SLC15A4

Summary

SLC15A4 (solute carrier family 15 member 4, HGNC:23090) is a protein-coding gene on chromosome 12q24.33, encoding Solute carrier family 15 member 4 (Q8N697). Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response.

Enables several functions, including L-histidine transmembrane transporter activity; peptide:proton symporter activity; and peptidoglycan transmembrane transporter activity. Involved in dipeptide import across plasma membrane; peptidoglycan transport; and positive regulation of pattern recognition receptor signaling pathway. Located in endolysosome membrane.

Source: NCBI Gene 121260 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 85 total
• MANE Select transcript: NM_145648

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23090
Approved symbol	SLC15A4
Name	solute carrier family 15 member 4
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	PHT1, PTR4
Ensembl gene	ENSG00000139370
Ensembl biotype	protein_coding
OMIM	615806
Entrez	121260

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000266771, ENST00000366292, ENST00000376740, ENST00000376744, ENST00000535272, ENST00000539703, ENST00000544112, ENST00000545031, ENST00000868021, ENST00000868022, ENST00000923390, ENST00000923391, ENST00000923392, ENST00000923393, ENST00000964260, ENST00000964261, ENST00000964262, ENST00000964263, ENST00000964264

RefSeq mRNA: 1 — MANE Select: NM_145648 NM_145648

CCDS: CCDS9264

Canonical transcript exons

ENST00000266771 — 8 exons

Exon	Start	End
ENSE00000937822	128809943	128810111
ENSE00001203278	128793194	128794356
ENSE00001203283	128823398	128823958
ENSE00003462507	128808788	128808956
ENSE00003482074	128809396	128809473
ENSE00003554402	128800854	128801009
ENSE00003564986	128814775	128815070
ENSE00003718044	128799259	128799417

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 97.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.7537 / max 434.1587, expressed in 1804 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
134129	13.3648	1803
134128	0.4781	136
134124	0.3743	98
134123	0.1969	43
134125	0.1161	25
134127	0.0745	12
134121	0.0509	9
134119	0.0391	10
134126	0.0270	7
134116	0.0122	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	97.61	gold quality
secondary oocyte	CL:0000655	96.56	gold quality
tibialis anterior	UBERON:0001385	96.32	gold quality
blood	UBERON:0000178	95.59	gold quality
sperm	CL:0000019	94.40	gold quality
deltoid	UBERON:0001476	94.25	gold quality
gastrocnemius	UBERON:0001388	93.77	gold quality
muscle of leg	UBERON:0001383	93.17	gold quality
cartilage tissue	UBERON:0002418	93.05	gold quality
skeletal muscle organ	UBERON:0014892	92.87	gold quality
epithelial cell of pancreas	CL:0000083	92.82	gold quality
synovial joint	UBERON:0002217	92.73	gold quality
thymus	UBERON:0002370	92.60	gold quality
granulocyte	CL:0000094	92.58	gold quality
quadriceps femoris	UBERON:0001377	92.11	gold quality
saphenous vein	UBERON:0007318	91.69	gold quality
skeletal muscle tissue	UBERON:0001134	91.65	gold quality
leukocyte	CL:0000738	91.56	gold quality
ascending aorta	UBERON:0001496	91.53	gold quality
thoracic aorta	UBERON:0001515	91.48	gold quality
descending thoracic aorta	UBERON:0002345	91.47	gold quality
upper arm skin	UBERON:0004263	91.42	gold quality
vastus lateralis	UBERON:0001379	91.38	gold quality
layer of synovial tissue	UBERON:0007616	91.37	gold quality
monocyte	CL:0000576	91.33	gold quality
calcaneal tendon	UBERON:0003701	91.32	gold quality
urethra	UBERON:0000057	91.20	gold quality
pericardium	UBERON:0002407	91.09	gold quality
muscle tissue	UBERON:0002385	91.06	gold quality
bone marrow	UBERON:0002371	90.95	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	48.26
E-MTAB-9467	yes	15.15
E-CURD-122	yes	13.79
E-MTAB-9067	yes	13.19
E-MTAB-8498	yes	12.14
E-ANND-3	yes	5.75
E-MTAB-6678	yes	4.79

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting SLC15A4, 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-4673	100.00	66.64	1490
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-124-3P	99.89	73.74	3043

Literature-anchored findings (GeneRIF, showing 16)

• Significant associations were found for the single nucleotide polymorphism rs10847697 of SLC15A4 with discoid rash in patients with systemic lupus erythematosus (PMID:20516000)
• PEPT1,PEPT2, PHT1, and PHT2 are expressed in human nasal epithelium. (PMID:21366347)
• LNCaP expresses high levels of PEPT2 and PHT1.PC-3 demonstrates strong expression of PEPT1 and PHT1. (PMID:22950754)
• Report role of SLC15A4 genetic variants in confering risk of systemic lupus erythematosus in Chinese population. (PMID:24091983)
• Mutations in SLC15A4,a peptide transporter in NFkB signaling pathway, have been implicated in Systemic Lupus Erythematosus development in susceptible individuals. (PMID:25034154)
• Under a dominant model the rs1385374 (TT+CT) SNP carried a higher risk of Systemic Lupus Erythematosus (SLE) than (CC). Under a codominant model the genotype frequencies of rs3765108 AG and rs7308691 AT were significantly higher in the SLE group than the control group. One SLC15A4 haplotype (TA), which consists of 2 SNPs (rs959989 and rs983492), was associated with SLE (PMID:27362648)
• Study established a novel cell model to evaluate the function of hPHT1 in vitro and confirmed that muramyl peptide and Tri-DAP were substrates of hPHT1. (PMID:29224352)
• Targeted sequencing of two candidate genes, SLC20A1 and SLC15A4, of the solute carrier membrane transport protein family in 200 additional patients demonstrated two further variants predicted as damaging for combined hormone deficiency. (PMID:29261175)
• 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)
• identification of TASL as the component that links endolysosomal TLRs to the IRF5 transcription factor via SLC15A4 provides a mechanistic explanation for the involvement of these proteins in systemic lupus erythematosus (PMID:32433612)
• Human SLC15A4 is crucial for TLR-mediated type I interferon production and mitochondrial integrity. (PMID:33560415)
• Whole exome sequencing identifies novel germline variants of SLC15A4 gene as potentially cancer predisposing in familial colorectal cancer. (PMID:35562597)
• Identification of SLC15A4/PHT1 Gene Products Upregulation Marking the Intestinal Epithelial Monolayer of Ulcerative Colitis Patients. (PMID:36361959)
• Oligopeptide/Histidine Transporter PHT1 and PHT2 - Function, Regulation, and Pathophysiological Implications Specifically in Immunoregulation. (PMID:37610621)
• A conformation-locking inhibitor of SLC15A4 with TASL proteostatic anti-inflammatory activity. (PMID:37863876)
• Structural basis for recruitment of TASL by SLC15A4 in human endolysosomal TLR signaling. (PMID:37863913)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	slc15a4	ENSDARG00000102612
mus_musculus	Slc15a4	ENSMUSG00000029416
rattus_norvegicus	Slc15a4	ENSRNOG00000000962

Paralogs (4): SLC15A1 (ENSG00000088386), SLC15A3 (ENSG00000110446), SLC15A2 (ENSG00000163406), SLC15A5 (ENSG00000188991)

Protein

Protein identifiers

Solute carrier family 15 member 4 — Q8N697 (reviewed: Q8N697)

Alternative names: Peptide transporter 4, Peptide/histidine transporter 1

All UniProt accessions (3): Q8N697, B6ZDF2, H7BYB7

UniProt curated annotations — full annotation on UniProt →

Function. Proton-coupled amino-acid transporter that mediates the transmembrane transport of L-histidine and some di- and tripeptides from inside the lysosome to the cytosol, and plays a key role in innate immune response. Preferably binds to short peptides with a basic residue at the first position and a hydrophobic residue at the second position. Able to transport a variety of di- and tripeptides, including carnosine and some peptidoglycans. Transporter activity is pH-dependent and maximized in the acidic lysosomal environment. Involved in the detection of microbial pathogens by toll-like receptors (TLRs) and NOD-like receptors (NLRs), probably by mediating transport of bacterial peptidoglycans across the endolysosomal membrane: catalyzes the transport of certain bacterial peptidoglycans, such as muramyl dipeptide (MDP), the NOD2 ligand, and L-alanyl-gamma-D-glutamyl-meso-2,6-diaminoheptanedioate (tri-DAP), the NOD1 ligand. Required for TLR7, TLR8 and TLR9-mediated type I interferon (IFN-I) productions in plasmacytoid dendritic cells (pDCs). Independently of its transporter activity, also promotes the recruitment of innate immune adapter TASL to endolysosome downstream of TLR7, TLR8 and TLR9: TASL recruitment leads to the specific recruitment and activation of IRF5. Required for isotype class switch recombination to IgG2c isotype in response to TLR9 stimulation. Required for mast cell secretory-granule homeostasis by limiting mast cell functions and inflammatory responses.

Subunit / interactions. May form a homodimer. Interacts with TASL (via N-terminus); leading to TASL recruitment to endolysosome.

Subcellular location. Lysosome membrane. Endosome membrane. Early endosome membrane.

Tissue specificity. Highly expressed in skeletal muscle. Moderately expressed in kidney, liver, and heart. Weakly expressed in colon and brain. Expressed in low levels throughout the gastrointestinal tract and in Caco-2 cells. Expressed in retinal fragment epithelium (RPE) and neural retina. Expressed in small intestine, stomach, duodenum, jejunum, ileum and colon.

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

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N697-1	1	yes
Q8N697-2	2

RefSeq proteins (1): NP_663623* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000109	POT_fam	Family
IPR018456	PTR2_symporter_CS	Conserved_site
IPR036259	MFS_trans_sf	Homologous_superfamily

Pfam: PF00854

Catalyzed reactions (Rhea), 5 shown:

• L-alanyl-gamma-D-glutamyl-meso-2,6-diaminopimelate(out) + n H(+)(out) = L-alanyl-gamma-D-glutamyl-meso-2,6-diaminopimelate(in) + n H(+)(in) (RHEA:64412)
• N-acetyl-D-muramoyl-L-alanyl-D-isoglutamine(out) + n H(+)(out) = N-acetyl-D-muramoyl-L-alanyl-D-isoglutamine(in) + n H(+)(in) (RHEA:76371)
• L-histidine(out) + n H(+)(out) = L-histidine(in) + n H(+)(in) (RHEA:76379)
• carnosine(out) + n H(+)(out) = carnosine(in) + n H(+)(in) (RHEA:76383)
• glycylglycylglycine(out) + n H(+)(out) = glycylglycylglycine(in) + n H(+)(in) (RHEA:76391)

UniProt features (80 total): helix 26, topological domain 13, transmembrane region 12, strand 8, turn 8, mutagenesis site 5, sequence conflict 3, modified residue 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
8JZX	ELECTRON MICROSCOPY	2.5
8QSL	ELECTRON MICROSCOPY	2.81
9IRC	ELECTRON MICROSCOPY	2.82
8WX3	ELECTRON MICROSCOPY	2.83
8JZS	ELECTRON MICROSCOPY	2.95
8JZU	ELECTRON MICROSCOPY	3.05
8WX4	ELECTRON MICROSCOPY	3.12
9IRB	ELECTRON MICROSCOPY	3.15
8JZR	ELECTRON MICROSCOPY	3.25
8QSK	ELECTRON MICROSCOPY	3.3
8QSN	ELECTRON MICROSCOPY	3.54
8P6A	ELECTRON MICROSCOPY	3.63
8QSM	ELECTRON MICROSCOPY	3.69
8WX5	ELECTRON MICROSCOPY	3.91

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N697-F1	85.27	0.54

Antibody-complex structures (SAbDab): 2 — 9IRB, 9IRC

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 (2): 279, 298

Mutagenesis-validated functional residues (5):

Position	Phenotype
14–15	abolished localization to the lysosome membrane and promotes relocalization to the plasma membrane; when associated with
44	does not affect interaction with tasl.
47	does not affect interaction with tasl.
318–319	abolished localization to the lysosome membrane and promotes relocalization to the plasma membrane; when associated with
465	abolished transmembrane transporter activity. abolished interaction with tasl.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-427975	Proton/oligopeptide cotransporters
R-HSA-6798695	Neutrophil degranulation
R-HSA-9860276	SLC15A4:TASL-dependent IRF5 activation
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-382551	Transport of small molecules
R-HSA-425393
R-HSA-425407	SLC-mediated transmembrane transport

MSigDB gene sets: 276 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_B_CELL_ACTIVATION, GOCC_VACUOLAR_MEMBRANE, GOBP_TOLL_LIKE_RECEPTOR_9_SIGNALING_PATHWAY, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_SIGNALING_PATHWAY, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_AMINO_ACID_TRANSMEMBRANE_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_ORGANIC_ACID_TRANSPORT

GO Biological Process (21): monoatomic ion transport (GO:0006811), protein transport (GO:0015031), histidine transport (GO:0015817), peptidoglycan transport (GO:0015835), mast cell homeostasis (GO:0033023), positive regulation of toll-like receptor 7 signaling pathway (GO:0034157), positive regulation of toll-like receptor 8 signaling pathway (GO:0034161), positive regulation of toll-like receptor 9 signaling pathway (GO:0034165), innate immune response (GO:0045087), positive regulation of innate immune response (GO:0045089), regulation of isotype switching to IgG isotypes (GO:0048302), regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway (GO:0070424), positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway (GO:0070430), positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway (GO:0070434), L-histidine transmembrane export from vacuole (GO:0089708), dipeptide import across plasma membrane (GO:0140206), immune system process (GO:0002376), oligopeptide transport (GO:0006857), peptide transport (GO:0015833), transmembrane transport (GO:0055085), proton transmembrane transport (GO:1902600)

GO Molecular Function (7): L-histidine transmembrane transporter activity (GO:0005290), peptide:proton symporter activity (GO:0015333), peptidoglycan transmembrane transporter activity (GO:0015647), dipeptide transmembrane transporter activity (GO:0071916), protein binding (GO:0005515), symporter activity (GO:0015293), transmembrane transporter activity (GO:0022857)

GO Cellular Component (9): lysosomal membrane (GO:0005765), plasma membrane (GO:0005886), membrane (GO:0016020), early endosome membrane (GO:0031901), specific granule membrane (GO:0035579), endolysosome membrane (GO:0036020), lysosome (GO:0005764), endosome (GO:0005768), endosome membrane (GO:0010008)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Innate Immune System	2
Toll-like Receptor Cascades	2
SLC-mediated transport of oligopeptides	1
Toll Like Receptor 9 (TLR9) Cascade	1
Toll Like Receptor 7/8 (TLR7/8) Cascade	1
Immune System	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
transport	4
positive regulation of pattern recognition receptor signaling pathway	3
positive regulation of intracellular signal transduction	3
nitrogen compound transport	2
positive regulation of nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	2
L-histidine transmembrane transport	2
dipeptide transmembrane transport	2
endosome membrane	2
intracellular protein localization	1
establishment of protein localization	1
basic amino acid transport	1
carbohydrate derivative transport	1
leukocyte homeostasis	1
myeloid cell homeostasis	1
toll-like receptor 7 signaling pathway	1
regulation of toll-like receptor 7 signaling pathway	1
toll-like receptor 8 signaling pathway	1
regulation of toll-like receptor 8 signaling pathway	1
toll-like receptor 9 signaling pathway	1
regulation of toll-like receptor 9 signaling pathway	1
immune response	1
defense response to symbiont	1
positive regulation of response to biotic stimulus	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
innate immune response	1
regulation of innate immune response	1
positive regulation of immune response	1
regulation of isotype switching	1
isotype switching to IgG isotypes	1
nucleotide-binding domain, leucine rich repeat containing receptor signaling pathway	1
regulation of cytoplasmic pattern recognition receptor signaling pathway	1
nucleotide-binding oligomerization domain containing 1 signaling pathway	1
regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway	1
nucleotide-binding oligomerization domain containing 2 signaling pathway	1
regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	1
amino acid transmembrane export from vacuole	1
L-histidine transport	1
basic amino acid transmembrane transport	1
oligopeptide import across plasma membrane	1

Protein interactions and networks

STRING

1248 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SLC15A4	TASL	Q9HAI6	711
SLC15A4	SLC20A1	Q8WUM9	615
SLC15A4	CARNS1	A5YM72	547
SLC15A4	NOD1	Q9Y239	486
SLC15A4	RBMS3	Q6XE24	472
SLC15A4	SLC7A4	O43246	471
SLC15A4	CLEC19A	Q6UXS0	468
SLC15A4	SLC36A1	Q7Z2H8	464
SLC15A4	TLR7	Q9NYK1	444
SLC15A4	IRF5	Q13568	441
SLC15A4	TLR9	Q9NR96	434
SLC15A4	RASGRP3	Q8IV61	433
SLC15A4	TNIP1	Q15025	431
SLC15A4	PPIL4	Q8WUA2	429
SLC15A4	SLC6A6	P31641	429

IntAct

63 interactions, top by confidence:

A	B	Type	Score
TASL	SLC15A4	psi-mi:“MI:0915”(physical association)	0.810
SLC15A4	TASL	psi-mi:“MI:0915”(physical association)	0.810
SLC15A4	TASL	psi-mi:“MI:0403”(colocalization)	0.810
SLC15A4	CLCN7	psi-mi:“MI:0915”(physical association)	0.560
GLP1R	SLC15A4	psi-mi:“MI:0915”(physical association)	0.540
SLC15A4	GLP1R	psi-mi:“MI:0403”(colocalization)	0.540
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
SLC15A4	PGRMC1	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
SLC30A2	RER1	psi-mi:“MI:0914”(association)	0.530
PTGIR	TMEM63A	psi-mi:“MI:0914”(association)	0.530
SIDT2	AP3D1	psi-mi:“MI:0914”(association)	0.530
SLC15A4	IRF5	psi-mi:“MI:0914”(association)	0.460
SLC15A3	SLC15A4	psi-mi:“MI:0915”(physical association)	0.400
SLC15A4	NOD2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (166): SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS), SLC15A4 (PCA), SLC15A4 (Affinity Capture-MS), SLC15A4 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2HW92, A6NDV4, A6NFX1, D2HKB0, D3ZVU9, F1NCD6, F1NJ67, F1PZV2, O09014, Q0IHM1, Q0P5M9, Q14728, Q14CX5, Q3T9M1, Q3U481, Q3UGX3, Q58CT4, Q58CV5, Q5JZQ7, Q5VTY9, Q66H95, Q6AY78, Q6NUT3, Q6PDE8, Q6UXD7, Q6W5G4, Q6ZMD2, Q7RTT9, Q80T22, Q8BFQ6, Q8CE47, Q8IVW8, Q8N697, Q8NA29, Q8R139, Q8TED4, Q8VCW4, Q8VCY8, Q8WUG5, Q91VM4

Diamond homologs: A6QQL0, O09014, Q68F72, Q8BPX9, Q8IY34, Q8N697, Q91W98, Q924V4, P91679, O01840

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
SLC15A4	“up-regulates activity”	“muramyl dipeptide”	relocalization

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1681 predictions. Top by Δscore:

Variant	Effect	Δscore
12:128799343:C:CT	acceptor_gain	1.0000
12:128799344:A:T	acceptor_gain	1.0000
12:128800848:CCTCA:C	donor_loss	1.0000
12:128800851:CA:C	donor_loss	1.0000
12:128800852:ACCTG:A	donor_loss	1.0000
12:128800898:TGCGG:T	donor_gain	1.0000
12:128801005:AATTC:A	acceptor_gain	1.0000
12:128801006:ATTC:A	acceptor_gain	1.0000
12:128801007:TTC:T	acceptor_gain	1.0000
12:128801007:TTCC:T	acceptor_loss	1.0000
12:128801008:TC:T	acceptor_gain	1.0000
12:128801009:CC:C	acceptor_gain	1.0000
12:128801009:CCTAG:C	acceptor_loss	1.0000
12:128801010:C:CC	acceptor_gain	1.0000
12:128808782:TCTTA:T	donor_loss	1.0000
12:128808783:CTTA:C	donor_loss	1.0000
12:128808784:TTA:T	donor_loss	1.0000
12:128808785:TACCT:T	donor_loss	1.0000
12:128808786:A:T	donor_loss	1.0000
12:128808787:CCTG:C	donor_gain	1.0000
12:128808957:C:CC	acceptor_gain	1.0000
12:128809390:TCTTA:T	donor_loss	1.0000
12:128809391:CTTAC:C	donor_loss	1.0000
12:128809392:TTACC:T	donor_loss	1.0000
12:128809393:TA:T	donor_loss	1.0000
12:128809395:C:CG	donor_loss	1.0000
12:128809474:C:CC	acceptor_gain	1.0000
12:128809941:A:AC	donor_gain	1.0000
12:128809942:C:CC	donor_gain	1.0000
12:128814769:GCTT:G	donor_loss	1.0000

AlphaMissense

3708 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:128799364:C:G	G490R	0.999
12:128799336:C:T	G499E	0.998
12:128799337:C:A	G499W	0.998
12:128799342:C:T	G497D	0.998
12:128800861:A:C	S469R	0.998
12:128800861:A:T	S469R	0.998
12:128800863:T:G	S469R	0.998
12:128800876:G:C	S464R	0.998
12:128800876:G:T	S464R	0.998
12:128800877:C:A	S464I	0.998
12:128800878:T:G	S464R	0.998
12:128809447:A:C	S346R	0.998
12:128809447:A:T	S346R	0.998
12:128809449:T:G	S346R	0.998
12:128809466:G:A	T340I	0.998
12:128815032:A:C	F195L	0.998
12:128815032:A:T	F195L	0.998
12:128815034:A:G	F195L	0.998
12:128815035:A:C	F194L	0.998
12:128815035:A:T	F194L	0.998
12:128815037:A:G	F194L	0.998
12:128823408:C:T	G179D	0.998
12:128799337:C:G	G499R	0.997
12:128799337:C:T	G499R	0.997
12:128799363:C:T	G490D	0.997
12:128799393:G:T	A480D	0.997
12:128799408:A:G	F475S	0.997
12:128799414:A:G	L473P	0.997
12:128800874:T:A	E465V	0.997
12:128800990:C:A	R426S	0.997

dbSNP variants (sampled 300 via entrez): RS1000114885 (12:128808665 A>G), RS1000205582 (12:128824400 C>G), RS1000280389 (12:128819899 T>C), RS1000322572 (12:128801228 G>A,T), RS1000342730 (12:128795712 C>T), RS1000389189 (12:128816381 A>C), RS1000563082 (12:128807433 G>A), RS1000632983 (12:128806177 A>G), RS1000676406 (12:128796733 T>C), RS1000722341 (12:128794720 G>C), RS1000837906 (12:128795870 C>A,G,T), RS1000917625 (12:128803835 G>A), RS1000939977 (12:128823562 T>C,G), RS1001096833 (12:128798353 G>A), RS1001177156 (12:128793053 C>T)

Disease associations

OMIM: gene MIM:615806 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000507_16	Systemic lupus erythematosus	2.000000e-11
GCST001795_27	Systemic lupus erythematosus	8.000000e-08
GCST001838_8	Palmitic acid (16:0) levels	5.000000e-06
GCST003075_14	Cognitive decline rate in late mild cognitive impairment	6.000000e-07
GCST003155_16	Systemic lupus erythematosus	1.000000e-13
GCST003156_40	Systemic lupus erythematosus	8.000000e-09
GCST003599_14	Systemic lupus erythematosus	2.000000e-06
GCST003622_39	Systemic lupus erythematosus	3.000000e-06
GCST004867_30	Systemic lupus erythematosus	7.000000e-06
GCST005752_130	Systemic lupus erythematosus	7.000000e-10
GCST007400_53	Systemic lupus erythematosus	2.000000e-08
GCST008442_1	Periodontal disease related phenotype (PCT5)	1.000000e-09
GCST011426_32	Systemic lupus erythematosus	8.000000e-08
GCST011956_140	Systemic lupus erythematosus	2.000000e-30
GCST90002379_57	Basophil count	3.000000e-13
GCST90002380_110	Basophil percentage of white cells	5.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007710	cognitive decline measurement
EFO:0007780	periodontal measurement
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes

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 — SLC15 family of peptide transporters

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
AJ2-30	Inhibition	5.74	pIC50

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	3
Acetaminophen	increases expression	2
Valproic Acid	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
terbufos	decreases methylation	1
sodium arsenite	affects expression	1
beta-methylcholine	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Benzo(a)pyrene	increases methylation	1
Cacodylic Acid	decreases expression	1
Cadmium	increases expression	1
Demecolcine	decreases expression	1
Fonofos	decreases methylation	1
Parathion	decreases methylation	1
Phthalic Acids	decreases methylation	1
Plant Extracts	affects cotreatment, increases expression	1
Smoke	decreases expression	1
Vincristine	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 3 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4CJ	HCT116-SLC15A4-KO-c10	Cancer cell line	Male
CVCL_D4CK	HCT116-SLC15A4-KO-c12	Cancer cell line	Male
CVCL_D4DN	HEK-SLC15A4-KO-c3	Transformed cell line	Female
CVCL_D4DP	HEK-SLC15A4-KO-c4	Transformed cell line	Female
CVCL_D9RP	Ubigene HEK293 SLC15A4 KO	Transformed cell line	Female
CVCL_E0NL	Ubigene HeLa SLC15A4 KO	Cancer cell line	Female
CVCL_TL59	HAP1 SLC15A4 (-) 1	Cancer cell line	Male
CVCL_TL60	HAP1 SLC15A4 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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