FCGR3A

Summary

FCGR3A (Fc gamma receptor IIIa, HGNC:3619) is a protein-coding gene on chromosome 1q23.3, encoding Low affinity immunoglobulin gamma Fc region receptor III-A (P08637). Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). In precision oncology, FCGR3A F212V confers sensitivity to Trastuzumab in Her2-receptor Positive Breast Cancer (CIViC Level B).

This gene encodes a receptor for the Fc portion of immunoglobulin G, and it is involved in the removal of antigen-antibody complexes from the circulation, as well as other responses, including antibody dependent cellular mediated cytotoxicity and antibody dependent enhancement of virus infections. This gene (FCGR3A) is highly similar to another nearby gene (FCGR3B) located on chromosome 1. The receptor encoded by this gene is expressed on natural killer (NK) cells as an integral membrane glycoprotein anchored through a transmembrane peptide, whereas FCGR3B is expressed on polymorphonuclear neutrophils (PMN) where the receptor is anchored through a phosphatidylinositol (PI) linkage. Mutations in this gene are associated with immunodeficiency 20, and have been linked to susceptibility to recurrent viral infections, susceptibility to systemic lupus erythematosus, and alloimmune neonatal neutropenia. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 2214 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity (Moderate, GenCC)
• GWAS associations: 18
• Clinical variants (ClinVar): 77 total
• Phenotypes (HPO): 13
• Druggable target: yes
• Precision-oncology evidence (CIViC): 1 curated variant–drug association
• MANE Select transcript: NM_000569

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3619
Approved symbol	FCGR3A
Name	Fc gamma receptor IIIa
Location	1q23.3
Locus type	gene with protein product
Status	Approved
Aliases	CD16, CD16a, FcgammaRIIIa, FcGRIIIA
Ensembl gene	ENSG00000203747
Ensembl biotype	protein_coding
OMIM	146740
Entrez	2214

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367967, ENST00000426740, ENST00000436743, ENST00000442336, ENST00000443193, ENST00000476031, ENST00000699395, ENST00000699396, ENST00000699397, ENST00000699398, ENST00000699399, ENST00000699400, ENST00000699401, ENST00000699493, ENST00000884927, ENST00000884928, ENST00000884929, ENST00000884930, ENST00000946729, ENST00000946730, ENST00000946731, ENST00000946732, ENST00000946733

RefSeq mRNA: 8 — MANE Select: NM_000569 NM_000569, NM_001127592, NM_001127593, NM_001127595, NM_001127596, NM_001329120, NM_001329122, NM_001386450

CCDS: CCDS44266, CCDS91089

Canonical transcript exons

ENST00000443193 — 5 exons

Exon	Start	End
ENSE00001446026	161549697	161549818
ENSE00001880956	161541759	161543199
ENSE00002415838	161544701	161544958
ENSE00003498401	161548421	161548678
ENSE00003612570	161549011	161549031

Expression profiles

Bgee: expression breadth ubiquitous, 130 present calls, max score 99.55.

FANTOM5 (CAGE): breadth broad, TPM avg 0.9861 / max 120.4424, expressed in 215 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
15647	0.8481	208
15649	0.1117	41
15648	0.0264	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.55	gold quality
leukocyte	CL:0000738	99.02	gold quality
monocyte	CL:0000576	98.97	gold quality
blood	UBERON:0000178	98.78	gold quality
spleen	UBERON:0002106	98.53	gold quality
vermiform appendix	UBERON:0001154	97.18	gold quality
placenta	UBERON:0001987	95.98	gold quality
right lung	UBERON:0002167	95.76	gold quality
upper lobe of left lung	UBERON:0008952	94.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	91.98	gold quality
left adrenal gland	UBERON:0001234	91.91	gold quality
right adrenal gland cortex	UBERON:0035827	91.83	gold quality
right coronary artery	UBERON:0001625	91.72	gold quality
left adrenal gland cortex	UBERON:0035825	91.60	gold quality
descending thoracic aorta	UBERON:0002345	91.38	gold quality
right adrenal gland	UBERON:0001233	91.23	gold quality
lung	UBERON:0002048	90.98	gold quality
bone marrow cell	CL:0002092	90.55	gold quality
adrenal gland	UBERON:0002369	89.73	gold quality
substantia nigra	UBERON:0002038	89.60	gold quality
thoracic aorta	UBERON:0001515	89.52	gold quality
gall bladder	UBERON:0002110	89.29	gold quality
ascending aorta	UBERON:0001496	89.10	gold quality
bone marrow	UBERON:0002371	88.52	gold quality
left coronary artery	UBERON:0001626	88.23	gold quality
liver	UBERON:0002107	87.66	gold quality
omental fat pad	UBERON:0010414	87.21	gold quality
smooth muscle tissue	UBERON:0001135	86.58	gold quality
right atrium auricular region	UBERON:0006631	86.26	gold quality
mucosa of stomach	UBERON:0001199	86.17	gold quality

Single-cell (SCXA)

Detected in 28 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-GEOD-150728	yes	3064.41
E-MTAB-10432	yes	2178.11
E-CURD-55	yes	2117.55
E-MTAB-9221	yes	1949.97
E-MTAB-7407	yes	1703.29
E-GEOD-149689	yes	1429.57
E-MTAB-8207	yes	1408.05
E-GEOD-139324	yes	1403.51
E-MTAB-6653	yes	1214.90
E-GEOD-75688	yes	1063.64
E-MTAB-9801	yes	268.94
E-HCAD-1	yes	133.67
E-HCAD-4	yes	109.47
E-MTAB-6701	yes	76.87
E-CURD-122	yes	68.09

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ESR1, ESR2, FOXP3, STAT1

miRNA regulators (miRDB)

39 targeting FCGR3A, 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-6758-5P	100.00	66.21	1470
HSA-MIR-4682	100.00	68.89	1258
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-199A-3P	99.75	70.48	929
HSA-MIR-199B-3P	99.75	70.48	929
HSA-MIR-3129-5P	99.75	70.46	914
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-7152-5P	99.60	69.33	2094
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-3160-5P	99.28	69.07	1938
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-7153-3P	99.00	65.35	608
HSA-MIR-382-3P	98.83	67.10	1074
HSA-MIR-3149	98.77	67.13	1639
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-6893-3P	97.79	64.91	1238

Literature-anchored findings (GeneRIF, showing 40)

• Two separate elements located in the 5’ 21-bp (-942/-922) and 3’ 72-bp (-921/-850) regions of the Fc gamma RIIIA promoter Pmed1 are highly specific in governing restriction to NK/T cell lines. (PMID:11884455)
• binding of human Fcgamma RIII to oligosaccharides (PMID:11986321)
• expression of mRNA specific for the FcgammaRIIIA and FcgammaRIIIB subclasses are upregulated by interferon-gamma in human keratinocytes (PMID:12445195)
• FCGR3A-176F/F genotype is considered to confer risk of susceptibility to rheumatoid arthritis through genetic interaction with HLA-DRB1 shared epitope in a Japanese population. (PMID:12486608)
• To a limited extent, the presence of high-binding alleles at the FcgRIIIA locus or at the FcgRIIIA-FcgRIIA haplotype might predispose to RA in SE positive individuals. (PMID:12734884)
• specific sequences in the FcgammaRIIIA and FcgammaRI transmembrane domains govern their different interactions with the gamma chain in cell surface expression and phagocytosis (PMID:12756162)
• putative susceptibility factor for periodontitis in Northern European Caucasians (PMID:12834496)
• Polymorphism of the Fc gamma IIIa receptor influences neither susceptibility nor clinical disease course of multiple sclerosis. (PMID:12864991)
• Defucosylated IgG1 exhibited higher antibody-dependent cellular cytotoxicity (ADCC) than S298A/E333A/K334A-IgG1, showing a correlation between IgG1 affinity for FcgammaRIIIa and ADCC. (PMID:15037082)
• Estrogen can modulate proinflammatory cytokine release from activated monocytes and/or macrophages, in part through modulation of CD16 expression. (PMID:15188374)
• FcgammaRIIIa-158V homozygotes were more frequent in the HIT group than in the group with Abs to H/PF4 without HIT group, a difference that was more pronounced in patients with high levels of anti-H/PF4 Abs (PMID:15191947)
• CD14 and CD16 in monocytes may have a role in development of coronary atherosclerosis and expression of TNF-alpha (PMID:15269840)
• the orientation and length of P-selectin, E-selectin, or CD16A receptor influences its rate of encountering and binding a surface ligand but does not subsequently affect the stability of binding (PMID:15299021)
• Results suggest that Fc gammaRIII genotypes may represent mild disease-modifying factors in GBS. (PMID:15833371)
• Data provide evidence for association between FcgammaRIIIA allelic variants and coronary atherosclerosis; genetic variation in this IgG-receptor may influence the clearance of antibodies by monocyte-derived macrophages involved in the pathogenesis of CAD. (PMID:15910853)
• Polymorphisms of FcgammaRIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via FcgammaRs. (PMID:16221721)
• Increased soluble FcgammaRIIIa(Mphi) in plasma from patients with coronary artery diseases. (PMID:16310791)
• Asn-162 of FcgammaRIIIa is required for high affinity binding to non-fucosylated IgG glycoforms (PMID:16330541)
• Increased association with an FCGR3A-FCGR3B haplotype suggests that other polymorphic variants or in linkage disequilibrium may also contribute to rheumatoid arthritis pathogenesis. (PMID:16356189)
• The FCGR3A single nucleotide polymorphism (SNP) is predictive of response to R-CHOP, but does not correlate with survival in patients with DLBCL. (PMID:16609067)
• The length of the stalk region of the alpha-chain is an important determinant of Fc gamma receptor IIIA stability on the cell surface. (PMID:16709862)
• Increased association with FCGR2A-FCGR3A haplotype suggests presence of additional genetic polymorphisms in linkage disequilibrium with this haplotype that may contribute to disease susceptibility. (PMID:16846526)
• CD16-IgG interaction could directly drive capture and activation of flowing neutrophils, or potentiate activation of cells captured by other routes. (PMID:16934243)
• No association could be observed between FCGR3A-158 gene polymorphism and the clinical response to infliximab in Crohn’s disease. (PMID:17108815)
• measured the kinetic rates and equilibrium dissociation constants of IgG binding to a soluble FcgammaRIIIa fused with Ig Fc (sCD16a) using the surface plasmon resonance technique. sCD16a interacted with monomeric human IgG and its subtypes IgG1 and IgG3 (PMID:17202140)
• There is wide linkage within and between polymorphisms in FcgammaRIIIa and FcgammaRIIa and might provide an explanation for why polymorphisms at FcgammaRIIa are associated with rituximab responses despite a lack of impact on IgG1 binding. (PMID:17324336)
• FcgammaRIIIa (158 F/V) polymorphism may modulate susceptibility to acquire bullous pemphigoid. (PMID:17457599)
• CD16-expressing monocytes are preferentially susceptible to HIV-1 entry, more permissive for replication, and constitute a continuing source of viral persistence during HAART antiretroviral therapy. (PMID:17475889)
• individuals expressing at least one valine at FcgammaRIIIa-158 might, in part, have better clinical outcomes due to increased CD16 expression, rituximab binding, and rituximab-mediated antibody-dependent cellular cytotoxicity (PMID:17475906)
• study concludes that polymorphic variants of the CRP & Fcgamma-receptor genes are associated with the clinical phenotype in systemic lupus erythematosus (PMID:17596285)
• allele and genotype frequencies of the G559T allele of the FcGRIIIA gene were significantly different in CD patients compared to controls (PMID:17600378)
• FcgammaRIIIa and FcgRIIa polymorphisms did not influence response, event-free or overall survival in treatment of diffuse large B-cell lymphoma (PMID:17606457)
• the FcgRIIIa*559CC genotype is associated with rheumatoid arthritis. (PMID:17652100)
• polymorphisms may markers to predict clinical outcome in metastatic CRC patients treated with be useful molecular cetuximab and that polymorphisms were independently associated with progression-free survival (PMID:17704420)
• The FCGR2A 131RR and FCGR3A 158VV genotypes were over-represented [OR: 1.67 (1.05-2.63) and 2.04 (1.06-4.00), respectively] whereas the FCGR3B NA2NA2 was under-represented in patients with cryptococcosis (28% vs. 40% in controls). (PMID:17710620)
• may explain the preferential accumulation of CD56(bright) NK cells often seen in environments rich in reactive oxygen species, such as at sites of chronic inflammation and in tumors (PMID:17878347)
• Analysis of phosphatidylcholine-specific phospholipase C and CD16 distribution in natural killer cell plasma membrane demonstrates that the proteins are physically associated and partially accumulated in lipid rafts. (PMID:17899539)
• role of FCGR3A gene in susceptibility to systemic lupus erythematosus (SLE) (PMID:17922423)
• The level of CD16 expression by monocytes was elevated in patients with tumor necrosis factor receptor-associated periodic syndrome, as a feature of the underlying constitutive inflammation status. (PMID:18050249)
• These data suggest that dual recruitment of FcgammaRIIIa and the IL-12R to lipid raft microdomains allows for enhanced activation of downstream signaling events that lead to IFN-gamma production. (PMID:18174382)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Fcgr4	ENSMUSG00000059089
rattus_norvegicus	Fcgr3a	ENSRNOG00000024382

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), FCGR2C (ENSG00000244682), PECAM1 (ENSG00000261371), MILR1 (ENSG00000271605)

Protein

Protein identifiers

Low affinity immunoglobulin gamma Fc region receptor III-A — P08637 (reviewed: P08637)

Alternative names: CD16-II, CD16a antigen, Fc-gamma RIII-alpha, FcR-10, IgG Fc receptor III-2

All UniProt accessions (7): A0A8V8TNB3, A0A8V8TNB8, A0A8V8TPL1, A0A8V8TQ03, C9JC71, P08637, H0Y755

UniProt curated annotations — full annotation on UniProt →

Function. Receptor for the invariable Fc fragment of immunoglobulin gamma (IgG). Optimally activated upon binding of clustered antigen-IgG complexes displayed on cell surfaces, triggers lysis of antibody-coated cells, a process known as antibody-dependent cellular cytotoxicity (ADCC). Does not bind free monomeric IgG, thus avoiding inappropriate effector cell activation in the absence of antigenic trigger. Mediates IgG effector functions on natural killer (NK) cells. Binds antigen-IgG complexes generated upon infection and triggers NK cell-dependent cytokine production and degranulation to limit viral load and propagation. Involved in the generation of memory-like adaptive NK cells capable to produce high amounts of IFNG and to efficiently eliminate virus-infected cells via ADCC. Regulates NK cell survival and proliferation, in particular by preventing NK cell progenitor apoptosis. Following the engagement of antigen-IgG complexes, triggers phosphorylation of immunoreceptor tyrosine-based activation motif (ITAM)-containing adapters with subsequent activation of phosphatidylinositol 3-kinase signaling and sustained elevation of intracellular calcium that ultimately drive NK cell activation. The ITAM-dependent signaling coupled to receptor phosphorylation by PKC mediates robust intracellular calcium flux that leads to production of pro-inflammatory cytokines, whereas in the absence of receptor phosphorylation it mainly activates phosphatidylinositol 3-kinase signaling leading to cell degranulation. Costimulates NK cells and trigger lysis of target cells independently of IgG binding. Mediates the antitumor activities of therapeutic antibodies. Upon ligation on monocytes triggers TNFA-dependent ADCC of IgG-coated tumor cells. Mediates enhanced opsonisation and ADCC in response to afucosylated IgGs. (Microbial infection) Involved in Dengue virus pathogenesis via antibody-dependent enhancement (ADE) mechanism. Secondary infection with Dengue virus triggers elevated levels of afucosylated non-neutralizing IgG1s with reactivity to viral envelope/E protein. Viral antigen-IgG1 complexes bind with high affinity to FCGR3A, facilitating virus entry in myeloid cells and subsequent viral replication.

Subunit / interactions. Forms a heterooligomeric complex with ITAM-containing signaling subunits, either a homodimer of CD247, a homodimer of FCER1G or a heterodimer of CD247 and FCER1G. Interacts (via transmembrane domain) with signaling subunits; this interaction is a prerequisite for receptor complex expression on the cell surface and intracellular signal transduction. Binds the Fc region of antigen-complexed IgG with a preference for IgG1 and IgG3 isotypes. Interacts with CD2; this interaction is involved in NK cell activation and cytotoxicity. Interacts with S100A4; this interaction inhibits PKC-dependent phosphorylation of FCGR3A.

Subcellular location. Cell membrane. Secreted.

Tissue specificity. Expressed in natural killer cells (at protein level). Expressed in a subset of circulating monocytes (at protein level).

Post-translational modifications. Glycosylated. Contains high mannose- and complex-type oligosaccharides. Glycosylation at Asn-180 is mandatory for high affinity binding to the Fc and for discrimination between fucosylated and afucosylated IgG glycoforms. Undergoes rapid ectodomain shedding upon NK cell stimulation. The soluble form is produced by a proteolytic cleavage mediated by ADAM17. Repeated stimulation causes receptor shedding, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells while avoiding activation-induced NK cell apoptosis. Phosphorylated at RSSTR motif by PKC. The relevant physiological PKCs might be PRKCI, PRKCG, PRKCE, PRKCH and PRKCQ.

Disease relevance. Immunodeficiency 20 (IMD20) [MIM:615707] A rare autosomal recessive primary immunodeficiency characterized by functional deficiency of NK cells. Affected individuals typically present with severe herpes viral infections, particularly Epstein Barr virus (EBV), and human papillomavirus (HPV). The disease is caused by variants affecting the gene represented in this entry.

Induction. Up-regulated in a monocyte subset upon exposure to IL10, TGFB and MCSF.

Miscellaneous. Encoded by one of two nearly identical genes: FCGR3A (shown here) and FCGR3B which are expressed in a tissue-specific manner. The Phe-203 in III-A determines the transmembrane domains whereas the ‘Ser-203’ in III-B determines the GPI-anchoring. FCGR3A in mammals is the true ortholog of FCGR4 in rodents. The FCGR2A-HSPA6-FCGR4-FCGR2B module was duplicated in great apes through non-allelic homologous recombination, giving rise to two FCGR4-type genes and to FCGR2C, a hybrid gene combining FCGR2A and FCGR2B. While FCGR3A kept the original FCGR4 functionality, FCGR3B rapidly evolved and acquired specific features coding for a GPI-anchored receptor.

RefSeq proteins (8): NP_000560, NP_001121064, NP_001121065, NP_001121067, NP_001121068, NP_001316049, NP_001316051, NP_001373379 (=MANE)

Domains & families (InterPro)

ID	Name	Type
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 (66 total): strand 19, mutagenesis site 18, sequence variant 6, glycosylation site 5, helix 3, modified residue 2, disulfide bond 2, topological domain 2, sequence conflict 2, domain 2, site 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
9PRU	X-RAY DIFFRACTION	1.9
7SEG	X-RAY DIFFRACTION	2.16
3AY4	X-RAY DIFFRACTION	2.2
3SGJ	X-RAY DIFFRACTION	2.2
5VU0	X-RAY DIFFRACTION	2.26
5ML9	X-RAY DIFFRACTION	2.35
5MN2	X-RAY DIFFRACTION	2.35
3SGK	X-RAY DIFFRACTION	2.4
5XJE	X-RAY DIFFRACTION	2.4
7URU	X-RAY DIFFRACTION	2.4
5XJF	X-RAY DIFFRACTION	2.5
5YC5	X-RAY DIFFRACTION	2.71
3WN5	X-RAY DIFFRACTION	2.78
5BW7	X-RAY DIFFRACTION	3
5D6D	X-RAY DIFFRACTION	3.13

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08637-F1	85.65	0.66

Antibody-complex structures (SAbDab): 1 — 7SEG

Functional residue map

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

Catalytic / active sites (2): 195–196 (cleavage; by adam17); 222 (important for receptor turnover)

Post-translational modifications (2): 237, 236

Disulfide bonds (2): 47–89, 128–172

Glycosylation sites (5): 56, 63, 92, 180, 187

Mutagenesis-validated functional residues (18):

Position	Phenotype
197	impairs receptor shedding. impairs the detachment of nk cells from opsonized target cells upon sequential activation.
203	disrupts transmembrane anchoring.
203	enables membrane anchoring via glycosylphosphatidylinositol. disrupts transmembrane anchoring.
203	enables only transmembrane anchoring.
208	decreases the association with either cd247 or fcer1g.
210	has no effect on complex association with cd247 or fcer1g. decreases cell surface expression; when associated with a-211
211	decreases the association with either cd247 or fcer1g. decreases cell surface expression; when associated with a-210 and
212	has no effect on complex formation with cd247 or fcer1g. decreases cell surface expression; when associated with a-210 a
219	decreases the association with either cd247 or fcer1g. decreases cell surface expression.
222	decreases the association with either cd247 or fcer1g. strongly increases cell surface expression.
222	strongly decreases complex formation with cd247 or fcer1g.
222	has little effect on complex formation with cd247 or fcer1g.
223	decreases the association with either cd247 or fcer1g. decreases cell surface expression.
226	decreases the association with either cd247 or fcer1g. decreases cell surface expression; when associated with a-227 and
227	decreases the association with either cd247 or fcer1g. decreases cell surface expression; when associated with a-226 and
228	has little effect on complex formation with cd247 or fcer1g. decreases cell surface expression; when associated with a-2
235–237	loss of pkc-dependent phosphorylation. abolishes pro-inflammatory cytokine production while enhancing cell degranulation
249–254	impairs the interaction with s100a4.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-2029481	FCGR activation
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2029485	Role of phospholipids in phagocytosis
R-HSA-9664323	FCGR3A-mediated IL10 synthesis
R-HSA-9664422	FCGR3A-mediated phagocytosis

MSigDB gene sets: 311 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, MODULE_45, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOCC_CELL_SURFACE, MODULE_478, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION

GO Biological Process (17): antibody-dependent cellular cytotoxicity (GO:0001788), immune response (GO:0006955), cell surface receptor signaling pathway (GO:0007166), calcium-mediated signaling (GO:0019722), natural killer cell activation (GO:0030101), positive regulation of tumor necrosis factor production (GO:0032760), positive regulation of natural killer cell proliferation (GO:0032819), Fc-gamma receptor signaling pathway (GO:0038094), macrophage activation (GO:0042116), natural killer cell mediated cytotoxicity (GO:0042267), natural killer cell degranulation (GO:0043320), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), T cell mediated cytotoxicity (GO:0001913), immune system process (GO:0002376), protein import (GO:0017038), protein transmembrane transport (GO:0071806), granzyme-mediated programmed cell death signaling pathway (GO:0140507)

GO Molecular Function (5): IgG receptor activity (GO:0019770), low-affinity IgG receptor activity (GO:0019772), IgG binding (GO:0019864), immune receptor activity (GO:0140375), protein binding (GO:0005515)

GO Cellular Component (7): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), Fc-gamma receptor III complex (GO:0033001), extracellular exosome (GO:0070062), extracellular region (GO:0005576), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Fcgamma receptor (FCGR) dependent phagocytosis	3
Adaptive Immune System	1
Anti-inflammatory response favouring Leishmania parasite infection	1
Leishmania phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
leukocyte mediated cytotoxicity	3
signal transduction	2
intracellular signaling cassette	2
protein transport	2
cellular anatomical structure	2
type IIa hypersensitivity	1
immune system process	1
response to stimulus	1
lymphocyte activation	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
natural killer cell proliferation	1
positive regulation of natural killer cell activation	1
regulation of natural killer cell proliferation	1
positive regulation of lymphocyte proliferation	1
Fc receptor signaling pathway	1
myeloid leukocyte activation	1
natural killer cell mediated immunity	1
natural killer cell activation involved in immune response	1
natural killer cell mediated cytotoxicity	1
leukocyte degranulation	1
T cell mediated immunity	1
biological_process	1
transmembrane transport	1
programmed cell death	1
immunoglobulin receptor activity	1
IgG binding	1
Fc-gamma receptor signaling pathway	1
IgG receptor activity	1
immunoglobulin binding	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
Fc receptor complex	1
extracellular vesicle	1

Protein interactions and networks

STRING

3440 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FCGR3A	CD19	P15391	998
FCGR3A	FCER1G	P30273	997
FCGR3A	CD247	P20963	995
FCGR3A	TNFRSF8	P28908	990
FCGR3A	NCAM1	P13591	990
FCGR3A	NCR1	O76036	985
FCGR3A	CD33	P20138	973
FCGR3A	FCGR1A	P12314	959
FCGR3A	TYROBP	O43914	955
FCGR3A	KLRK1	P26718	952
FCGR3A	ANPEP	P15144	950
FCGR3A	CD8A	P01732	941
FCGR3A	CD4	P01730	940
FCGR3A	TLR4	O00206	931
FCGR3A	IFNG	P01579	924

IntAct

14 interactions, top by confidence:

A	B	Type	Score
FCGR3A	RNF40	psi-mi:“MI:0915”(physical association)	0.500
FCGR3A	MYH9	psi-mi:“MI:0915”(physical association)	0.400
FCGR3A	KIR2DL4	psi-mi:“MI:0915”(physical association)	0.400
	FCGR3A	psi-mi:“MI:0915”(physical association)	0.400
FCGR3A	ZBTB25	psi-mi:“MI:0915”(physical association)	0.370
FCGR3A	CFTR	psi-mi:“MI:0915”(physical association)	0.370
FCGR3A	GK	psi-mi:“MI:0914”(association)	0.350
FCGR3A	RTL8C	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
FCGR3B	FCGR3A	psi-mi:“MI:0914”(association)	0.350
FCGR3A	FCGR1A	psi-mi:“MI:2364”(proximity)	0.270
FCGR3A		psi-mi:“MI:0915”(physical association)	0.000

BioGRID (38): FCGR3B (Affinity Capture-MS), GK (Affinity Capture-MS), RNF40 (Affinity Capture-MS), FCGR1A (Co-localization), RAB32 (Affinity Capture-MS), NCS1 (Affinity Capture-MS), GK (Affinity Capture-MS), LCK (Affinity Capture-Western), FCGR3A (Biochemical Activity), FCGR3A (Biochemical Activity), S100A4 (Two-hybrid), S100A4 (Affinity Capture-Western), S100A4 (Reconstituted Complex), SHC1 (Affinity Capture-Western), FCGR3A (Affinity Capture-Western)

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

2 interactions.

A	Effect	B	Mechanism
“Immune complexes”	“up-regulates activity”	FCGR3A
FCGR3A	“up-regulates quantity by expression”	TNF

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	9
Benign	7

Top pathogenic / likely-pathogenic (0)

SpliceAI

960 predictions. Top by Δscore:

Variant	Effect	Δscore
1:161548951:ATGG:A	donor_gain	1.0000
1:161549863:T:TA	donor_gain	1.0000
1:161548676:CTT:C	acceptor_gain	0.9900
1:161548679:C:CC	acceptor_gain	0.9900
1:161549032:C:CC	acceptor_gain	0.9900
1:161549879:T:TA	donor_gain	0.9900
1:161545658:A:AC	donor_gain	0.9800
1:161545659:C:CC	donor_gain	0.9800
1:161548413:CAACT:C	donor_loss	0.9800
1:161548414:AACT:A	donor_loss	0.9800
1:161548415:AC:A	donor_loss	0.9800
1:161548416:CTC:C	donor_loss	0.9800
1:161548417:TCA:T	donor_loss	0.9800
1:161548418:CACCG:C	donor_loss	0.9800
1:161548419:A:AC	donor_gain	0.9800
1:161548419:A:T	donor_loss	0.9800
1:161548420:C:CC	donor_gain	0.9800
1:161548485:T:A	donor_gain	0.9800
1:161549032:C:CA	acceptor_loss	0.9800
1:161549691:ACTT:A	donor_loss	0.9800
1:161549692:CTT:C	donor_loss	0.9800
1:161549693:TTA:T	donor_loss	0.9800
1:161549694:TA:T	donor_loss	0.9800
1:161549695:A:AC	donor_gain	0.9800
1:161549696:C:CC	donor_gain	0.9800
1:161549696:C:CG	donor_loss	0.9800
1:161549860:ATTT:A	donor_gain	0.9800
1:161549889:T:TA	donor_gain	0.9800
1:161543199:CC:C	acceptor_loss	0.9700
1:161543200:C:A	acceptor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000122921 (1:161546285 A>C), RS1000155393 (1:161546637 G>A), RS1001799924 (1:161547651 G>C), RS1002504498 (1:161551894 T>C), RS1003019634 (1:161544505 A>T), RS1003462350 (1:161549990 A>C,G), RS1004696799 (1:161545997 T>G), RS1005200248 (1:161541981 G>A), RS1005501076 (1:161549511 A>G,T), RS1005747445 (1:161541710 A>G,T), RS1006371600 (1:161547049 C>G), RS1006402620 (1:161547510 G>T), RS1007037929 (1:161551327 C>G,T), RS1007176664 (1:161550895 T>A), RS1008539474 (1:161545643 G>A)

Disease associations

OMIM: gene MIM:146740 | disease phenotypes: MIM:615707

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity	Moderate	Autosomal recessive

Mondo (1): autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity (MONDO:0014313)

Orphanet (1): Autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity (Orphanet:437552)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000403	Recurrent otitis media
HP:0002205	Recurrent respiratory infections
HP:0002721	Immunodeficiency
HP:0003593	Infantile onset
HP:0011108	Recurrent sinusitis
HP:0012177	Abnormal natural killer cell physiology
HP:0020086	BCGitis
HP:0030828	Wheezing
HP:0032170	Severe varicella zoster infection
HP:0033166	Recurrent viral upper respiratory tract infections
HP:0040218	Reduced total natural killer cell count
HP:0410028	Recurrent oral herpes

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST001725_37	Inflammatory bowel disease	2.000000e-38
GCST002188_2	Functional impairment in major depressive disorder, bipolar disorder and schizophrenia	3.000000e-06
GCST004131_77	Inflammatory bowel disease	9.000000e-14
GCST004133_13	Ulcerative colitis	2.000000e-18
GCST005752_27	Systemic lupus erythematosus	1.000000e-06
GCST006863_3	Takayasu arteritis	6.000000e-12
GCST006984_1	Takayasu arteritis	7.000000e-12
GCST008362_142	Birth weight	2.000000e-10
GCST011773_23	Type 1 diabetes (age at diagnosis)	6.000000e-06
GCST90002379_10	Basophil count	1.000000e-13
GCST90002379_11	Basophil count	7.000000e-12
GCST90002380_87	Basophil percentage of white cells	6.000000e-16
GCST90002380_89	Basophil percentage of white cells	2.000000e-21
GCST90002383_338	Hematocrit	2.000000e-11
GCST90002384_13	Hemoglobin	4.000000e-17
GCST90002394_88	Monocyte percentage of white cells	9.000000e-15
GCST90002401_367	Platelet distribution width	8.000000e-17
GCST90011898_29	Alanine aminotransferase levels	8.000000e-11

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0005412	functional impairment measurement
EFO:0004344	birth weight
EFO:0004918	age at diagnosis
EFO:0005090	basophil count
EFO:0007992	basophil percentage of leukocytes
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0007989	monocyte percentage of leukocytes
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3856162 (SINGLE PROTEIN)

Clinical evidence (CIViC)

Drug × variant × indication: 1 predictive associations from 1 curated evidence items; also 1 prognostic.

Variant	Therapy	Indication	Effect	Level	CIViC
FCGR3A F212V	Trastuzumab	Her2-receptor Positive Breast Cancer	Sensitivity/Response	CIViC B	EID1087

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

PharmGKB clinical annotations

8 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs396991	Efficacy	2B	rituximab	Neuromyelitis Optica;Rheumatoid arthritis
rs396991	Other	3	antithymocyte globulin	Kidney Transplantation
rs396991	Efficacy	3	infliximab	Rheumatoid arthritis
rs396991	Efficacy	3	adalimumab;etanercept;infliximab	Psoriasis
rs396991	Efficacy	3	cetuximab	Neoplasms
rs396991	Efficacy	3	tocilizumab	Rheumatoid arthritis
rs396991	Efficacy	3	trastuzumab	Breast Neoplasms
rs396991	Efficacy	3	rituximab

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs396991	FCGR3A	2B	8.00	8	rituximab;cetuximab;adalimumab;etanercept;infliximab;tocilizumab;infliximab;trastuzumab;antithymocyte globulin

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
AFM13	Binding	9.41	pKd
bemarituzumab	Binding	8.04	pKd

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment, decreases expression	2
Tretinoin	increases expression	2
GSK-J4	decreases expression	1
bisphenol A	decreases expression, decreases reaction	1
sodium arsenite	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
4-nonylphenol	affects cotreatment, increases expression	1
endotoxin, Escherichia coli	decreases expression, decreases reaction	1
CGP 52608	affects binding, increases reaction	1
4-tert-octylphenol	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Decitabine	decreases expression, decreases reaction	1
Arsenic Trioxide	increases expression	1
Acetaminophen	affects cotreatment, decreases expression	1
Air Pollutants, Occupational	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Calcitriol	decreases expression	1
Doxorubicin	decreases expression	1
Mercury	decreases expression	1
Nickel	decreases expression	1
Progesterone	increases expression	1
Smoke	decreases expression, decreases reaction	1
Tobacco Smoke Pollution	increases expression	1
Vitallium	decreases expression	1
Ziram	decreases expression	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

30 cell lines: 23 cancer cell line, 6 spontaneously immortalized cell line, 1 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_1E21	TZM-bl/FcgammaRIIIa	Cancer cell line	Female
CVCL_A7ZT	Jurkat-Lucia NFAT-CD16	Cancer cell line	Male
CVCL_B5ZE	NK92-CD16	Cancer cell line	Male
CVCL_B5ZF	NK92-41BB	Cancer cell line	Male
CVCL_B8FY	Abcam HCT 116 FCGR3A KO	Cancer cell line	Male
CVCL_B8VS	Abcam MCF-7 FCGR3A KO	Cancer cell line	Female
CVCL_B9I5	Abcam A-549 FCGR3A KO	Cancer cell line	Male
CVCL_C4RP	WAe001-A-81	Embryonic stem cell	Male
CVCL_DF02	CHO-K1.Cl6	Spontaneously immortalized cell line	Female
CVCL_DF03	CHO-K1.Cl7	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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