TREML4

Summary

TREML4 (triggering receptor expressed on myeloid cells like 4, HGNC:30807) is a protein-coding gene on chromosome 6p21.1, encoding Trem-like transcript 4 protein (Q6UXN2). Positively regulates Toll-like receptor TLR7 signaling in macrophages.

Predicted to enable signaling receptor activity. Involved in positive regulation of toll-like receptor 7 signaling pathway. Predicted to be located in endoplasmic reticulum; endosome membrane; and lysosomal membrane. Predicted to be active in cell surface.

Source: NCBI Gene 285852 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 37 total
• MANE Select transcript: NM_198153

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30807
Approved symbol	TREML4
Name	triggering receptor expressed on myeloid cells like 4
Location	6p21.1
Locus type	gene with protein product
Status	Approved
Aliases	TLT4
Ensembl gene	ENSG00000188056
Ensembl biotype	protein_coding
OMIM	614664
Entrez	285852

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 nonsense_mediated_decay

ENST00000341495, ENST00000448827, ENST00000461240

RefSeq mRNA: 1 — MANE Select: NM_198153 NM_198153

CCDS: CCDS34446

Canonical transcript exons

ENST00000341495 — 6 exons

Exon	Start	End
ENSE00001366062	41230062	41230122
ENSE00001379965	41228714	41229044
ENSE00001417288	41228349	41228490
ENSE00001871201	41237055	41238882
ENSE00002488005	41229521	41229571
ENSE00003528113	41236486	41236617

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 93.15.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7903 / max 186.3070, expressed in 74 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
67744	0.3965	48
67742	0.2515	27
67741	0.0936	24
67743	0.0488	27

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.15	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.70	gold quality
monocyte	CL:0000576	69.10	gold quality
leukocyte	CL:0000738	68.69	gold quality
blood	UBERON:0000178	68.30	gold quality
bone marrow cell	CL:0002092	61.48	gold quality
right lung	UBERON:0002167	56.91	gold quality
skin of hip	UBERON:0001554	55.57	gold quality
spleen	UBERON:0002106	51.81	gold quality
granulocyte	CL:0000094	51.41	silver quality
bone marrow	UBERON:0002371	50.43	gold quality
upper leg skin	UBERON:0004262	50.24	silver quality
vermiform appendix	UBERON:0001154	49.78	gold quality
upper lobe of left lung	UBERON:0008952	48.05	gold quality
caecum	UBERON:0001153	47.57	gold quality
upper lobe of lung	UBERON:0008948	46.88	gold quality
islet of Langerhans	UBERON:0000006	45.78	gold quality
amniotic fluid	UBERON:0000173	45.48	gold quality
sural nerve	UBERON:0015488	45.18	gold quality
oviduct epithelium	UBERON:0004804	44.97	silver quality
left uterine tube	UBERON:0001303	44.82	gold quality
lung	UBERON:0002048	43.64	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
gall bladder	UBERON:0002110	43.28	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
middle temporal gyrus	UBERON:0002771	42.52	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
hindlimb stylopod muscle	UBERON:0004252	41.31	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

61 targeting TREML4, 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-7110-3P	100.00	73.18	2486
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-377-5P	99.70	65.28	712
HSA-MIR-6086	99.70	65.38	699
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-5700	99.64	69.88	2280
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-1207-5P	99.49	69.11	2983

Literature-anchored findings (GeneRIF, showing 4)

• determined by von Kossa staining that TREML4 colocalizes with areas of microcalcification within coronary plaques. Overall, we present integrative RNA, DNA, and protein evidence implicating TREML4 in coronary artery calcification (PMID:24975946)
• TREML4 mRNA Expression and Polymorphisms in Blood Leukocytes are Associated with Atherosclerotic Lesion Extension in Coronary Artery Disease. (PMID:31076644)
• TREML4 Promotes Inflammatory Programs in Human and Murine Macrophages and Alters Atherosclerosis Lesion Composition in the Apolipoprotein E Deficient Mouse. (PMID:32292401)
• TREML4 polymorphisms increase the mRNA in blood leukocytes in the progression of atherosclerosis. (PMID:36329152)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Treml4	ENSMUSG00000051682
rattus_norvegicus	Treml4	ENSRNOG00000042360

Paralogs (2): NCR2 (ENSG00000096264), TREML2 (ENSG00000112195)

Protein

Protein identifiers

Trem-like transcript 4 protein — Q6UXN2 (reviewed: Q6UXN2)

Alternative names: Triggering receptor expressed on myeloid cells-like protein 4

All UniProt accessions (2): Q6UXN2, H7C4X5

UniProt curated annotations — full annotation on UniProt →

Function. Positively regulates Toll-like receptor TLR7 signaling in macrophages.

Subcellular location. Secreted.

RefSeq proteins (1): NP_937796* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR052314	Immune_rcpt_domain	Family

Pfam: PF07686

UniProt features (8 total): sequence variant 3, signal peptide 1, chain 1, domain 1, glycosylation site 1, disulfide bond 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UXN2-F1	77.44	0.54

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 (1): 40–109

Glycosylation sites (1): 93

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: 90 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, PU1_Q6, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_INTRACELLULAR_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_CYTOPLASMIC_PATTERN_RECOGNITION_RECEPTOR_SIGNALING_PATHWAY, GOBP_REGULATION_OF_DEFENSE_RESPONSE, GOBP_ACTIVATION_OF_INNATE_IMMUNE_RESPONSE

GO Biological Process (3): positive regulation of toll-like receptor 7 signaling pathway (GO:0034157), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (1): signaling receptor activity (GO:0038023)

GO Cellular Component (3): extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986)

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
toll-like receptor 7 signaling pathway	1
regulation of toll-like receptor 7 signaling pathway	1
positive regulation of pattern recognition receptor signaling pathway	1
positive regulation of intracellular signal transduction	1
immune response	1
defense response to symbiont	1
biological_process	1
molecular transducer activity	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

394 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TREML4	TREML1	Q86YW5	507
TREML4	TREM2	Q9NZC2	429
TREML4	CLEC9A	Q6UXN8	421
TREML4	TREM1	Q9NP99	415
TREML4	LY75	O60449	375
TREML4	CD207	Q9UJ71	352
TREML4	C4orf17	Q53FE4	348
TREML4	ERBB2	P04626	346
TREML4	OR1N2	Q8NGR9	339
TREML4	XCR1	P46094	315
TREML4	IRF8	Q02556	290
TREML4	ITGAM	P11215	290
TREML4	BATF3	Q9NR55	278
TREML4	TLR7	Q9NYK1	278
TREML4	TYROBP	O43914	275

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A2A7V7, A2TGX5, A5D7B2, A8K4G0, B6A8R8, C0HJX2, C0HJX3, O15389, O43699, O95944, P12318, P20138, P24071, P27645, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P50283, Q1ERP8, Q3LRV9, Q3U497, Q566E6, Q60513, Q6DN72, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6UXG3, Q6UXN2, Q6UXZ3, Q7TSN2, Q8K249, Q8N109, Q8NHK3, Q8R4Y0, Q8SPV8

Diamond homologs: A2A7V7, A2TGX5, O70570, O95944, P01833, P0DUB1, P15083, P81265, Q08708, Q2LA85, Q3LRV9, Q3U497, Q496F6, Q5RDA5, Q5T2D2, Q6UXN2, Q6UXZ3, Q8K249, Q99NH8, Q9JKE2, Q9UGN4, A0A0K2S4Q6, A1KXC4, A8K4G0, O60667, P01832, Q29244, Q2TB54, Q5M871, Q5R770, Q8WWV6, A5D7B2, Q1ERP8, Q566E6, Q6SJQ7, Q8TDQ1, Q8VCH2, G3X8R9, P0DMS9, Q6SJQ0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	27
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

820 predictions. Top by Δscore:

Variant	Effect	Δscore
6:41228698:C:A	acceptor_gain	1.0000
6:41229519:A:AG	acceptor_gain	1.0000
6:41229520:G:GA	acceptor_gain	1.0000
6:41229570:AGGTA:A	donor_loss	1.0000
6:41229572:GTAG:G	donor_loss	1.0000
6:41228705:T:A	acceptor_gain	0.9900
6:41228706:G:A	acceptor_gain	0.9900
6:41228710:AAAG:A	acceptor_gain	0.9900
6:41229040:TCCAG:T	donor_loss	0.9900
6:41229041:CCAG:C	donor_loss	0.9900
6:41229042:CAGG:C	donor_loss	0.9900
6:41229046:T:G	donor_loss	0.9900
6:41229515:CTTTA:C	acceptor_loss	0.9900
6:41229516:TTTA:T	acceptor_loss	0.9900
6:41229517:TTA:T	acceptor_loss	0.9900
6:41229518:TAGCC:T	acceptor_loss	0.9900
6:41229519:AG:A	acceptor_loss	0.9900
6:41229520:GC:G	acceptor_gain	0.9900
6:41229520:GCC:G	acceptor_gain	0.9900
6:41229520:GCCC:G	acceptor_gain	0.9900
6:41229520:GCCCC:G	acceptor_gain	0.9900
6:41230060:A:AG	acceptor_gain	0.9900
6:41230061:G:GA	acceptor_gain	0.9900
6:41230061:GTTCT:G	acceptor_gain	0.9800
6:41228504:A:T	donor_gain	0.9700
6:41229034:G:GA	donor_gain	0.9700
6:41229572:G:GG	donor_gain	0.9700
6:41230118:ACCAG:A	donor_loss	0.9700
6:41230119:CCAGG:C	donor_loss	0.9700
6:41230120:CAGG:C	donor_loss	0.9700

AlphaMissense

1282 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:41228806:A:C	K52N	0.969
6:41228806:A:T	K52N	0.969
6:41228812:G:C	W54C	0.948
6:41228812:G:T	W54C	0.948
6:41228975:T:A	C109S	0.941
6:41228976:G:C	C109S	0.941
6:41228855:A:C	S69R	0.938
6:41228857:C:A	S69R	0.938
6:41228857:C:G	S69R	0.938
6:41228813:T:A	C55S	0.931
6:41228814:G:C	C55S	0.931
6:41228837:T:A	C63S	0.930
6:41228838:G:C	C63S	0.930
6:41228768:T:A	C40S	0.929
6:41228769:G:C	C40S	0.929
6:41228805:A:T	K52I	0.922
6:41228924:T:C	F92L	0.911
6:41228926:C:A	F92L	0.911
6:41228926:C:G	F92L	0.911
6:41228810:T:A	W54R	0.906
6:41228810:T:C	W54R	0.906
6:41228898:T:C	I83T	0.898
6:41228904:A:C	D85A	0.894
6:41228775:A:G	Y42C	0.891
6:41228837:T:C	C63R	0.883
6:41228903:G:C	D85H	0.883
6:41228969:T:G	Y107D	0.883
6:41228805:A:C	K52T	0.878
6:41228898:T:A	I83N	0.877
6:41228815:T:G	C55W	0.873

dbSNP variants (sampled 300 via entrez): RS1000926736 (6:41235169 A>G), RS1001152977 (6:41236046 T>C), RS1001201250 (6:41227484 T>C,G), RS1001255266 (6:41227311 C>A), RS1001267993 (6:41230613 C>A), RS1001590873 (6:41232591 T>C), RS1001863016 (6:41236648 A>G), RS1002202341 (6:41228643 C>A,G,T), RS1002294173 (6:41236947 C>A,G,T), RS1002307010 (6:41235336 G>T), RS1002422196 (6:41230651 T>C), RS1002632166 (6:41227477 G>A), RS1002652438 (6:41233440 T>C,G), RS1003010794 (6:41227293 G>A), RS1003939418 (6:41237810 C>A)

Disease associations

OMIM: gene MIM:614664 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST005356_4	Severe malaria	1.000000e-07
GCST005357_14	Severe malaria (adjusted for sickle cell variant rs334)	4.000000e-07
GCST009391_869	Metabolite levels	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010535	sucrose measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs13204353	Efficacy	3	duloxetine	Major Depressive Disorder
rs9369266	Efficacy	3	duloxetine	Major Depressive Disorder

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs13204353	TREML4	3	0.00	1	duloxetine
rs9369266	TREML4	3	0.00	1	duloxetine

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects cotreatment, affects response to substance	1
Benzo(a)pyrene	decreases methylation	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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