FCGR2C

Summary

FCGR2C (Fc gamma receptor IIc (gene/pseudogene), HGNC:15626) is a protein-coding gene on chromosome 1q23.3, encoding Low affinity immunoglobulin gamma Fc region receptor II-c (P31995). Receptor for the Fc region of complexed immunoglobulins gamma.

This gene encodes one of three members of a family of low-affinity immunoglobulin gamma Fc receptors found on the surface of many immune response cells. The encoded protein is a transmembrane glycoprotein and may be involved in phagocytosis and clearing of immune complexes. An allelic polymorphism in this gene results in both coding and non-coding variants.

Source: NCBI Gene 9103 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 62 total
• Phenotypes (HPO): 20

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15626
Approved symbol	FCGR2C
Name	Fc gamma receptor IIc (gene/pseudogene)
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	hFcRII-C, CD32C, Fc-gamma-RIIc, FcgammaRIIc
Ensembl gene	ENSG00000244682
Ensembl biotype	protein_coding
OMIM	612169
Entrez	9103

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding_CDS_not_defined, 1 protein_coding_LoF, 1 retained_intron

ENST00000465075, ENST00000466542, ENST00000467903, ENST00000473530, ENST00000473712, ENST00000482226, ENST00000496692, ENST00000502411, ENST00000507374, ENST00000508651

RefSeq mRNA: 0 — MANE Select: None

Canonical transcript exons

ENST00000465075 — 5 exons

Exon	Start	End
ENSE00002036205	161590081	161590218
ENSE00002057021	161591144	161591291
ENSE00002247924	161581346	161581549
ENSE00003516200	161588422	161588442
ENSE00003542556	161589562	161589819

Expression profiles

Bgee: expression breadth ubiquitous, 169 present calls, max score 98.57.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.57	gold quality
monocyte	CL:0000576	97.56	gold quality
mononuclear cell	CL:0000842	97.26	gold quality
leukocyte	CL:0000738	96.70	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	96.40	gold quality
mucosa of stomach	UBERON:0001199	93.09	gold quality
gall bladder	UBERON:0002110	91.40	gold quality
tibial nerve	UBERON:0001323	90.11	gold quality
calcaneal tendon	UBERON:0003701	89.64	gold quality
omental fat pad	UBERON:0010414	89.26	gold quality
peritoneum	UBERON:0002358	89.17	gold quality
apex of heart	UBERON:0002098	88.20	gold quality
left adrenal gland cortex	UBERON:0035825	87.70	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.64	gold quality
right adrenal gland cortex	UBERON:0035827	87.46	gold quality
upper lobe of left lung	UBERON:0008952	87.38	gold quality
right adrenal gland	UBERON:0001233	87.01	gold quality
blood	UBERON:0000178	86.80	gold quality
left coronary artery	UBERON:0001626	86.60	gold quality
left adrenal gland	UBERON:0001234	86.57	gold quality
small intestine Peyer’s patch	UBERON:0003454	86.43	gold quality
smooth muscle tissue	UBERON:0001135	86.29	gold quality
right coronary artery	UBERON:0001625	86.10	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	86.10	gold quality
vermiform appendix	UBERON:0001154	85.74	gold quality
muscle layer of sigmoid colon	UBERON:0035805	85.72	gold quality
right atrium auricular region	UBERON:0006631	85.53	gold quality
upper lobe of lung	UBERON:0008948	85.44	gold quality
sural nerve	UBERON:0015488	85.44	gold quality
lower esophagus muscularis layer	UBERON:0035833	85.32	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.66

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 18)

• activating FCGR2C-ORF genotype predisposes to idiopathic thrombocytopenic purpura by altering the balance of activating and inhibitory FcgammaR on immune cells (PMID:17827395)
• Only FCGR3A, FCGR2C and FCGR3B show copy number variation, in contrast to FCGR2A and FCGR2B. (PMID:19309690)
• Fragment c gamma receptor gene polymorphisms is not associated with breast cancer. (PMID:20978933)
• Two additional variations in FcgammaRIIb/c expression on leukocytes have now been identified; findings demonstrate a more extensive and previously unnoticed variation in FcgammaR expression with relevance to immunity and inflammation. (PMID:22198951)
• Genomic pathology of SLE-associated copy-number variation at the FCGR2C/FCGR3B/FCGR2B locus.(28-40) Status: Complete Incomplete Delete (PMID:23261299)
• study concludes gene copy number of FcgammaR2C and FcgammaR3B influences IVIG treatment response and predisposes individuals to Kawasaki disease, providing potential insights into understanding the mechanism of the FcgammaR gene family in the IVIG pathway (PMID:23778324)
• We report the discovery of allele-dependent expression of the activating FcgammaRIIc on B cells. Identical to FcgammaRIIb in the extracellular domain, FcgammaRIIc has a tyrosine-based activation motif in its cytoplasmic domain. (PMID:24353158)
• sequenced exons and surrounding areas of FcR-encoding genes and found one FCGR2C tag SNP (rs114945036) that associated with vaccine efficacy against HIV-1 subtype CRF01_AE, with lysine at position 169 (169K) in the V2 loop (CRF01_AE 169K) (PMID:25105367)
• Data show that gains or losses in copy numbers of Fc gamma receptors FCGR3A were less frequent than for FCGR3B and FCGR2C. (PMID:26032265)
• These include an FCGR2A/2C chimeric gene that causes a decreased expression (PMID:26133275)
• The findings of this study highlight further ethnic variation at the FCGR gene locus, in particular for FCGR2C, a gene with increasingly recognized clinical significance. (PMID:26673965)
• FCGR2A and FCGR2C polymorphisms may also contribute to immunocomplexemia present in sarcoidosis. (PMID:26801149)
• FCGR2C SNPs that associated with vaccine efficacy in RV144 also strongly associated with the expression of FCGR2A/C and one of them also associated with the expression of Fc receptor-like A (FCRLA), another Fc-gamma receptor (FcgammaR) gene (PMID:27015273)
• When higher-affinity genotypes for FCGR2A, FCGR3A, and FCGR2C were considered together, they were associated with significantly increased tumor shrinkage and prolonged survival in response to HD-IL2… this is the first study to show associations of FCGR genotypes with outcome following HD-IL2 treatment (PMID:27742794)
• Gene copy number variation (CNV) of the PKLR, FCGR2A, FCGR2C, and FCGR3 genes is associated with malaria severity, and our results provide evidence for a role of CNV in host responses to malaria. (PMID:28605553)
• The nonclassical open reading frame in the FCGR2C gene (FCGR2C.nc-ORF) was strongly associated with a decreased alloimmunization risk (odds ratio [OR] 0.26, 95% confidence [CI] 0.11-0.64). (PMID:28899854)
• In a cohort of HIV-1-infected South African controllers (n = 71) and progressors (n = 73), the c.134-96C>T minor allele significantly associated with increased odds of HIV-1 disease progression; these data provide additional evidence towards a role for FCGR2C c.134-96C>T in the context of HIV-1. (PMID:30563969)
• An HIV Vaccine Protective Allele in FCGR2C Associates With Increased Odds of Perinatal HIV Acquisition. (PMID:34917081)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fcgr2b	ENSMUSG00000026656
mus_musculus	Fcgr3	ENSMUSG00000059498
rattus_norvegicus	Fcgr2b	ENSRNOG00000046452
rattus_norvegicus	Fcgr2a	ENSRNOG00000046663
rattus_norvegicus	Fcgr2a	ENSRNOG00000049422
rattus_norvegicus	Fcgr2al1	ENSRNOG00000058500

Paralogs (17): FCGR2B (ENSG00000072694), FCRLA (ENSG00000132185), FCRL2 (ENSG00000132704), FCGR2A (ENSG00000143226), FCRL5 (ENSG00000143297), FCGR1A (ENSG00000150337), FCRL3 (ENSG00000160856), FCRLB (ENSG00000162746), FCGR3B (ENSG00000162747), FCRL4 (ENSG00000163518), FCRL1 (ENSG00000163534), FCER1A (ENSG00000179639), FCRL6 (ENSG00000181036), C17orf99 (ENSG00000187997), FCGR3A (ENSG00000203747), PECAM1 (ENSG00000261371), MILR1 (ENSG00000271605)

Protein

Protein identifiers

Low affinity immunoglobulin gamma Fc region receptor II-c — P31995 (reviewed: P31995)

Alternative names: CDw32, Fc-gamma RII-c

All UniProt accessions (0):

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the Fc region of complexed immunoglobulins gamma. Low affinity receptor. Involved in a variety of effector and regulatory functions such as phagocytosis of immune complexes and modulation of antibody production by B-cells.

Subcellular location. Cytoplasm Cell membrane Cell membrane Cell membrane.

Tissue specificity. Isoform IIC1 is detected in monocytes, macrophages, polymorphonuclear cells and natural killer cells.

Post-translational modifications. Phosphorylated by SRC-type Tyr-kinases such as LYN, BLK, FYN and SYK.

Domain organisation. Contains an intracytoplasmic twice repeated motif referred as immunoreceptor tyrosine-based activator motif (ITAM). These motifs are involved in triggering cell activation upon receptors aggregation.

Isoforms (4)

UniProt ID	Names	Canonical?
P31995-1	IIC1, C1	yes
P31995-2	IIC2
P31995-3	IIC3
P31995-4	IIC4

RefSeq proteins (0): (*=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

UniProt features (41 total): strand 18, glycosylation site 3, splice variant 3, helix 3, disulfide bond 2, sequence conflict 2, topological domain 2, domain 2, modified residue 2, signal peptide 1, chain 1, transmembrane region 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6YAX	X-RAY DIFFRACTION	2.8
3WJL	X-RAY DIFFRACTION	2.86

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P31995-F1	77.13	0.54

Antibody-complex structures (SAbDab): 1 — 6YAX

Functional residue map

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

Post-translational modifications (2): 294, 310

Disulfide bonds (2): 71–113, 152–196

Glycosylation sites (3): 106, 180, 187

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 169 (showing top): GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_INFLAMMATORY_RESPONSE, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_TUMOR_NECROSIS_FACTOR_SUPERFAMILY_CYTOKINE_PRODUCTION, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_CYTOKINE_PRODUCTION, IRF1_Q6, GOBP_FC_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (5): antibody-dependent cellular cytotoxicity (GO:0001788), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of phagocytosis (GO:0050766)

GO Molecular Function (3): transmembrane signaling receptor activity (GO:0004888), IgG receptor activity (GO:0019770), IgG binding (GO:0019864)

GO Cellular Component (3): cytoplasm (GO:0005737), external side of plasma membrane (GO:0009897), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
type IIa hypersensitivity	1
leukocyte mediated cytotoxicity	1
immune system process	1
response to stimulus	1
signal transduction	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
signaling receptor activity	1
immunoglobulin receptor activity	1
IgG binding	1
Fc-gamma receptor signaling pathway	1
immunoglobulin binding	1
intracellular anatomical structure	1
plasma membrane	1
cell surface	1
side of membrane	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

12 interactions, top by confidence:

A	B	Type	Score
FCGR2C	CRP	psi-mi:“MI:0915”(physical association)	0.400
CRP	FCGR2C	psi-mi:“MI:0915”(physical association)	0.400
FCGR2C	CRK	psi-mi:“MI:0915”(physical association)	0.400
FCGR2C	SRC	psi-mi:“MI:0915”(physical association)	0.400
FYN	FCGR2C	psi-mi:“MI:0915”(physical association)	0.400
GRB2	FCGR2C	psi-mi:“MI:0915”(physical association)	0.400
FCGR2C	NCK1	psi-mi:“MI:0915”(physical association)	0.400
FCGR2C	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
FCGR2A	PLPBP	psi-mi:“MI:0914”(association)	0.350
FCGR2A	STAMBP	psi-mi:“MI:0914”(association)	0.350

BioGRID (4): FCGR2C (Affinity Capture-MS), FCGR2C (Affinity Capture-MS), FCGR2C (Affinity Capture-MS), FCGR2C (Affinity Capture-MS)

ESM2 similar proteins: A0A0B4J1G0, A0A0G2KBC9, A3RFZ7, B6A8R8, E2RP87, G1T7E7, G1TR84, H0VDZ8, M3XWH1, O75015, P08101, P08508, P08637, P0DTI4, P12314, P12318, P12319, P12371, P13597, P13598, P20489, P26151, P27645, P31995, P35330, P50283, P51866, P79107, P82957, Q00238, Q08481, Q09TM2, Q09TM4, Q14952, Q28942, Q3B8P2, Q3SWT0, Q5NKV1, Q5NKV2, Q60513

Diamond homologs: A0A0B4J1G0, A3RFZ7, E2RP87, G1T7E7, G1TR84, H0VDZ8, M3XWH1, O75015, P08101, P08508, P08637, P0DTI4, P12314, P12318, P12319, P12371, P20489, P26151, P27645, P31994, P31995, P79107, Q09TM2, Q09TM4, Q28110, Q28942, Q3B8P2, Q5DRQ8, Q60513, Q63203, Q6BAA4, Q6XPU4, Q8SPV8, Q8SPW2, Q920A9, Q92637, Q96PJ5, Q96RD9, Q9N2I5, Q68SN8

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
BLK	“up-regulates activity”	FCGR2C	phosphorylation
SYK	“up-regulates activity”	FCGR2C	phosphorylation
LYN	“up-regulates activity”	FCGR2C	phosphorylation
FYN	“up-regulates activity”	FCGR2C	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	6
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1285 predictions. Top by Δscore:

Variant	Effect	Δscore
1:161583178:GCAA:G	donor_gain	1.0000
1:161583181:A:AG	donor_gain	1.0000
1:161589755:G:GT	donor_gain	1.0000
1:161589755:G:T	donor_gain	1.0000
1:161591394:CCAAG:C	donor_loss	1.0000
1:161591395:CAAGG:C	donor_loss	1.0000
1:161591396:AAGG:A	donor_loss	1.0000
1:161591397:AGG:A	donor_loss	1.0000
1:161591398:GG:G	donor_loss	1.0000
1:161591399:G:T	donor_loss	1.0000
1:161591400:T:G	donor_loss	1.0000
1:161592127:A:AG	acceptor_gain	1.0000
1:161592128:G:GG	acceptor_gain	1.0000
1:161592238:TTCAG:T	donor_loss	1.0000
1:161592239:TCAGG:T	donor_loss	1.0000
1:161592240:CAG:C	donor_loss	1.0000
1:161592241:AGG:A	donor_loss	1.0000
1:161592242:GGTT:G	donor_loss	1.0000
1:161592243:G:A	donor_loss	1.0000
1:161592244:T:A	donor_loss	1.0000
1:161581432:G:GT	donor_gain	0.9900
1:161583181:A:G	donor_gain	0.9900
1:161588420:A:AG	acceptor_gain	0.9900
1:161588421:G:GG	acceptor_gain	0.9900
1:161588442:GGTA:G	donor_loss	0.9900
1:161588443:G:T	donor_loss	0.9900
1:161588444:TAA:T	donor_loss	0.9900
1:161589561:GCA:G	acceptor_gain	0.9900
1:161589729:TTC:T	donor_gain	0.9900
1:161589830:G:GT	donor_gain	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000033311 (1:161596863 GTCTC>G), RS1000328761 (1:161582212 T>C), RS1000329538 (1:161587014 C>T), RS1000982202 (1:161594757 A>G), RS1001013343 (1:161595212 C>T), RS1001601527 (1:161588959 T>C), RS1001713102 (1:161599157 G>T), RS1003303985 (1:161592103 C>T), RS1003874186 (1:161596626 A>G), RS1003926384 (1:161596102 T>A,C), RS1004473747 (1:161580191 G>T), RS1004930460 (1:161593722 C>G,T), RS1005294679 (1:161582595 G>A), RS1006110066 (1:161586833 T>C), RS1006557554 (1:161588202 G>A,C)

Disease associations

OMIM: gene MIM:612169 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

20 total (20 of 20 shown, HPO-id order):

HPO	Term
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000790	Hematuria
HP:0000967	Petechiae
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0001342	Cerebral hemorrhage
HP:0001873	Thrombocytopenia
HP:0002239	Gastrointestinal hemorrhage
HP:0004420	Arterial thrombosis
HP:0011885	Hemorrhage of the eye
HP:0025329	Anti-glutamic acid decarboxylase antibody positivity
HP:0025379	Anti-thyroid peroxidase antibody positivity
HP:0030908	Liver kidney microsome type 1 antibody positivity
HP:0032069	Anti-thyroglobulin antibody positivity
HP:0034062	Anti-insulin antibody positivity
HP:0034063	Anti-islet antigen-2 antibody positivity
HP:0034189	Anti-thyroid-stimulating hormone receptor antibody positivity
HP:0034263	Abnormal vaginal bleeding
HP:4000170	Anti-platelet antigen antibody positivity

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST000624_7	Ulcerative colitis	3.000000e-09
GCST005552_1	Systemic sclerosis (anti-centromere-positive)	6.000000e-14
GCST005554_2	Systemic sclerosis	3.000000e-08
GCST005555_1	Limited cutaneous systemic scleroderma	3.000000e-13
GCST005752_27	Systemic lupus erythematosus	1.000000e-06
GCST008362_143	Birth weight	4.000000e-10
GCST008362_93	Birth weight	4.000000e-11
GCST008363_18	Offspring birth weight	8.000000e-09
GCST011956_55	Systemic lupus erythematosus	2.000000e-30
GCST90013405_124	Liver enzyme levels (alanine transaminase)	2.000000e-28

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008536	anti-centromere-antibody-positive systemic scleroderma
EFO:1001017	limited scleroderma
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

11 total (human), top 11 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
GSK-J4	decreases expression	1
cinnamaldehyde	increases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	affects cotreatment, increases expression, decreases expression	1
Biological Factors	increases expression	1
Cytarabine	increases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Antirheumatic Agents	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_KA31	CHO-K1/CD32C 13Gln	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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