560
SLC15A2	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A2	MAST1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A2	SHANK1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A2	PDZK1	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A2	PDZD7	psi-mi:“MI:0407”(direct interaction)	0.440
SLC15A2	GRID2IP	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (76): UQCRH (Co-fractionation), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), SLC15A2 (Two-hybrid), TLX3 (Two-hybrid), SMARCC1 (Two-hybrid)

ESM2 similar proteins: A0A0R4ILB2, A0A8M9Q308, A1A4N1, A2CER7, A5D7V7, A8WGF7, B0S5Y3, B2RXV4, B5X4H8, O00400, O00476, O01735, O23596, P30638, P36836, P46029, P60815, Q11073, Q16348, Q28722, Q28FF3, Q503P5, Q5F4B8, Q5RBM3, Q5XGK0, Q63424, Q6AYY8, Q6DDL7, Q6DIT7, Q6GMG6, Q6PB15, Q7Z3Q1, Q84XI3, Q86WB7, Q91X85, Q944P0, Q99808, Q99J27, Q9BZD2, Q9C8X2

Diamond homologs: A0A2R9TD79, A1JRI8, A2RMA8, B4EY98, D0ZGL2, O07380, P0C2U2, P0C2U3, P36836, P46029, P94408, Q16348, Q63424, Q8WMX5, Q8ZLD6, Q9ES07, A6T6E2, A8AJB3, B0S6T2, B5XZE5, C0PWD2, D0ZQC5, D2TNL4, P39276, P46059, P51574, P75742, P91679, Q17758, Q21219, Q57RM6, Q7CQY0, Q83S84, Q8X9D3, Q9JIP7, B6VMU9, O01840, Q0WP01, Q0WSZ6, Q84WG0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 96 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	5	49.2×	3e-06
Unblocking of NMDA receptors, glutamate binding and activation	5	46.9×	3e-06
Negative regulation of NMDA receptor-mediated neuronal transmission	5	46.9×	3e-06
Assembly and cell surface presentation of NMDA receptors	10	43.8×	3e-12
Dopamine Neurotransmitter Release Cycle	5	42.8×	3e-06
Long-term potentiation	5	41.0×	3e-06
Neurexins and neuroligins	10	34.0×	3e-11
Protein-protein interactions at synapses	6	27.5×	3e-06

GO biological processes:

GO term	Partners	Fold	FDR
establishment or maintenance of epithelial cell apical/basal polarity	9	60.1×	9e-12
protein localization to synapse	6	52.8×	2e-07
receptor clustering	7	50.2×	2e-08
regulation of postsynaptic membrane neurotransmitter receptor levels	7	39.9×	7e-08
protein-containing complex assembly	8	10.5×	8e-05
cell-cell adhesion	8	9.3×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	94
Likely benign	5
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3663 predictions. Top by Δscore:

Variant	Effect	Δscore
3:121897530:G:GG	donor_gain	1.0000
3:121897535:G:GT	donor_gain	1.0000
3:121913121:G:GG	donor_gain	1.0000
3:121925034:G:GG	donor_gain	1.0000
3:121928980:A:AG	acceptor_gain	1.0000
3:121928981:G:GG	acceptor_gain	1.0000
3:121929157:G:GT	donor_gain	1.0000
3:121930946:GGAGA:G	donor_gain	1.0000
3:121930947:GAGA:G	donor_gain	1.0000
3:121930947:GAGAG:G	donor_gain	1.0000
3:121930948:A:T	donor_gain	1.0000
3:121930949:GA:G	donor_gain	1.0000
3:121930951:G:GG	donor_gain	1.0000
3:121939346:A:AG	acceptor_gain	1.0000
3:121939347:A:G	acceptor_gain	1.0000
3:121896404:A:AG	acceptor_gain	0.9900
3:121896405:G:GG	acceptor_gain	0.9900
3:121896405:GACA:G	acceptor_gain	0.9900
3:121897386:A:AG	acceptor_gain	0.9900
3:121897387:G:GG	acceptor_gain	0.9900
3:121911667:G:GG	donor_gain	0.9900
3:121913020:GA:G	acceptor_gain	0.9900
3:121913118:CAT:C	donor_gain	0.9900
3:121915280:G:T	donor_gain	0.9900
3:121915610:CTTTA:C	acceptor_loss	0.9900
3:121915611:TTTA:T	acceptor_loss	0.9900
3:121915613:TAGGA:T	acceptor_loss	0.9900
3:121915614:A:AG	acceptor_gain	0.9900
3:121915615:G:GG	acceptor_gain	0.9900
3:121915615:G:GT	acceptor_loss	0.9900

AlphaMissense

4801 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:121896470:G:C	R57P	0.998
3:121913065:G:A	G158E	0.995
3:121915248:T:C	F184L	0.995
3:121915250:C:A	F184L	0.995
3:121915250:C:G	F184L	0.995
3:121896468:G:C	E56D	0.994
3:121896468:G:T	E56D	0.994
3:121897505:C:A	A104D	0.994
3:121913075:A:C	K161N	0.994
3:121913075:A:T	K161N	0.994
3:121897495:G:C	A101P	0.993
3:121913053:C:A	A154D	0.993
3:121913058:G:T	G156W	0.993
3:121913095:G:A	G168D	0.992
3:121913106:T:C	F172L	0.992
3:121913108:T:A	F172L	0.992
3:121913108:T:G	F172L	0.992
3:121897459:T:C	F89L	0.991
3:121897461:C:A	F89L	0.991
3:121897461:C:G	F89L	0.991
3:121897504:G:C	A104P	0.991
3:121913077:C:A	P162H	0.991
3:121913081:T:G	C163W	0.991
3:121913107:T:C	F172S	0.991
3:121897492:G:A	G100R	0.990
3:121897492:G:C	G100R	0.990
3:121913058:G:A	G156R	0.990
3:121913058:G:C	G156R	0.990
3:121913059:G:A	G156E	0.990
3:121913077:C:G	P162R	0.990

dbSNP variants (sampled 300 via entrez): RS1000101122 (3:121915541 C>A,G), RS1000141095 (3:121941201 G>A), RS1000289445 (3:121906679 T>C), RS1000361921 (3:121912433 C>G,T), RS1000427025 (3:121900527 A>G), RS1000547982 (3:121931402 T>A), RS1000590145 (3:121918711 A>C), RS1000638083 (3:121932891 C>A), RS1000668531 (3:121914777 G>T), RS1000711561 (3:121919061 G>T), RS1000773788 (3:121912469 G>A), RS1000851231 (3:121894695 C>G,T), RS1000860065 (3:121939164 G>A), RS1000890804 (3:121901767 A>G,T), RS1000944367 (3:121901507 A>G)

Disease associations

OMIM: gene MIM:602339 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001198_78	Multiple sclerosis	2.000000e-08
GCST005038_4	Allergic disease (asthma, hay fever or eczema)	2.000000e-08
GCST005984_8	Glomerular filtration rate	2.000000e-08
GCST007124_4	Multiple sclerosis and HDL levels (pleiotropy)	4.000000e-08
GCST007344_39	Estimated glomerular filtration rate	2.000000e-10
GCST007876_11	Estimated glomerular filtration rate	4.000000e-14
GCST008058_70	Estimated glomerular filtration rate	5.000000e-25
GCST008059_75	Estimated glomerular filtration rate	2.000000e-21
GCST008747_178	Estimated glomerular filtration rate	1.000000e-13
GCST008747_94	Estimated glomerular filtration rate	2.000000e-13
GCST010083_346	Hemoglobin levels	1.000000e-12
GCST90002383_371	Hematocrit	1.000000e-13
GCST90002384_213	Hemoglobin	2.000000e-13
GCST90002400_393	Plateletcrit	2.000000e-09
GCST90002402_318	Platelet count	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004509	hemoglobin measurement
EFO:0004348	hematocrit
EFO:0007985	platelet crit
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1743125 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

8 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 516,135 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200356	CYCLACILLIN	4	8,320
CHEMBL1605	CEFTIBUTEN	4	17,652
CHEMBL1644	CEFADROXIL	4	6,102
CHEMBL1727	CEPHALEXIN ANHYDROUS	4	59,411
CHEMBL174	AMPICILLIN	4	334,414
CHEMBL680	CEFACLOR ANHYDROUS	4	34,121
CHEMBL1235931	LEVULINIC ACID	3	34,122
CHEMBL242948	CARNOSINE	3	21,993

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2257212	Efficacy	3	sorafenib	Hepatocellular Carcinoma

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2257212	SLC15A2	3	2.50	1	sorafenib
rs1143671	SLC15A2		0.00	0
rs1143672	SLC15A2		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: transporter — SLC15 family of peptide transporters

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
Lys[Z(NO2)]-Lys[Z(NO2)]	Inhibition	8.0	pKi
Lys[Z(NO2)]-Val	Inhibition	7.0	pKi
Lys[Z(NO2)]-Pro	Inhibition	6.2	pKi
4-AMBA	Inhibition	2.5	pKi

ChEMBL bioactivities

46 potent at pChembl≥5 of 119 total, top 44 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.52	Ki	300	nM	CHEMBL434535
6.52	Ki	302	nM	CHEMBL434535
6.10	Ki	800	nM	CHEMBL286852
6.10	Ki	794.3	nM	CHEMBL286852
5.77	Ki	1700	nM	CHEMBL364928
5.77	Ki	1698	nM	CHEMBL364928
5.70	Ki	2000	nM	CHEMBL190272
5.70	Ki	1995	nM	CHEMBL190272
5.60	Ki	2500	nM	CEFADROXIL
5.60	Ki	2500	nM	CHEMBL90069
5.60	Ki	2512	nM	CHEMBL90069
5.55	Ki	2800	nM	CEFADROXIL
5.52	Ki	3000	nM	CEFADROXIL
5.52	Ki	3000	nM	CHEMBL1222165
5.52	Ki	3020	nM	CEFADROXIL
5.52	Ki	3020	nM	CHEMBL1222165
5.46	Ki	3500	nM	CHEMBL91241
5.46	Ki	3467	nM	CHEMBL91241
5.42	Ki	3800	nM	MDL-28170
5.42	Ki	3802	nM	MDL-28170
5.40	Ki	4000	nM	CHEMBL188866
5.40	Ki	3981	nM	CHEMBL188866
5.36	Ki	4400	nM	CHEMBL316103
5.36	Ki	4365	nM	CHEMBL316103
5.22	Ki	6000	nM	CHEMBL17697
5.22	Ki	6000	nM	CHEMBL190179
5.22	Ki	6000	nM	CHEMBL1814492
5.22	Ki	6000	nM	CHEMBL1814495
5.22	Ki	6026	nM	CHEMBL17697
5.22	Ki	6026	nM	CHEMBL190179
5.22	Ki	6026	nM	CHEMBL1814492
5.22	Ki	6026	nM	CHEMBL1814495
5.16	Ki	7000	nM	CHEMBL94250
5.16	Ki	7000	nM	CHEMBL192867
5.15	Ki	7079	nM	CHEMBL94250
5.15	Ki	7079	nM	CHEMBL192867
5.10	Ki	8000	nM	CHEMBL66839
5.10	Ki	8000	nM	CHEMBL91090
5.10	Ki	7943	nM	CHEMBL91090
5.05	Ki	9000	nM	CHEMBL447844
5.05	Ki	9000	nM	CHEMBL189887
5.05	Ki	8913	nM	CHEMBL447844
5.05	Ki	8913	nM	CHEMBL189887
5.00	Ki	1e+04	nM	CHEMBL189210

PubChem BioAssay actives

46 with measured affinity, of 185 total; 22 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	0.3000	uM
(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]-3-(1H-indol-3-yl)propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	0.7943	uM
(2S)-2-[[2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]acetyl]amino]-3-(4-hydroxyphenyl)propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	1.6982	uM
(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-4-methylsulfanylbutanoyl]amino]-4-methylsulfanylbutanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	1.9953	uM
Cefadroxil	679833: TP_TRANSPORTER: inhibition of Chephalexin uptake in SKPT cells	ki	2.5000	uM
(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	2.5000	uM
(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-4-methylsulfanylbutanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	3.0000	uM
(2S)-2-[(2-aminoacetyl)amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	3.4674	uM
(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]-3-phenylpropanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	3.8000	uM
(2S)-2-[[(2S)-2-amino-3-(1H-indol-3-yl)propanoyl]amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	3.9811	uM
(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	4.3652	uM
(2S)-2-[[(2S)-2-aminopropanoyl]amino]-3-hydroxypropanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	6.0000	uM
(2S)-2-[[(2S)-2-[[(2R)-2-amino-4-methylsulfanylbutanoyl]amino]-4-methylsulfanylbutanoyl]amino]-4-methylsulfanylbutanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	6.0000	uM
(2S)-2-[[(2S)-2-aminopropanoyl]amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	6.0000	uM
(2S)-2-[[(2S)-6-amino-2-(benzylamino)hexanoyl]amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	6.0000	uM
2-[[(2S)-2-aminopropanoyl]amino]acetic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	7.0000	uM
(2S)-2-[[(2S)-2-amino-3-hydroxypropanoyl]amino]propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	7.0000	uM
(2S)-2-[[(2S,3S)-2-amino-3-methylpentanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	7.9433	uM
(2S)-6-amino-2-[[(2S)-2-amino-3-carboxypropanoyl]amino]hexanoic acid	678822: TP_TRANSPORTER: inhibition of Gly-Sar uptake in PEPT2-expressing HeLa cells	ki	8.0000	uM
(2S)-2-[[(2S)-2-[[(2S)-2-amino-3-methylbutanoyl]amino]propanoyl]amino]-4-methylpentanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	8.9125	uM
(2S)-2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]-3-phenylpropanoic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	8.9125	uM
(2S)-1-[(2S)-2-amino-4-methylpentanoyl]pyrrolidine-2-carboxylic acid	612540: Binding affinity to human PepT2 in SKTP cells	ki	10.0000	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tobacco Smoke Pollution	affects expression, decreases expression	5
Progesterone	affects cotreatment, increases expression, decreases expression	3
glycylsarcosine	decreases reaction, increases uptake	2
Aerosols	decreases expression	2
Estradiol	affects cotreatment, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
benazepril	decreases reaction, increases uptake	1
spirapril	decreases reaction, increases uptake	1
quinaprilat	decreases reaction, increases uptake	1
di-n-butylphosphoric acid	affects expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
(+)-JQ1 compound	increases expression	1
Temozolomide	affects response to substance	1
Sunitinib	decreases expression	1
Zoledronic Acid	decreases expression	1
Quinapril	decreases reaction, increases uptake	1
Air Pollutants	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Calcitriol	increases expression, affects cotreatment	1
Carmustine	affects response to substance	1
Enalapril	decreases reaction, increases uptake	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Dihydrotestosterone	increases expression	1
Testosterone	affects cotreatment, increases expression	1

ChEMBL screening assays

20 unique, capped per target: 16 functional, 4 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1743154	ADMET	Substrates of transporters of clinical importance in the absorption and disposition of drugs, PEPT2	Membrane transporters in drug development. — Nat Rev Drug Discov
CHEMBL2075812	Functional	TP_TRANSPORTER: inhibition of Chephalexin uptake in SKPT cells	Differential recognition of beta -lactam antibiotics by intestinal and renal peptide transporters, PEPT 1 and PEPT 2. — J Biol Chem

Cellosaurus cell lines

2 cell lines: 1 transformed cell line, 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4DM	HEK-SLC15A2-KO-c9	Transformed cell line	Female
CVCL_D4HW	HCT116-SLC15A2-KO-c9	Cancer cell line	Male

Clinical trials (associated diseases)

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