TREML2

Summary

TREML2 (triggering receptor expressed on myeloid cells like 2, HGNC:21092) is a protein-coding gene on chromosome 6p21.1, encoding Trem-like transcript 2 protein (Q5T2D2). Cell surface receptor that may play a role in the innate and adaptive immune response.

TREML2 is located in a gene cluster on chromosome 6 with the single Ig variable (IgV) domain activating receptors TREM1 (MIM 605085) and TREM2 (MIM 605086), but it has distinct structural and functional properties (Allcock et al., 2003 [PubMed 12645956]).

Source: NCBI Gene 79865 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 58 total
• MANE Select transcript: NM_024807

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21092
Approved symbol	TREML2
Name	triggering receptor expressed on myeloid cells like 2
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ13693, TLT2, dJ238O23.1
Ensembl gene	ENSG00000112195
Ensembl biotype	protein_coding
OMIM	609715
Entrez	79865

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000483722

RefSeq mRNA: 1 — MANE Select: NM_024807 NM_024807

CCDS: CCDS4853

Canonical transcript exons

ENST00000483722 — 5 exons

Exon	Start	End
ENSE00000750552	41192801	41192901
ENSE00000849877	41194425	41194833
ENSE00000849878	41198109	41198429
ENSE00001932857	41189749	41192506
ENSE00001952672	41200954	41201149

Expression profiles

Bgee: expression breadth ubiquitous, 102 present calls, max score 88.14.

FANTOM5 (CAGE): breadth broad, TPM avg 1.6366 / max 421.6046, expressed in 205 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73533	0.5706	104
73532	0.5191	96
73534	0.4600	147
73531	0.0529	16
73535	0.0340	11

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	88.14	gold quality
granulocyte	CL:0000094	81.69	gold quality
sperm	CL:0000019	78.88	gold quality
placenta	UBERON:0001987	77.95	gold quality
male germ cell	CL:0000015	77.70	gold quality
triceps brachii	UBERON:0001509	74.54	gold quality
leukocyte	CL:0000738	73.46	gold quality
spleen	UBERON:0002106	73.19	gold quality
gluteal muscle	UBERON:0002000	72.83	gold quality
monocyte	CL:0000576	72.74	gold quality
mononuclear cell	CL:0000842	72.64	gold quality
bone marrow	UBERON:0002371	72.60	gold quality
lymph node	UBERON:0000029	72.15	gold quality
vermiform appendix	UBERON:0001154	71.31	gold quality
bone marrow cell	CL:0002092	68.54	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	66.82	gold quality
caecum	UBERON:0001153	66.33	gold quality
vastus lateralis	UBERON:0001379	66.00	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	64.16	gold quality
olfactory bulb	UBERON:0002264	63.41	gold quality
biceps brachii	UBERON:0001507	63.36	gold quality
type B pancreatic cell	CL:0000169	63.08	gold quality
substantia nigra pars reticulata	UBERON:0001966	61.55	gold quality
epithelial cell of pancreas	CL:0000083	61.07	gold quality
deltoid	UBERON:0001476	60.87	gold quality
substantia nigra pars compacta	UBERON:0001965	60.81	gold quality
trabecular bone tissue	UBERON:0002483	60.62	gold quality
cerebellar vermis	UBERON:0004720	60.10	silver quality
nasal cavity epithelium	UBERON:0005384	59.96	gold quality
right lung	UBERON:0002167	59.13	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-MTAB-6386	no	477.43
E-ANND-3	no	2.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

79 targeting TREML2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-766-3P	99.47	65.24	1811

Literature-anchored findings (GeneRIF, showing 14)

• TLT2 may be involved in the innate immune response based on its expression profile and the fact that it is up-regulated in response to inflammation. (PMID:16670310)
• analysis of an interaction between B7-H3 and TLT-2 that preferentially enhances CD8(+) T cell activation (PMID:18650384)
• Data do not point to a role for TREML2 as a receptor for B7-H3. (PMID:19544488)
• Missense variant in TREML2 protects against Alzheimer’s disease. (PMID:24439484)
• A missense variant in TREML2 was associated with a reduced risk of Alzheimer’s Disease in a Han Chinese population. (PMID:26797517)
• Its mutation plays a role in pathogenesis of Alzheimer’s disease. (PMID:27084067)
• Study characterized the expression of TREM genes in cerebellum and temporal cortex and determined TREML1 and TREM2 to be the only reliably expressed TREM genes in these brain regions; identified rs9357347 as a putative regulatory variant that is associated with protection from Alzheimer’s disease and with increased TREML1 and TREM2 brain levels. (PMID:27939925)
• Mutation of TREML2 is a major factor leading to ankylosing spondylitis for HLA-B27 (+) members in a large family and that TREML2 is also a susceptibility gene promoting the development of ankylosing spondylitis in HLA-B27 (+) individuals. (PMID:29778423)
• An analysis of the proteome differences between the TLT-2(+)CD8(+)T and TLT-2(-)CD8(+)T cells revealed that TLT-2 affected CD8(+)T cell activation by regulating Granzyme B expression and by further action on the NF-kappaB signalling pathway. (PMID:30361846)
• rs6915083 and rs7754593 of TREML2 were associated with acute liver allograft rejection. (PMID:31044564)
• A TREML2 missense variant influences specific hippocampal subfield volumes in cognitively normal elderly subjects. (PMID:32073739)
• TLT2 Suppresses Th1 Response by Promoting IL-6 Production in Monocyte Through JAK/STAT3 Signal Pathway in Tuberculosis. (PMID:33042115)
• TREML2 Gene Expression and Its Missense Variant rs3747742 Associate with White Matter Hyperintensity Volume and Alzheimer’s Disease-Related Brain Atrophy in the General Population. (PMID:36430248)
• Associations Between TREML2 Gene Variants and Alzheimer’s Disease: Biomarkers, Neuroimage, and Cognition. (PMID:37980675)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Treml2	ENSMUSG00000071068
rattus_norvegicus	Treml2	ENSRNOG00000013554

Paralogs (2): NCR2 (ENSG00000096264), TREML4 (ENSG00000188056)

Protein

Protein identifiers

Trem-like transcript 2 protein — Q5T2D2 (reviewed: Q5T2D2)

Alternative names: Triggering receptor expressed on myeloid cells-like protein 2

All UniProt accessions (1): Q5T2D2

UniProt curated annotations — full annotation on UniProt →

Function. Cell surface receptor that may play a role in the innate and adaptive immune response. Acts as a counter-receptor for CD276 and interaction with CD276 on T-cells enhances T-cell activation.

Subunit / interactions. Interacts with CD276 and this interaction enhances T-cell activation.

Subcellular location. Cell membrane.

Tissue specificity. Detected in cultured B-cells, T-cell leukemia and monocyte leukemia. Expressed constitutively on CD8 T-cells and induced on CD4 T-cells after activation.

Induction. Induced in CD4 T-cells by concanavalin-A.

RefSeq proteins (1): NP_079083* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052314	Immune_rcpt_domain	Family

UniProt features (20 total): sequence variant 4, sequence conflict 4, disulfide bond 2, topological domain 2, compositionally biased region 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T2D2-F1	65.13	0.24

Functional residue map

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

Disulfide bonds (2): 41–105, 56–63

Glycosylation sites (1): 89

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell

MSigDB gene sets: 184 (showing top): GSE45365_NK_CELL_VS_BCELL_DN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOCC_CELL_SURFACE, GGGTGGRR_PAX4_03, FOSTER_TOLERANT_MACROPHAGE_DN, RYTTCCTG_ETS2_B, RGAGGAARY_PU1_Q6, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, ETS_Q4, SMAD4_Q6, DODD_NASOPHARYNGEAL_CARCINOMA_DN, MIKKELSEN_ES_LCP_WITH_H3K4ME3, GOBP_LYMPHOCYTE_ACTIVATION, GOBP_T_CELL_ACTIVATION, LEF1_UP.V1_UP

GO Biological Process (1): T cell activation (GO:0042110)

GO Molecular Function (2): signaling receptor activity (GO:0038023), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
lymphocyte activation	1
molecular transducer activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

1168 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TREML2	TREML1	Q86YW5	971
TREML2	CD276	Q5ZPR3	953
TREML2	TREM2	Q9NZC2	918
TREML2	TREM1	Q9NP99	909
TREML2	TYROBP	O43914	752
TREML2	STAT3	P40763	577
TREML2	CASS4	Q9NQ75	555
TREML2	INPP5D	Q92835	523
TREML2	PRSS36	Q5K4E3	455
TREML2	MS4A6A	Q9H2W1	434
TREML2	DEF8	Q6ZN54	420
TREML2	VTCN1	Q7Z7D3	419
TREML2	ABCA7	Q8IZY2	406
TREML2	SCIMP	Q6UWF3	404
TREML2	CLU	P10909	375

IntAct

9 interactions, top by confidence:

A	B	Type	Score
TREML2	SNX2	psi-mi:“MI:0914”(association)	0.530
TREML2	HAPLN1	psi-mi:“MI:0915”(physical association)	0.400
LRRTM2	TREML2	psi-mi:“MI:0915”(physical association)	0.400
LTF	TREML2	psi-mi:“MI:0915”(physical association)	0.400
TREML2	ADGRF5	psi-mi:“MI:0915”(physical association)	0.400
	VPS37C	psi-mi:“MI:0914”(association)	0.350
TREML2	DNM1L	psi-mi:“MI:0914”(association)	0.350

BioGRID (41): ATP2A3 (Affinity Capture-MS), RETSAT (Affinity Capture-MS), DHRS7 (Affinity Capture-MS), CYP51A1 (Affinity Capture-MS), SNX6 (Affinity Capture-MS), SNX2 (Affinity Capture-MS), PDZD8 (Affinity Capture-MS), SQLE (Affinity Capture-MS), RAB6A (Affinity Capture-MS), EPHX1 (Affinity Capture-MS), UPK3BL (Affinity Capture-MS), ESYT1 (Affinity Capture-MS), ZBTB1 (Affinity Capture-MS), ALG11 (Affinity Capture-MS), ZBTB1 (Affinity Capture-MS)

ESM2 similar proteins: A2A7V7, A2TGX5, A5D7B2, G3X8R9, O88875, O95944, P0DMS9, P11912, P12318, P15530, P16410, P22273, P31785, P31994, P31995, P34902, P40259, P50283, Q02242, Q1ERP8, Q2LA85, Q2YFS1, Q2YFS2, Q2YFS3, Q3LRV9, Q3U497, Q566E6, Q5T2D2, Q60513, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6TYI6, Q6UXG3, Q6UXN2, Q7TSN2, Q86YW5, Q8K558, Q8SPV8, Q8TDQ1

Diamond homologs: A2A7V7, A2TGX5, O70570, O95944, P01833, P0DUB1, P15083, P81265, Q08708, Q2LA85, Q3LRV9, Q3U497, Q496F6, Q5RDA5, Q5T2D2, Q6UXN2, Q6UXZ3, Q8K249, Q99NH8, Q9JKE2, Q9UGN4, Q566E6, Q6SJQ0, Q8VCH2, A0A0K2S4Q6, Q7TSN2, Q8WWV6, Q6UXG3, Q9JKE1, A5D7B2, A8K4G0, P0DMS9, Q1ERP8, Q2TB54, Q6SJQ5, Q6SJQ7, Q8TDQ1, P01832, Q6QUN5, Q6TYI6

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	42
Likely benign	9
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

749 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41192799:A:AC	donor_gain	1.0000
6:41192800:C:CA	donor_gain	1.0000
6:41192800:CTTG:C	donor_gain	1.0000
6:41194831:GAGC:G	acceptor_loss	1.0000
6:41194834:C:CC	acceptor_gain	1.0000
6:41194834:C:T	acceptor_loss	1.0000
6:41194835:T:G	acceptor_loss	1.0000
6:41200951:CAC:C	donor_loss	1.0000
6:41200952:A:C	donor_loss	1.0000
6:41200953:C:T	donor_loss	1.0000
6:41192443:T:TA	donor_gain	0.9900
6:41192505:GCC:G	acceptor_loss	0.9900
6:41192507:C:CC	acceptor_gain	0.9900
6:41192508:T:C	acceptor_loss	0.9900
6:41192793:CTACT:C	donor_loss	0.9900
6:41192795:ACT:A	donor_loss	0.9900
6:41192797:T:TG	donor_loss	0.9900
6:41192798:C:CC	donor_loss	0.9900
6:41192799:A:C	donor_loss	0.9900
6:41192800:C:A	donor_loss	0.9900
6:41192800:CTT:C	donor_gain	0.9900
6:41192899:TGC:T	acceptor_gain	0.9900
6:41192900:GC:G	acceptor_gain	0.9900
6:41192901:CC:C	acceptor_gain	0.9900
6:41192901:CCTGA:C	acceptor_loss	0.9900
6:41192902:C:CA	acceptor_loss	0.9900
6:41192902:C:CC	acceptor_gain	0.9900
6:41192903:T:G	acceptor_loss	0.9900
6:41194829:GGGAG:G	acceptor_gain	0.9900
6:41194830:GGAG:G	acceptor_gain	0.9900

AlphaMissense

2065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41198320:C:A	W55C	0.997
6:41198320:C:G	W55C	0.997
6:41198177:T:C	Y103C	0.995
6:41198322:A:G	W55R	0.995
6:41198322:A:T	W55R	0.995
6:41198171:C:G	C105S	0.994
6:41198172:A:T	C105S	0.994
6:41198318:C:G	C56S	0.994
6:41198319:A:T	C56S	0.994
6:41198165:C:G	R107P	0.992
6:41198178:A:C	Y103D	0.991
6:41198189:T:A	D99V	0.991
6:41198189:T:G	D99A	0.991
6:41198363:C:G	C41S	0.991
6:41198364:A:T	C41S	0.991
6:41198170:G:C	C105W	0.990
6:41198172:A:G	C105R	0.990
6:41198177:T:G	Y103S	0.989
6:41198189:T:C	D99G	0.989
6:41198201:A:T	L95H	0.989
6:41198285:A:C	F67C	0.988
6:41198297:C:G	C63S	0.988
6:41198298:A:T	C63S	0.988
6:41198171:C:T	C105Y	0.987
6:41198178:A:G	Y103H	0.987
6:41198284:A:C	F67L	0.986
6:41198284:A:T	F67L	0.986
6:41198286:A:G	F67L	0.986
6:41198319:A:G	C56R	0.986
6:41198364:A:G	C41R	0.986

dbSNP variants (sampled 300 via entrez): RS1000134381 (6:41203048 G>A), RS1000272195 (6:41202796 T>C), RS1000465879 (6:41191568 C>G), RS1000732933 (6:41202915 G>A), RS1001011354 (6:41190047 G>A), RS1001084174 (6:41196362 T>A), RS1001096082 (6:41197359 C>T), RS1001354185 (6:41194963 G>C), RS1001533264 (6:41195254 G>A), RS1001635046 (6:41189398 G>C,T), RS1001812982 (6:41196921 G>T), RS1001950313 (6:41196702 T>C), RS1002240858 (6:41190703 G>A), RS1002359878 (6:41196251 TC>T), RS1002491271 (6:41190813 T>C)

Disease associations

OMIM: gene MIM:609715 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002245_24	Alzheimer’s disease (late onset)	6.000000e-07
GCST004625_32	Monocyte count	1.000000e-10
GCST006585_82	Blood protein levels	2.000000e-233
GCST008114_3	Type 2 diabetes	2.000000e-06
GCST008151_46	Waist circumference	5.000000e-06
GCST008160_41	Waist circumference	5.000000e-06
GCST90002393_78	Monocyte count	2.000000e-20
GCST90002405_189	Reticulocyte count	7.000000e-11
GCST90002407_258	White blood cell count	2.000000e-15

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005091	monocyte count
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sulforaphane	increases expression	1
sodium arsenite	decreases expression	1
perfluorooctanoic acid	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cisplatin	increases expression	1
Iron	increases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Tretinoin	increases expression	1
beta-Naphthoflavone	decreases expression	1

Clinical trials (associated diseases)

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