LAIR2

Summary

LAIR2 (leukocyte associated immunoglobulin like receptor 2, HGNC:6478) is a protein-coding gene on chromosome 19q13.42, encoding Leukocyte-associated immunoglobulin-like receptor 2 (Q6ISS4).

The protein encoded by this gene is a member of the immunoglobulin superfamily. It was identified by its similarity to leukocyte-associated immunoglobulin-like receptor 1, a membrane-bound receptor that modulates innate immune response. The protein encoded by this locus is a soluble receptor that may play roles in both inhibition of collagen-induced platelet aggregation and vessel formation during placental implantation. This gene maps to a region of 19q13.4, termed the leukocyte receptor cluster, which contains 29 genes in the immunoglobulin superfamily. Alternatively spliced transcript variants have been described for this gene.

Source: NCBI Gene 3904 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 30 total
• MANE Select transcript: NM_002288

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6478
Approved symbol	LAIR2
Name	leukocyte associated immunoglobulin like receptor 2
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	CD306, LAIR-2
Ensembl gene	ENSG00000167618
Ensembl biotype	protein_coding
OMIM	602993
Entrez	3904

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000301202, ENST00000351841, ENST00000412608, ENST00000610651, ENST00000956664

RefSeq mRNA: 2 — MANE Select: NM_002288 NM_002288, NM_021270

CCDS: CCDS12897, CCDS12898

Canonical transcript exons

ENST00000301202 — 5 exons

Exon	Start	End
ENSE00001114999	54507891	54508184
ENSE00001115004	54510526	54510687
ENSE00001338191	54502831	54502952
ENSE00002483700	54503700	54503735
ENSE00002512516	54509035	54509085

Expression profiles

Bgee: expression breadth ubiquitous, 122 present calls, max score 90.07.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8407 / max 167.5896, expressed in 397 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
177525	1.9268	315
177524	0.8039	266
208928	0.0670	37
208927	0.0430	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	90.07	gold quality
placenta	UBERON:0001987	82.52	gold quality
blood	UBERON:0000178	73.13	gold quality
lymph node	UBERON:0000029	70.64	gold quality
leukocyte	CL:0000738	70.40	gold quality
vermiform appendix	UBERON:0001154	69.65	gold quality
monocyte	CL:0000576	69.11	gold quality
bone marrow	UBERON:0002371	63.31	gold quality
spleen	UBERON:0002106	62.15	gold quality
right coronary artery	UBERON:0001625	61.21	gold quality
right lung	UBERON:0002167	60.51	gold quality
duodenum	UBERON:0002114	58.51	gold quality
gall bladder	UBERON:0002110	58.40	gold quality
pituitary gland	UBERON:0000007	58.29	gold quality
upper lobe of left lung	UBERON:0008952	57.00	gold quality
smooth muscle tissue	UBERON:0001135	56.54	gold quality
adenohypophysis	UBERON:0002196	56.14	gold quality
bone marrow cell	CL:0002092	55.29	silver quality
rectum	UBERON:0001052	55.13	gold quality
lung	UBERON:0002048	53.72	gold quality
right adrenal gland cortex	UBERON:0035827	53.15	gold quality
sural nerve	UBERON:0015488	51.11	silver quality
right adrenal gland	UBERON:0001233	50.87	gold quality
left adrenal gland cortex	UBERON:0035825	50.15	gold quality
tonsil	UBERON:0002372	50.01	gold quality
muscle tissue	UBERON:0002385	49.88	gold quality
left adrenal gland	UBERON:0001234	49.18	gold quality
small intestine	UBERON:0002108	49.02	gold quality
mucosa of stomach	UBERON:0001199	48.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	48.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.01
E-HCAD-30	no	33.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

9 targeting LAIR2, 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-3924	100.00	72.09	2394
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-6867-3P	98.12	66.07	1305

Literature-anchored findings (GeneRIF, showing 13)

• LAIR-2 prevents binding of human LAIR-1 to collagens and LAIR-1 cross-linking in vitro, suggesting that the protein has an immunoregulatory function in vivo. (PMID:18209062)
• Human collagen II peptides II-17, -27, -30, -35, -38, -42, -49 & -56; and collagen III peptides III-1, 5, -8, -10, -12, -13, -22, -30, -38, -40, -44, -45, and -51 specifically interacted with hLAIR-2 expressed on K562 cells (PMID:19345263)
• LAIR-2/Fc has the capacity to interfere with platelet-collagen interactions mediated by Glycoprotein VI and the VWF/Glycoprotein Ib axis. (PMID:20730098)
• Two markers in two different genes (CNOT3 and LAIR2) showed significant association with ankylosing spondylitis. (PMID:22294640)
• LAIR2-expressing extravillous trophoblasts associate with maternal spiral arterioles undergoing physiologic conversion (PMID:23332415)
• the presence of high LAIR-2 levels in 74/80 sera from patients with autoimmune thyroid diseases (PMID:23691008)
• recombinant LAIR-2-Fc inhibits complement-mediated lysis of cells sensitized with anti-HLA antibodies (PMID:24192271)
• We suggest that LAIR1 and LAIR2 genetic variants are associated with regulation of gene expression and variable pemphigus foliaceus susceptibility, and show indirect association of LAIR2 differential mRNA expression with pemphigus foliaceus pathogenesis. (PMID:26721477)
• genetic polymorphism is associated with pemphigus foliaceus (PMID:30216441)
• These data suggest that species-specific genes are pivotal to the evolution of a more aggressive human placenta to match the physiological demands of human development. (PMID:31548102)
• PNOC Expressed by B Cells in Cholangiocarcinoma Was Survival Related and LAIR2 Could Be a T Cell Exhaustion Biomarker in Tumor Microenvironment: Characterization of Immune Microenvironment Combining Single-Cell and Bulk Sequencing Technology. (PMID:33841428)
• Association of LncRNA-PAX8-AS1 and LAIR-2 polymorphisms along with their expression with clinical and subclinical hypothyroidism. (PMID:36593237)
• Dissecting T-cell heterogeneity in esophageal squamous cell carcinoma reveals the potential role of LAIR2 in antitumor immunity. (PMID:37422711)

Cross-species orthologs

0 orthologs

Paralogs (25): GP6 (ENSG00000088053), LILRB1 (ENSG00000104972), LILRA1 (ENSG00000104974), LILRB5 (ENSG00000105609), A1BG (ENSG00000121410), KIR2DL1 (ENSG00000125498), LILRB2 (ENSG00000131042), IGSF1 (ENSG00000147255), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRB4 (ENSG00000186818), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), VSTM1 (ENSG00000189068), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), KIR2DS4 (ENSG00000221957), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

Leukocyte-associated immunoglobulin-like receptor 2 — Q6ISS4 (reviewed: Q6ISS4)

All UniProt accessions (3): A0A087X1V4, C9JFQ0, Q6ISS4

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Secreted.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ISS4-1	1, LAIR-2a	yes
Q6ISS4-2	2, LAIR-2b

RefSeq proteins (2): NP_002279, NP_067154 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF13895

UniProt features (9 total): sequence variant 3, signal peptide 1, chain 1, domain 1, region of interest 1, disulfide bond 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ISS4-F1	86.36	0.64

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): 49–101

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 60 (showing top): REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_IMMUNE_RESPONSE, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_DN, GNF2_IL2RB, DANG_BOUND_BY_MYC, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_UP, GOBP_IMMUNE_RESPONSE_REGULATING_SIGNALING_PATHWAY, GOBP_IMMUNE_RESPONSE_INHIBITING_SIGNAL_TRANSDUCTION, RAF_UP.V1_UP, CTIP_DN.V1_UP, KRAS.PROSTATE_UP.V1_UP, GOMF_IMMUNE_RECEPTOR_ACTIVITY, EBNA1BP2_TARGET_GENES, ZNF146_TARGET_GENES

GO Biological Process (1): immune response-regulating signaling pathway (GO:0002764)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), plasma membrane (GO:0005886)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	1
regulation of immune response	1
binding	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

528 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
LAIR2	SFTPD	P35247	731
LAIR2	LENG8	Q96PV6	574
LAIR2	LILRA4	P59901	478
LAIR2	CD300C	Q08708	476
LAIR2	TTYH1	Q9H313	460
LAIR2	CD247	P20963	459
LAIR2	LILRB1	Q8NHL6	433
LAIR2	FCAR	P24071	404
LAIR2	UNK	Q9C0B0	387
LAIR2	NCR1	O76036	382
LAIR2	RPS9	P46781	353
LAIR2	ALCAM	Q13740	353
LAIR2	CDC42EP5	Q6NZY7	350
LAIR2	SEMA3C	Q99985	348
LAIR2	IGFBP1	P08833	341

IntAct

29 interactions, top by confidence:

A	B	Type	Score
LAIR2	SGTA	psi-mi:“MI:0915”(physical association)	0.720
SGTA	LAIR2	psi-mi:“MI:0915”(physical association)	0.720
EMILIN1	LAIR2	psi-mi:“MI:0915”(physical association)	0.670
LAIR2	EMILIN1	psi-mi:“MI:0915”(physical association)	0.670
LAIR2	EMILIN1	psi-mi:“MI:0915”(physical association)	0.560
LAIR2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
LAIR2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
LCN2	LAIR2	psi-mi:“MI:0915”(physical association)	0.560
LAIR2	LAMA5	psi-mi:“MI:0914”(association)	0.530
PAEP	PROS1	psi-mi:“MI:0914”(association)	0.530
LAIR2	FGFR4	psi-mi:“MI:0915”(physical association)	0.400
MECOM	ATP2A1	psi-mi:“MI:0914”(association)	0.350
LAIR2	PLOD3	psi-mi:“MI:0914”(association)	0.350
LAIR2	AGRN	psi-mi:“MI:0914”(association)	0.350
HINT2	PAEP	psi-mi:“MI:0914”(association)	0.350
LAIR2	EMILIN1	psi-mi:“MI:0915”(physical association)	0.000
LAIR2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
LAIR2	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
LAIR2	SGTA	psi-mi:“MI:0915”(physical association)	0.000
LAIR2	LCN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (50): SGTA (Two-hybrid), EMILIN1 (Two-hybrid), LAIR2 (Two-hybrid), LAIR2 (Two-hybrid), LAIR2 (Two-hybrid), LAIR2 (Two-hybrid), UBQLN2 (Two-hybrid), C1QL1 (Affinity Capture-MS), YAP1 (Affinity Capture-MS), VWA1 (Affinity Capture-MS), PDIA5 (Affinity Capture-MS), SCARA3 (Affinity Capture-MS), COL1A1 (Affinity Capture-MS), AIM1 (Affinity Capture-MS), COL14A1 (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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

800 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54502951:AGGT:A	donor_loss	0.9900
19:54502952:GGT:G	donor_loss	0.9900
19:54502953:GT:G	donor_loss	0.9900
19:54502954:T:A	donor_loss	0.9900
19:54508835:G:GT	donor_gain	0.9900
19:54502953:G:GG	donor_gain	0.9800
19:54508852:G:GT	donor_gain	0.9800
19:54509033:A:AG	acceptor_gain	0.9800
19:54509034:G:GG	acceptor_gain	0.9800
19:54509034:GAAA:G	acceptor_gain	0.9800
19:54509082:GCTG:G	donor_gain	0.9700
19:54508091:G:GG	donor_gain	0.9500
19:54509029:TTACA:T	acceptor_loss	0.9500
19:54509030:TACAG:T	acceptor_loss	0.9500
19:54509031:ACAG:A	acceptor_loss	0.9500
19:54509033:A:C	acceptor_loss	0.9500
19:54510524:AG:A	acceptor_gain	0.9500
19:54510525:GG:G	acceptor_gain	0.9500
19:54502947:GCC:G	donor_gain	0.9400
19:54502948:CCTAG:C	donor_gain	0.9400
19:54502950:TAG:T	donor_gain	0.9400
19:54503698:A:AG	acceptor_gain	0.9400
19:54503699:G:GG	acceptor_gain	0.9400
19:54509034:GAA:G	acceptor_gain	0.9400
19:54510511:ATTTT:A	acceptor_loss	0.9400
19:54510520:TCACA:T	acceptor_loss	0.9400
19:54510521:CACAG:C	acceptor_loss	0.9400
19:54510523:C:G	acceptor_loss	0.9400
19:54510525:G:GC	acceptor_loss	0.9400
19:54502946:GGCC:G	donor_gain	0.9300

AlphaMissense

966 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:54507992:T:C	F58L	0.997
19:54507994:C:A	F58L	0.997
19:54507994:C:G	F58L	0.997
19:54508076:T:C	F86L	0.997
19:54508078:C:A	F86L	0.997
19:54508078:C:G	F86L	0.997
19:54508077:T:C	F86S	0.996
19:54508077:T:G	F86C	0.996
19:54507965:T:A	C49S	0.995
19:54507966:G:C	C49S	0.995
19:54507996:G:C	R59P	0.995
19:54508121:T:A	C101S	0.995
19:54508122:G:C	C101S	0.995
19:54508147:G:C	W109C	0.993
19:54508147:G:T	W109C	0.993
19:54508158:G:T	S113I	0.993
19:54508115:T:G	Y99D	0.992
19:54508149:C:T	S110F	0.992
19:54507906:C:A	P29H	0.991
19:54508121:T:C	C101R	0.991
19:54508157:A:C	S113R	0.991
19:54508159:T:A	S113R	0.991
19:54508159:T:G	S113R	0.991
19:54507965:T:C	C49R	0.990
19:54507993:T:C	F58S	0.990
19:54508116:A:G	Y99C	0.990
19:54508123:C:G	C101W	0.990
19:54507960:T:C	F47S	0.989
19:54507966:G:A	C49Y	0.989
19:54507967:C:G	C49W	0.989

dbSNP variants (sampled 300 via entrez): RS1000215794 (19:54507031 T>C), RS1000352534 (19:54508888 C>T), RS1001757696 (19:54510061 C>G), RS1002131700 (19:54505280 G>A), RS1002342492 (19:54501627 A>C,T), RS1002384514 (19:54500870 G>A), RS1003002363 (19:54503181 G>A,C), RS1003162728 (19:54506231 C>CTACA), RS1003294316 (19:54502439 G>A), RS1003765841 (19:54501660 T>C), RS1003858269 (19:54508572 A>G), RS1003957596 (19:54503846 A>G), RS1004014677 (19:54504102 A>C,G), RS1004130609 (19:54511002 T>A,C), RS1006229472 (19:54509522 C>A,G,T)

Disease associations

OMIM: gene MIM:602993 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008478_55	Neurological blood protein biomarker levels	2.000000e-28
GCST008478_56	Neurological blood protein biomarker levels	2.000000e-11

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

28 total (human), top 28 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	5
Cyclosporine	increases expression	3
Estradiol	increases expression	2
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
manganese chloride	decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Ampicillin	decreases expression	1
Arsenic	affects methylation	1
Carbamazepine	affects expression	1
Demecolcine	increases expression	1
Diuron	decreases expression	1
Fonofos	increases methylation	1
Formaldehyde	increases expression	1
Manganese	decreases expression, increases abundance	1
Methyl Methanesulfonate	decreases expression	1
Parathion	increases methylation	1
Quercetin	increases expression	1
Tretinoin	increases expression	1
Vincristine	increases expression	1
Zinc	decreases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	increases expression	1

Clinical trials (associated diseases)

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