LILRA3

Summary

LILRA3 (leukocyte immunoglobulin like receptor A3, HGNC:6604) is a protein-coding gene on chromosome 19q13.4 alternate reference locus, encoding Leukocyte immunoglobulin-like receptor subfamily A member 3 (Q8N6C8). Acts as a soluble receptor for class I MHC antigens.

This gene encodes a member of a family of immunoreceptors that are expressed predominantly in monocytes and B cells, and at lower levels in dendritic cells and natural killer cells. The encoded protein lacks the transmembrane region found in other members of this family. It acts as a soluble receptor for class I major histocompatibility complex (MHC) antigens. Alternatively spliced transcript variants encoding different isoforms have been found. This gene is located in a cluster of related genes on chromosome 19 and is polymorphic in human populations, with many individuals containing a deletion of this genomic region.

Source: NCBI Gene 11026 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 14 total
• MANE Select transcript: NM_006865

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6604
Approved symbol	LILRA3
Name	leukocyte immunoglobulin like receptor A3
Location	19q13.4 alternate reference locus
Locus type	gene with protein product
Status	Approved
Aliases	LIR-4, HM43, ILT6, HM31, LIR4, CD85e
Ensembl gene	ENSG00000276175
OMIM	604818
Entrez	11026

Gene structure

Transcript identifiers

Ensembl transcripts: 0

RefSeq mRNA: 2 — MANE Select: NM_006865 NM_001172654, NM_006865

Canonical transcript exons

ENST00000612127 — 0 exons

Expression profiles

Top tissues by expression

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

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 30)

• A deletion of LILRA3 gene was found in a minority of British population (PMID:12651072)
• Six alleles characterised, of which four will encode unique peptides, one of which is likely to directly influence ligand binding. (PMID:12750859)
• our results suggest that both the nonfunctional LILRA3 alleles and the low-expressing LILRB2 alleles identified in our study have increased in Northeast Asians because of natural selection. (PMID:18439545)
• Multiple sclerosis associates with LILRA3 deletion. (PMID:19421224)
• ILT6 deficiency may be a genetic risk factor for Sjogren’s syndrome. (PMID:19790059)
• These results suggest that LILRA3 may play a role in chronic inflammatory conditions such as rheumatoid arthritis. (PMID:20595277)
• LILRA1 and LILRA3 generally display a greater binding preference for binding to HLA-C free heavy chain, particularly following removal of beta2-microglobulin by acid treatment. (PMID:21270408)
• LILRA3 binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1/LILRB2 (PMID:21559424)
• Data did not indicate any association of LILRA3 deletion with multiple sclerosis (MS) susceptibility, however, patients negative for the deletion may begin to suffer from MS significantly earlier than patients who are positive. (PMID:23238213)
• The current study was conducted to investigate the association of rs103294 of LILRA3 with benign prostatic hyperplasia risk. (PMID:23615473)
• LILRA3 is an immunostimulatory molecule, whose deficiency is associated with higher frequency of B-non-Hodgkin’s lymphoma. (PMID:24363809)
• functional LILRA3 is a novel genetic risk factor for rheumatoid arthritis (RA), especially in males. It appears to highly predispose to ACPA-positive RA and confers an increased risk of disease severity in patients with early RA. (PMID:24757135)
• Mutations in the genes glucokinase regulatory protein (GCKR), RNase L (RNASEL), leukocyte immunoglobulin-like receptor 3 (LILRA3), and dynein axonemal heavy chain 10 (DNAH10) segregated with elevated HDLc levels in families, while no mutations associated with low HDLc. (PMID:24891332)
• ILT6 deletion polymorphism does not appear to be a lupus susceptibility gene in South Indian Tamils, but may behave as a genetic modifier of autoantibody phenotype by influencing the production of anti-Ro60 and anti-Ro52 autoantibodies (PMID:24899637)
• LILRA3 is a new susceptibility factor for systemic lupus erythematosus (SLE) and primary Sjogren’s syndrome (pSS). It predisposes to certain phenotypes such as leucopenia, thrombocytopenia, autoantibody positivity and increased disease activity. (PMID:24906639)
• Evidence showed lack of significant association between LILRA3 deletion and multiple sclerosis pathogenesis. [meta-analysis] (PMID:26274821)
• LILRA3 significantly reversed Nogo-66-mediated inhibition of neurite outgrowth and promoted synapse formation in primary cortical neurons through regulation of the ERK/MEK pathway. (PMID:26826187)
• LILRA3 gene deletion was not associated with Multiple Sclerosis susceptibility and did not affect the age of disease onset, clinical subtype or disease severity. (PMID:26871720)
• Experiments point towards a beneficial role for LILRA3 in virus infections, especially in ssRNA viruses, like HIV, that engage TLR8; however, the potentially beneficial role of LILRA3 is abrogated during a HIV infection. (PMID:26969150)
• Letter: LILRA3 gene deletion is not involved in the giant cell arteritis and systemic sclerosis predisposition in Spanish patients. (PMID:27462831)
• The homozygous LILRA3 deletion is associated with a higher susceptibility for HIV disease and with a faster disease progression. (PMID:27755104)
• LILRA3 polymorphism is associated with Takayasu arteritis. (PMID:30498034)
• Study found possible protective effect of the T allele of LILRB1 rs1061680:T>C and no association with insertion/deletion polymorphisms of LILRA3 with ankylosing spondylitis (AS) (PMID:30892832)
• in systemic lupus erythematosus serum level elevated and correlated with disease activity and severity (PMID:31209706)
• Leukocyte immunoglobulin-like receptor A3 is increased in IBD patients and functions as an anti-inflammatory modulator. (PMID:33006756)
• Association of the Leukocyte Immunoglobulin-like Receptor A3 Gene With Neutrophil Activation and Disease Susceptibility in Adult-Onset Still’s Disease. (PMID:33381895)
• A susceptibility locus in the IL12B but not LILRA3 region is associated with vascular damage in Takayasu arteritis. (PMID:34211061)
• Soluble LILRA3 is aberrantly expressed in antiphospholipid syndrome (APS) and is a potential marker of thrombotic APS. (PMID:35325077)
• Leukocyte Ig-like receptor A3 facilitates inflammation, migration and invasion of synovial tissue-derived fibroblasts via ERK/JNK activation. (PMID:37462532)
• Leukocyte immunoglobulin-like receptor A3 gene deletion in five Chinese populations and protective association with nasopharyngeal carcinoma. (PMID:38015196)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Leukocyte immunoglobulin-like receptor subfamily A member 3 — Q8N6C8 (reviewed: Q8N6C8)

Alternative names: CD85 antigen-like family member E, Immunoglobulin-like transcript 6, Leukocyte immunoglobulin-like receptor 4, Monocyte inhibitory receptor HM43/HM31

All UniProt accessions (4): A0A0G2JLV5, A0A0G2JM97, A0A0G2JMY9, Q8N6C8

UniProt curated annotations — full annotation on UniProt →

Function. Acts as a soluble receptor for class I MHC antigens. Binds both classical and non-classical HLA class I molecules but with reduced affinities compared to LILRB1 or LILRB2. Binds with high affinity to the surface of monocytes, leading to abolish LPS-induced TNF production by monocytes.

Subcellular location. Secreted.

Tissue specificity. Detected in B-cells, and at lower levels in natural killer (NK) cells. Detected in peripheral blood monocytes and lung.

Post-translational modifications. N-glycosylation is required for ligand binding.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8N6C8-1	1	yes
Q8N6C8-2	2
Q8N6C8-3	3

RefSeq proteins (2): NP_001166125, NP_006856* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR016332	A1B_glyco/leuk_Ig-like_rcpt	Family
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF13895

UniProt features (38 total): strand 9, glycosylation site 5, disulfide bond 5, domain 4, sequence conflict 4, sequence variant 3, helix 3, splice variant 2, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3Q2C	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N6C8-F1	87.43	0.73

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 (5): 49–98, 145–197, 157–167, 246–297, 346–397

Glycosylation sites (5): 431, 140, 281, 302, 341

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-6798695	Neutrophil degranulation
R-HSA-1280218	Adaptive Immune System
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 85 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOCC_SECRETORY_GRANULE, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GNF2_CD1D, GOBP_ADAPTIVE_IMMUNE_RESPONSE, GNF2_HCK, MODULE_46, GOCC_SECRETORY_VESICLE, GOCC_SPECIFIC_GRANULE, GOCC_SECRETORY_GRANULE_MEMBRANE, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION

GO Biological Process (4): adaptive immune response (GO:0002250), immune response-regulating signaling pathway (GO:0002764), interleukin-10-mediated signaling pathway (GO:0140105), immune system process (GO:0002376)

GO Molecular Function (1): inhibitory MHC class I receptor activity (GO:0032396)

GO Cellular Component (5): extracellular region (GO:0005576), plasma membrane (GO:0005886), specific granule membrane (GO:0035579), tertiary granule membrane (GO:0070821), ficolin-1-rich granule membrane (GO:0101003)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Immune System	2
Adaptive Immune System	1
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
secretory granule membrane	3
tertiary granule	2
immune response	1
signal transduction	1
regulation of immune response	1
cytokine-mediated signaling pathway	1
biological_process	1
MHC class I receptor activity	1
cellular anatomical structure	1
membrane	1
cell periphery	1
specific granule	1
ficolin-1-rich granule	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

20 interactions, top by confidence:

A	B	Type	Score
LILRB2	LILRA3	psi-mi:“MI:0915”(physical association)	0.560
LILRA3	NARS1	psi-mi:“MI:0914”(association)	0.530
LILRA3	LILRA1	psi-mi:“MI:0914”(association)	0.530
LILRA6	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
BTN3A1	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	BTNL8	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	IL18BP	psi-mi:“MI:0915”(physical association)	0.400
IL6R	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	PILRA	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	PILRB	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF10B	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
LILRA3	LILRB2	psi-mi:“MI:0915”(physical association)	0.400
SEMA3G	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
TNFRSF12A	LILRA3	psi-mi:“MI:0915”(physical association)	0.400
ECE1	LILRA3	psi-mi:“MI:0915”(physical association)	0.370
EWSR1	LILRA3	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (18): LILRA3 (Affinity Capture-MS), MYCBP2 (Affinity Capture-MS), NARS (Affinity Capture-MS), LILRA1 (Affinity Capture-MS), LILRB2 (Affinity Capture-MS), LILRB1 (Affinity Capture-MS), LILRA3 (Two-hybrid), LILRB2 (Affinity Capture-MS), LILRB1 (Affinity Capture-MS), LILRA1 (Affinity Capture-MS), NARS (Affinity Capture-MS), LILRB2 (Affinity Capture-MS), LILRA3 (Affinity Capture-MS), LILRA1 (Affinity Capture-MS), NARS (Affinity Capture-MS)

ESM2 similar proteins: A0A0K2S4Q6, A2A7V7, A6NI73, A8K4G0, O43699, O75019, O75022, O75023, O75871, O76036, P0C191, P20138, P24071, P40198, P59901, P80943, Q08708, Q13410, Q28110, Q3U497, Q496F6, Q64JA4, Q6GTX8, Q6ISS4, Q6PI73, Q6UXZ3, Q7TSN2, Q863H2, Q8C567, Q8K249, Q8MJZ2, Q8MJZ7, Q8N149, Q8N423, Q8N6C8, Q8NHJ6, Q8NHL6, Q8VBT3, Q8VCH2, Q95JB9

Diamond homologs: A0A0G2KBC9, A6NI73, C0HJX2, C0HJX3, D3ZQX2, O75019, O75022, O75023, O76036, P0C191, P24071, P43626, P43629, P43630, P59901, P83556, P97484, Q14943, Q14954, Q61450, Q64281, Q6GTX8, Q6ISS4, Q6PI73, Q7TQA1, Q863H2, Q8C567, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q95JB9, Q9HCN6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	5	33.5×	7e-06
Adaptive Immune System	5	11.5×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
adaptive immune response	5	28.1×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	4
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000898583 (19:54296550 C>T), RS1001874535 (19:54296944 G>A,C), RS1004966870 (19:54296008 A>G), RS1005040884 (19:54296297 C>G,T), RS1008525058 (19:54295545 T>C), RS1013276942 (19:54296828 G>A,T), RS1013935146 (19:54296925 C>G,T), RS1014829407 (19:54296822 G>A), RS1017811457 (19:54295572 G>T), RS1020081996 (19:54296570 A>G), RS1023615303 (19:54296137 G>A,C,T), RS1024275510 (19:54296333 A>G), RS1027760667 (19:54295661 A>G), RS1028942387 (19:54296592 C>G,T), RS1029223819 (19:54296689 G>A)

Disease associations

OMIM: gene MIM:604818 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000755_38	HDL cholesterol	4.000000e-16
GCST001702_3	Prostate cancer	5.000000e-16
GCST002223_3	HDL cholesterol	3.000000e-23
GCST002899_35	HDL cholesterol	6.000000e-13
GCST004207_11	HDL cholesterol	3.000000e-08
GCST004232_12	HDL cholesterol levels	5.000000e-30
GCST006575_55	Takayasu arteritis	4.000000e-06
GCST007827_2	Alzheimer’s disease or HDL levels (pleiotropy)	6.000000e-12
GCST008070_58	HDL cholesterol levels	5.000000e-17
GCST008070_80	HDL cholesterol levels	1.000000e-10
GCST008075_146	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	4.000000e-55
GCST008075_8	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-48
GCST008084_110	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	2.000000e-55
GCST008084_131	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-06
GCST008084_151	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	1.000000e-64
GCST008085_128	HDL cholesterol levels in current drinkers	4.000000e-22
GCST008085_48	HDL cholesterol levels in current drinkers	7.000000e-29
GCST010241_169	Apolipoprotein A1 levels	1.000000e-61
GCST010242_507	HDL cholesterol levels	1.000000e-74
GCST90002404_542	Red cell distribution width	2.000000e-09

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004614	apolipoprotein A 1 measurement
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation	1
tamibarotene	increases expression	1
(+)-JQ1 compound	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Allergens	increases expression, affects cotreatment	1
Vehicle Emissions	increases expression, affects cotreatment	1
Benzo(a)pyrene	decreases methylation	1
Diazinon	increases methylation	1
Methotrexate	decreases expression	1
Ozone	increases expression	1
Tretinoin	increases expression	1
Aflatoxin B1	increases methylation	1
beta-Naphthoflavone	decreases expression	1
Nanotubes, Carbon	increases expression	1

Clinical trials (associated diseases)

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