FCRL2

Summary

FCRL2 (Fc receptor like 2, HGNC:14875) is a protein-coding gene on chromosome 1q23.1, encoding Fc receptor-like protein 2 (Q96LA5). May have an regulatory role in normal and neoplastic B cell development.

This gene encodes a member of the immunoglobulin receptor superfamily and is one of several Fc receptor-like glycoproteins clustered on the long arm of chromosome 1. The encoded protein has four extracellular C2-type immunoglobulin domains, a transmembrane domain and a cytoplasmic domain that contains one immunoreceptor-tyrosine activation motif and two immunoreceptor-tyrosine inhibitory motifs. This protein may be a prognostic marker for chronic lymphocytic leukemia. Alternatively spliced transcript variants have been described, but their biological validity has not been determined.

Source: NCBI Gene 79368 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_030764

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14875
Approved symbol	FCRL2
Name	Fc receptor like 2
Location	1q23.1
Locus type	gene with protein product
Status	Approved
Aliases	FCRH2, IRTA4, CD307b
Ensembl gene	ENSG00000132704
Ensembl biotype	protein_coding
OMIM	606509
Entrez	79368

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 5 protein_coding, 2 retained_intron

ENST00000361516, ENST00000368178, ENST00000368181, ENST00000462774, ENST00000469986, ENST00000864375, ENST00000957326

RefSeq mRNA: 2 — MANE Select: NM_030764 NM_001159488, NM_030764

CCDS: CCDS1168

Canonical transcript exons

ENST00000361516 — 12 exons

Exon	Start	End
ENSE00001435012	157768414	157768701
ENSE00001435024	157769866	157770150
ENSE00002328070	157767231	157767509
ENSE00003460405	157766855	157766971
ENSE00003484250	157777043	157777132
ENSE00003541459	157775775	157775795
ENSE00003589941	157749650	157749677
ENSE00003598787	157770409	157770666
ENSE00003599413	157748553	157748618
ENSE00003606562	157746871	157746899
ENSE00003622965	157745733	157746774
ENSE00003664258	157748875	157748960

Expression profiles

Bgee: expression breadth ubiquitous, 118 present calls, max score 93.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7154 / max 138.9511, expressed in 54 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15280	0.7154	54

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	93.16	silver quality
spleen	UBERON:0002106	92.00	gold quality
lymph node	UBERON:0000029	87.87	gold quality
epithelium of nasopharynx	UBERON:0001951	86.79	gold quality
granulocyte	CL:0000094	86.75	gold quality
vermiform appendix	UBERON:0001154	84.98	gold quality
caecum	UBERON:0001153	80.76	gold quality
tonsil	UBERON:0002372	79.40	gold quality
small intestine Peyer’s patch	UBERON:0003454	76.49	gold quality
superficial temporal artery	UBERON:0001614	76.26	gold quality
ileal mucosa	UBERON:0000331	75.39	gold quality
blood	UBERON:0000178	75.38	gold quality
bone marrow cell	CL:0002092	73.78	gold quality
rectum	UBERON:0001052	72.97	gold quality
small intestine	UBERON:0002108	72.97	gold quality
mucosa of transverse colon	UBERON:0004991	72.09	gold quality
bone marrow	UBERON:0002371	70.56	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.37	gold quality
colonic epithelium	UBERON:0000397	64.98	gold quality
leukocyte	CL:0000738	64.42	gold quality
duodenum	UBERON:0002114	63.80	gold quality
trabecular bone tissue	UBERON:0002483	63.13	silver quality
mononuclear cell	CL:0000842	62.82	gold quality
tibia	UBERON:0000979	62.66	silver quality
monocyte	CL:0000576	62.59	gold quality
gall bladder	UBERON:0002110	61.68	gold quality
mucosa of sigmoid colon	UBERON:0004993	61.31	silver quality
transverse colon	UBERON:0001157	60.83	gold quality
colonic mucosa	UBERON:0000317	60.43	gold quality
pigmented layer of retina	UBERON:0001782	59.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	20.76
E-ANND-3	yes	12.18

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

48 targeting FCRL2, 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-548AW	99.99	72.57	3559
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-16-5P	99.90	72.80	2780
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-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-10393-5P	99.65	68.01	1368

Literature-anchored findings (GeneRIF, showing 9)

• FCRL2 has robust predictive value for determining IGHV gene mutation status and clinical progression and thus may further improve prognostic definition in chronic lymphocytic leukemia. (PMID:18314442)
• Fc receptor-like 1-5 molecules are similarly expressed in progressive and indolent clinical subtypes of B-cell chronic lymphocytic leukemia. (PMID:18704934)
• Down-regulation of FCRL2 is associated with acute lymphoblastic leukemia. (PMID:18802695)
• B-CLL patients with high FCRL2 expression had a significantly longer treatment-free survival & overall survival than those with low FCRL2. (PMID:19682311)
• a negative immunomodulatory function for FCRL2 in the regulation of memory B cells. (PMID:21068405)
• FCRL2 overexpression in B cells from Hashimoto and Graves disease patients compared to normal subjects. (PMID:25738996)
• decreased FCRL4 expression and association of FCRL2 expression with inflammatory markers and disease activity suggested the contribution of these molecules to rheumatoid arthritis inflammatory processes. (PMID:27193470)
• we have shown that FCRL2 is a powerful predictor of both TFT and OS in CLL and have validated the prognostic significance of FCRL2 in a new cohort of patients. (PMID:31092813)
• Expression profile of Fc receptor-like molecules in patients with IgA nephropathy. (PMID:33597097)

Cross-species orthologs

0 orthologs

Paralogs (17): FCGR2B (ENSG00000072694), FCRLA (ENSG00000132185), FCGR2A (ENSG00000143226), FCRL5 (ENSG00000143297), FCGR1A (ENSG00000150337), FCRL3 (ENSG00000160856), FCRLB (ENSG00000162746), FCGR3B (ENSG00000162747), FCRL4 (ENSG00000163518), FCRL1 (ENSG00000163534), FCER1A (ENSG00000179639), FCRL6 (ENSG00000181036), C17orf99 (ENSG00000187997), FCGR3A (ENSG00000203747), FCGR2C (ENSG00000244682), PECAM1 (ENSG00000261371), MILR1 (ENSG00000271605)

Protein

Protein identifiers

Fc receptor-like protein 2 — Q96LA5 (reviewed: Q96LA5)

Alternative names: Fc receptor homolog 2, IFGP family protein 4, Immunoglobulin receptor translocation-associated protein 4, SH2 domain-containing phosphatase anchor protein 1

All UniProt accessions (1): Q96LA5

UniProt curated annotations — full annotation on UniProt →

Function. May have an regulatory role in normal and neoplastic B cell development.

Subunit / interactions. The tyrosine-phosphorylated isoform 2 interacts with PTPN6.

Subcellular location. Cell membrane.

Tissue specificity. Expressed in the secondary lymphoid organs, spleen and lymph node. Expression is limited to the mature B-cell lines. Highly expressed in CD19 and within the mantle zones of the tonsil tissue. Isoform 2 is expressed in the spleen, peripheral blood and bone marrow. Isoform 2 and isoform 4 are expressed in B-cell lines. Preferentially expressed in memory B-cells (at protein level).

Post-translational modifications. Isoform 2 is N- and O-glycosylated, and phosphorylated.

Domain organisation. Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). The phosphorylated ITIM motif bind the SH2 domain of PTPN6.

Isoforms (5)

UniProt ID	Names	Canonical?
Q96LA5-1	1	yes
Q96LA5-2	2, SPAP1A
Q96LA5-3	3, SPAP1B
Q96LA5-4	4, SPAP1C
Q96LA5-5	5

RefSeq proteins (2): NP_001152960, NP_110391* (*=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
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050488	Ig_Fc_receptor	Family

Pfam: PF13895, PF13927

UniProt features (32 total): splice variant 8, glycosylation site 5, short sequence motif 4, domain 4, disulfide bond 3, topological domain 2, signal peptide 1, chain 1, compositionally biased region 1, transmembrane region 1, sequence variant 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LA5-F1	80.56	0.63

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 (3): 128–177, 226–275, 321–368

Glycosylation sites (5): 204, 234, 343, 355, 365

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 96 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOCC_CELL_SURFACE, GOBP_CELL_CELL_SIGNALING, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, MODULE_301, BILBAN_B_CLL_LPL_DN, MODULE_188, TGGAAA_NFAT_Q4_01, GOCC_SIDE_OF_MEMBRANE, GOMF_PROTEIN_PHOSPHATASE_BINDING, GOMF_PHOSPHATASE_BINDING, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_SIGNALING_ADAPTOR_ACTIVITY, DODD_NASOPHARYNGEAL_CARCINOMA_DN, MODULE_292

GO Biological Process (3): immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), cell-cell signaling (GO:0007267)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), protein phosphatase binding (GO:0019903), signaling adaptor activity (GO:0035591), protein binding (GO:0005515)

GO Cellular Component (4): external side of plasma membrane (GO:0009897), cell surface (GO:0009986), membrane (GO:0016020), plasma membrane (GO:0005886)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
immune system process	1
response to stimulus	1
signal transduction	1
cell communication	1
signaling	1
signaling receptor activity	1
phosphatase binding	1
protein-macromolecule adaptor activity	1
binding	1
plasma membrane	1
cell surface	1
side of membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

678 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FCRL2	PIGR	P01833	750
FCRL2	FCGR2A	P12318	601
FCRL2	FCGR2B	P31994	588
FCRL2	MUC1	P13931	497
FCRL2	BCL9	O00512	424
FCRL2	PTPN11	Q06124	391
FCRL2	CAPN8	A6NHC0	382
FCRL2	KIRREL1	Q96J84	374
FCRL2	CD5L	O43866	362
FCRL2	CD72	P21854	358
FCRL2	CD1E	P15812	353
FCRL2	SIT1	Q9Y3P8	324
FCRL2	PTPN6	P29350	319
FCRL2	SIGLEC5	O15389	314
FCRL2	TMEM156	Q8N614	305

IntAct

7 interactions, top by confidence:

A	B	Type	Score
FCRL2	METAP2	psi-mi:“MI:0915”(physical association)	0.590
NCK2	FCRL2	psi-mi:“MI:0915”(physical association)	0.560
FCRL2	NCK2	psi-mi:“MI:0915”(physical association)	0.560
FCRL2	HBD	psi-mi:“MI:0914”(association)	0.350

BioGRID (12): FCRL2 (Two-hybrid), METAP2 (Affinity Capture-MS), FCRL2 (Two-hybrid), JAGN1 (Two-hybrid), MAL (Two-hybrid), ZDHHC22 (Two-hybrid), FCRL2 (Affinity Capture-MS), METAP2 (Affinity Capture-MS), HBD (Affinity Capture-MS), TNFSF9 (Affinity Capture-MS), NEDD8-MDP1 (Affinity Capture-MS), F3 (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: A1YIY0, P12314, P23505, Q6DN72, Q7L513, Q96LA5, Q96LA6, Q96P31, Q96RD9, A0A087WV53, A1KZ92, A2AJ76, A4IFW2, A4IGL7, A6NDA9, B0BNK7, B0V2N1, D2HFT7, D3YXG0, D4A1J9, D4ABX8, F1NWE3, G5EG78, O15146, O73775, O75325, O94898, P07722, P15364, P20916, P20917, P23468, P43146, P48960, P53813, P70193, P70211, Q03142, Q08761, Q08879

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MARCHF9	“down-regulates quantity by destabilization”	FCRL2	ubiquitination

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	5
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1636 predictions. Top by Δscore:

Variant	Effect	Δscore
1:157770547:A:C	donor_gain	1.0000
1:157770557:AT:A	donor_gain	1.0000
1:157770558:T:TA	donor_gain	1.0000
1:157746772:GTCC:G	acceptor_loss	0.9900
1:157746773:TCCTG:T	acceptor_loss	0.9900
1:157746774:CCTG:C	acceptor_loss	0.9900
1:157747653:C:CT	acceptor_gain	0.9900
1:157748615:CCCA:C	acceptor_gain	0.9900
1:157748616:CCA:C	acceptor_gain	0.9900
1:157748616:CCAC:C	acceptor_gain	0.9900
1:157748617:CAC:C	acceptor_gain	0.9900
1:157748619:C:CC	acceptor_gain	0.9900
1:157748956:CCCCT:C	acceptor_gain	0.9900
1:157748957:CCCT:C	acceptor_gain	0.9900
1:157748957:CCCTC:C	acceptor_gain	0.9900
1:157748958:CCTC:C	acceptor_gain	0.9900
1:157763107:CACA:C	acceptor_gain	0.9900
1:157763109:CA:C	acceptor_gain	0.9900
1:157746775:C:CC	acceptor_gain	0.9800
1:157746900:C:CC	acceptor_gain	0.9800
1:157747654:A:T	acceptor_gain	0.9800
1:157748617:CA:C	acceptor_gain	0.9800
1:157748958:CCT:C	acceptor_gain	0.9800
1:157748959:CT:C	acceptor_gain	0.9800
1:157748959:CTC:C	acceptor_gain	0.9800
1:157748960:TCT:T	acceptor_gain	0.9800
1:157748961:C:CC	acceptor_gain	0.9800
1:157748961:C:G	acceptor_gain	0.9800
1:157749645:CTCAC:C	donor_loss	0.9800
1:157749646:TCACC:T	donor_loss	0.9800

AlphaMissense

3298 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:157769931:C:G	C177S	0.979
1:157769932:A:T	C177S	0.979
1:157768620:C:G	C226S	0.968
1:157768621:A:T	C226S	0.968
1:157770032:G:C	F143L	0.968
1:157770032:G:T	F143L	0.968
1:157770034:A:G	F143L	0.968
1:157770078:C:G	C128S	0.968
1:157770079:A:T	C128S	0.968
1:157769891:G:C	S190R	0.966
1:157769891:G:T	S190R	0.966
1:157769893:T:G	S190R	0.966
1:157768582:A:G	W239R	0.960
1:157768582:A:T	W239R	0.960
1:157770474:C:G	C82S	0.960
1:157770475:A:T	C82S	0.960
1:157768586:G:C	F237L	0.955
1:157768586:G:T	F237L	0.955
1:157768588:A:G	F237L	0.955
1:157768621:A:G	C226R	0.955
1:157768619:G:C	C226W	0.954
1:157770606:C:G	C38S	0.953
1:157770607:A:T	C38S	0.953
1:157768439:G:C	S286R	0.952
1:157768439:G:T	S286R	0.952
1:157768441:T:G	S286R	0.952
1:157770079:A:G	C128R	0.952
1:157767391:A:C	F334L	0.951
1:157767391:A:T	F334L	0.951
1:157767393:A:G	F334L	0.951

dbSNP variants (sampled 300 via entrez): RS1000119805 (1:157754053 A>G), RS1000166808 (1:157755817 A>T), RS1000193249 (1:157753848 A>C), RS1000392734 (1:157764614 A>G), RS1000420311 (1:157747626 A>C,G), RS1000460502 (1:157749171 A>C), RS1000566752 (1:157766496 TC>T), RS1000628957 (1:157776948 C>G,T), RS1000683483 (1:157761616 A>G), RS1000723360 (1:157776498 A>T), RS1000749667 (1:157749451 C>G), RS1000764219 (1:157766713 C>T), RS1001038447 (1:157748810 T>C), RS1001131683 (1:157755333 A>G), RS1001168667 (1:157757265 T>C)

Disease associations

OMIM: gene MIM:606509 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
butyraldehyde	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	increases reaction, affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Zoledronic Acid	increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	increases methylation	1
Copper	affects cotreatment, decreases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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