FCN3

Summary

FCN3 (ficolin 3, HGNC:3625) is a protein-coding gene on chromosome 1p36.11, encoding Ficolin-3 (O75636). Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system.

Ficolins are a group of proteins which consist of a collagen-like domain and a fibrinogen-like domain. In human serum, there are two types of ficolins, both of which have lectin activity. The protein encoded by this gene is a thermolabile beta-2-macroglycoprotein found in all human serum and is a member of the ficolin/opsonin p35 lectin family. The protein, which was initially identified based on its reactivity with sera from patients with systemic lupus erythematosus, has been shown to have a calcium-independent lectin activity. The protein can activate the complement pathway in association with MASPs and sMAP, thereby aiding in host defense through the activation of the lectin pathway. Alternative splicing occurs at this locus and two variants, each encoding a distinct isoform, have been identified.

Source: NCBI Gene 8547 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency due to ficolin3 deficiency (Moderate, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 79 total — 3 likely-pathogenic
• Phenotypes (HPO): 6
• MANE Select transcript: NM_003665

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3625
Approved symbol	FCN3
Name	ficolin 3
Location	1p36.11
Locus type	gene with protein product
Status	Approved
Aliases	FCNH, HAKA1
Ensembl gene	ENSG00000142748
Ensembl biotype	protein_coding
OMIM	604973
Entrez	8547

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 18 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000270879, ENST00000354982, ENST00000481748, ENST00000498393, ENST00000699962, ENST00000699963, ENST00000859498, ENST00000859499, ENST00000859500, ENST00000859501, ENST00000859502, ENST00000859503, ENST00000859504, ENST00000859505, ENST00000859506, ENST00000859507, ENST00000966010, ENST00000966011, ENST00000966012, ENST00000966013, ENST00000966014

RefSeq mRNA: 2 — MANE Select: NM_003665 NM_003665, NM_173452

CCDS: CCDS300, CCDS301

Canonical transcript exons

ENST00000270879 — 8 exons

Exon	Start	End
ENSE00000956155	27374356	27374451
ENSE00000956156	27373965	27374009
ENSE00000956157	27373488	27373520
ENSE00000956158	27373136	27373263
ENSE00000956160	27370596	27370730
ENSE00001153243	27374728	27374824
ENSE00003525283	27370843	27370972
ENSE00003903709	27369110	27369477

Expression profiles

Bgee: expression breadth ubiquitous, 172 present calls, max score 99.89.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7267 / max 714.6708, expressed in 104 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
11226	1.7267	104

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	99.89	gold quality
upper lobe of left lung	UBERON:0008952	99.33	gold quality
upper lobe of lung	UBERON:0008948	99.14	gold quality
lower lobe of lung	UBERON:0008949	97.87	gold quality
adult organism	UBERON:0007023	97.41	gold quality
liver	UBERON:0002107	95.77	gold quality
lung	UBERON:0002048	94.44	gold quality
right lobe of liver	UBERON:0001114	94.19	gold quality
heart right ventricle	UBERON:0002080	91.07	gold quality
heart left ventricle	UBERON:0002084	90.90	gold quality
cardiac ventricle	UBERON:0002082	90.71	gold quality
metanephric glomerulus	UBERON:0004736	90.71	gold quality
renal glomerulus	UBERON:0000074	90.45	gold quality
right adrenal gland cortex	UBERON:0035827	89.95	gold quality
apex of heart	UBERON:0002098	89.91	gold quality
right adrenal gland	UBERON:0001233	89.45	gold quality
left adrenal gland	UBERON:0001234	89.42	gold quality
left adrenal gland cortex	UBERON:0035825	88.98	gold quality
omental fat pad	UBERON:0010414	88.42	gold quality
peritoneum	UBERON:0002358	88.29	gold quality
adrenal cortex	UBERON:0001235	87.72	gold quality
right lobe of thyroid gland	UBERON:0001119	87.47	gold quality
adipose tissue of abdominal region	UBERON:0007808	87.26	gold quality
adrenal gland	UBERON:0002369	86.12	gold quality
right atrium auricular region	UBERON:0006631	85.62	gold quality
heart	UBERON:0000948	85.11	gold quality
adult mammalian kidney	UBERON:0000082	83.98	gold quality
cardiac atrium	UBERON:0002081	82.96	gold quality
pancreatic ductal cell	CL:0002079	82.92	silver quality
kidney epithelium	UBERON:0004819	81.12	gold quality

Single-cell (SCXA)

Detected in 17 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-CURD-126	yes	21958.82
E-MTAB-8495	yes	14292.20
E-MTAB-10553	yes	13871.48
E-MTAB-6308	yes	10865.52
E-HCAD-15	yes	10051.20
E-HCAD-9	yes	6564.93
E-CURD-122	yes	5661.91
E-MTAB-7407	yes	5009.60
E-MTAB-8221	yes	4731.24
E-CURD-98	yes	4516.43
E-GEOD-130473	yes	3375.96
E-ANND-5	yes	714.04
E-HCAD-1	yes	42.03
E-MTAB-8271	yes	16.37
E-MTAB-6701	yes	11.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

7 targeting FCN3, 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-3662	99.99	73.82	5684
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-4718	98.55	68.61	814
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-5681A	97.99	67.17	1658
HSA-MIR-664B-5P	96.74	67.50	509

Literature-anchored findings (GeneRIF, showing 40)

• Hakata antigen, a ficolin associated with MBL-associated serine proteases and small MBL-associated protein, activates the lectin complement pathway. (PMID:11907111)
• Hakata circulates as Hakata-MASPs complex in the blood, binds Aerococcus viridans polysaccharide and inhibits A. viridans growth (PMID:12367778)
• The X-ray structures of H-ficolin trimeric recognition domains, alone and in complex with various ligands, have been solved. (PMID:17215869)
• variations in H-ficolin appear to be of limited importance in the pathogenesis of Crohn’s disease (PMID:17303612)
• Ficolin 3 mediates the clearance of late apoptotic cells, which suggests that this protein is involved in the maintenance of tissue homeostasis and might play a protective role against the development of autoimmunity. (PMID:17469142)
• Ficolin-3 has a high complement activating potential and is the only collagenase proteolytic resistant molecule among the lectin complement pathway initiators. (PMID:18006063)
• an FCN3+1637delC deletion variant disrupting the possibility for pattern recognition was detected; characterization of recombinant variant Ficolin-3 shows that homozygosity for the FCN3+1637delC deletion may lead to Ficolin-3 deficiency (PMID:18261799)
• L-ficolin residue lysine57 is a key component of the interaction with both the mannan-binding lectin (MBL)-associated serine proteases and calreticulin, providing a strong indication that MBL and ficolins share homologous binding sites for their partners. (PMID:19109177)
• Results suggest that the elevation of S-ficolin-3 and its association with specific manifestations in systemic lupus erythematosus may indicate a pathogenetic role of ficolin-3 in SLE. (PMID:19208603)
• MBL-associated serine protease-3 down-regulate Ficolin-3 mediated complement activation through the lectin pathway. (PMID:19939495)
• Data indicate that the deposition of both C4 and C3 showed a significant positive correlation with the serum concentration of Ficolin-3. (PMID:21085669)
• We found that ficolin-3 levels were elevated in the vitreous fluid of patients with proliferative diabetic retinopathy (PDR); and may be used as a new therapeutic target for treatment of PDR. (PMID:21851923)
• Cord blood MBL concentrations were significantly lower in intrauterine-growth-restriction (IUGR) cases than controls. No differences in H- and L-ficolin concentrations were observed between groups. (PMID:22082351)
• Both pre-term deliveries and low birth weight (independently of gestational age) were significantly associated with low H-ficolin concentrations but not with heterozygosity for the FCN3 1637delC frameshift mutation. (PMID:22226667)
• in whole serum. MASP-2 was co-purified with H-ficolin, and the purified H-ficolin.MASP-2 complex could activate complement as measured by cleavage of complement factor C4 (PMID:22238349)
• Found that a common variant of FCN3/CD164L2 is associated with hypertension in Chinese population. (PMID:22471352)
• The purpose of this study was to determine whether circulating levels of ficolin-2 and ficolin-3 are altered in normal pregnancy and pre-eclampsia. (PMID:22670778)
• H-ficolin has antiviral activity against influenza A virus (IAV). H-ficolin also fixes complement to a surface coated with IAV. (PMID:22851708)
• Increased fucosylation of ficolin 3 in plasma of the rheumatoid arthritis patients (PMID:23107985)
• Data indicate that the median concentration of MASP-2/ficolin-3 complexes was 119.7 AU/ml (range: 2.9-615.5 AU/ml). (PMID:23142462)
• Survival analyses showed that high pre-transplant serum levels of FCN3 were associated with decreased graft survival, suggesting an important role of FCN3 in the pathophysiology of kidney graft rejection (PMID:23416240)
• low levels of ficolin-3 are associated with advanced heart failure and outcome. The decrease of ficolin-3 was associated with increased complement activation. (PMID:23596511)
• Data show that the expression of ficolin-3(FCN3) in ovarian cancer (OC) was inversely correlated with serum ficolin-3 and lower in comparison with controls. (PMID:23744477)
• Data show that the plasmid pETb-ficolin 3 was cloned successfully and the purity of the protein His-ficolin 3 was over 90%. (PMID:25001927)
• Both ficolin-3 and MASP-2 levels correlated inversely with the time from the onset of the attack of hereditary angioedema until blood sampling (PMID:25042985)
• data suggest that high levels of the complement activating molecule H-ficolin are associated with an increased risk of future progression to microalbuminuria in patients with newly diagnosed type 1 diabetes. (PMID:25064124)
• This study aims to investigate whether an association exists between the ficolins that are part of the lectin complement pathway and systemic lupus erythematosus. (PMID:25069872)
• There is lack of association of serum mannose-binding lectin or ficolins with complement activation in patients with antiphospholipid antibodies. (PMID:25083730)
• High ficolin-3 level at the time of transplantation was an independent significant risk factor for shorter graft survival. (PMID:25222012)
• this study provide novel insight in the binding and complement activating capacity of the lectin pathway initiation molecules ficolin-2 and ficolin-3 towards relevant Gram-negative pathogens of pathophysiological relevance. (PMID:26074063)
• H-ficolin participates in A. fumigatus defence through the activation of the lectin complement pathway, enhanced fungus-host interactions and modulated immune responses. (PMID:26133042)
• Data indicate differences in the plasma concentrations of collectin liver 1 and collectin kidney 1, M-ficolin and H-ficol in systemic lupus erythematosus (SLE) patients compared to a group of healthy controls. (PMID:26154564)
• Monitoring serum H-ficolin levels was shown to be of no benefit in terms of predicting severe infection. (PMID:26377840)
• Lower serum ficolin-3 levels were correlated with injury severity following traumatic brain injury. (PMID:26627059)
• subjects that were heterozygote carriers of both FCN2 + 6424 and FCN3 + 1637delC were sufficient mannan-binding lectin producers (PMID:26795763)
• LPS induces a tissue-specific recruitment of ficolin-3 and ficolin-1 in the lung and systemic compartment, respectively, suggesting an important role of distinct lectin complement pathway initiators in the local pulmonary and systemic host defence. (PMID:26868430)
• Serum levels of ficolin-2 and ficolin-3 were significantly lower in the cardiac syndrome X patients compared to controls. (PMID:27312152)
• results suggest that anti-ficolin-3 antibodies could be useful for the diagnosis of active nephritis in SLE patients (PMID:27631981)
• this study shows that H-ficolin may aid clearance of influenza A virus by promoting monocyte uptake of the virus, while reducing viral replication and virus-induced TNF-a responses in these cells (PMID:27856789)
• in patients with systemic lupus erythematosus, there was no significant association between ficolin-1 and ficolin-3 with lupus nephritis (PMID:27981461)

Cross-species orthologs

0 orthologs

Paralogs (25): TNC (ENSG00000041982), FCN1 (ENSG00000085265), ANGPT2 (ENSG00000091879), ANGPT4 (ENSG00000101280), FGL1 (ENSG00000104760), FN1 (ENSG00000115414), TNR (ENSG00000116147), ANGPTL1 (ENSG00000116194), TNN (ENSG00000120332), FGL2 (ENSG00000127951), FIBCD1 (ENSG00000130720), ANGPTL6 (ENSG00000130812), ANGPTL3 (ENSG00000132855), ANGPTL2 (ENSG00000136859), FNDC7 (ENSG00000143107), ANGPT1 (ENSG00000154188), FCN2 (ENSG00000160339), MFAP4 (ENSG00000166482), ANGPTL4 (ENSG00000167772), TNXB (ENSG00000168477), FGG (ENSG00000171557), FGA (ENSG00000171560), FGB (ENSG00000171564), ANGPTL7 (ENSG00000171819), ANGPTL5 (ENSG00000187151)

Protein

Protein identifiers

Ficolin-3 — O75636 (reviewed: O75636)

Alternative names: Collagen/fibrinogen domain-containing lectin 3 p35, Collagen/fibrinogen domain-containing protein 3, H-ficolin, Hakata antigen

All UniProt accessions (3): O75636, A0A8V8TPG2, Q6UXM4

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent lectin, which acts as a pattern recognition receptor that initiates the lectin pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that strengthens the adaptive immune system. Specifically recognizes and binds carbohydrates on the pathogen surface, activating the MASP1 serine protease and initiating the proteolytic cascade of the lectin complement pathway. Specifically binds N-Acetylglucosamine (GlcNAc,) GalNAc (N-acetylgalactosamine) and D-fucose on the surface of pathogens, as well as mono/oligosaccharide and lipopolysaccharides from S.typhimurium and S.minnesota.

Subunit / interactions. Homotrimer. May form an octadecamer consisting of an elementary trimer unit. Interacts with MASP1 and MASP2.

Subcellular location. Secreted. Cell surface.

Tissue specificity. Liver and lung. In liver it is produced by bile duct epithelial cells and hepatocytes. In lung it is produced by both ciliated bronchial epithelial cells and type II alveolar epithelial cells.

Post-translational modifications. The N-terminus is blocked.

Disease relevance. Ficolin 3 deficiency (FCN3D) [MIM:613860] A disorder characterized by immunodeficiency, recurrent infections, brain abscesses and recurrent warts on the fingers. Affected individuals have normal levels of lymphocytes, normal T-cell responses, and normal antibodies, but a selective deficient antibody response to pneumococcal polysaccharide vaccine. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the ficolin lectin family.

Isoforms (2)

UniProt ID	Names	Canonical?
O75636-1	1	yes
O75636-2	2

RefSeq proteins (2): NP_003656, NP_775628 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002181	Fibrinogen_a/b/g_C_dom	Domain
IPR014716	Fibrinogen_a/b/g_C_1	Homologous_superfamily
IPR020837	Fibrinogen_CS	Conserved_site
IPR036056	Fibrinogen-like_C	Homologous_superfamily
IPR050373	Fibrinogen_C-term_domain	Family

Pfam: PF00147

UniProt features (45 total): strand 14, helix 7, modified residue 6, binding site 5, disulfide bond 3, domain 2, signal peptide 1, chain 1, glycosylation site 1, splice variant 1, sequence conflict 1, region of interest 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
2J5Z	X-RAY DIFFRACTION	1.73
2J60	X-RAY DIFFRACTION	1.8
2J64	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75636-F1	87.25	0.72

Functional residue map

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

Ligand- & substrate-binding residues (5): 258–259; 237; 239; 241; 243

Post-translational modifications (6): 50, 53, 59, 65, 68, 77

Disulfide bonds (3): 86–110, 93–121, 245–258

Glycosylation sites (1): 189

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-166662	Lectin pathway of complement activation
R-HSA-166663	Initial triggering of complement
R-HSA-2855086	Ficolins bind to repetitive carbohydrate structures on the target cell surface

MSigDB gene sets: 149 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, KAAB_FAILED_HEART_ATRIUM_DN, GOCC_COLLAGEN_TRIMER, REACTOME_CREATION_OF_C4_AND_C2_ACTIVATORS, GOCC_CELL_SURFACE, GOBP_APOPTOTIC_CELL_CLEARANCE, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, GOBP_VESICLE_MEDIATED_TRANSPORT, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM

GO Biological Process (16): complement activation, lectin pathway (GO:0001867), cell surface pattern recognition receptor signaling pathway (GO:0002752), proteolysis (GO:0006508), complement activation (GO:0006956), recognition of apoptotic cell (GO:0043654), host-mediated suppression of symbiont invasion (GO:0046597), defense response to virus (GO:0051607), negative regulation of RNA biosynthetic process (GO:1902679), positive regulation of opsonization (GO:1903028), activation of membrane attack complex (GO:0001905), immune system process (GO:0002376), opsonization (GO:0008228), zymogen activation (GO:0031638), killing of cells of another organism (GO:0031640), innate immune response (GO:0045087), protein maturation (GO:0051604)

GO Molecular Function (7): antigen binding (GO:0003823), signaling receptor binding (GO:0005102), carbohydrate binding (GO:0030246), pattern recognition receptor activity (GO:0038187), metal ion binding (GO:0046872), carbohydrate derivative binding (GO:0097367), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), collagen trimer (GO:0005581), obsolete extracellular space (GO:0005615), external side of plasma membrane (GO:0009897), blood microparticle (GO:0072562), symbiont cell surface (GO:0106139), serine-type endopeptidase complex (GO:1905370)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Creation of C4 and C2 activators	1
Complement cascade	1
Lectin pathway of complement activation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	4
complement activation	2
innate immune response	2
protein metabolic process	2
immune effector process	2
phagocytosis, recognition	2
cellular anatomical structure	2
innate immune response activating cell surface receptor signaling pathway	1
pattern recognition receptor signaling pathway	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
apoptotic cell clearance	1
host-mediated perturbation of symbiont process	1
defense response	1
response to virus	1
negative regulation of macromolecule biosynthetic process	1
RNA biosynthetic process	1
negative regulation of RNA metabolic process	1
regulation of RNA biosynthetic process	1
positive regulation of immune effector process	1
opsonization	1
positive regulation of phagocytosis	1
regulation of opsonization	1
biological_process	1
protein processing	1
cell killing	1
disruption of cell in another organism	1
immune response	1
defense response to symbiont	1
gene expression	1
protein binding	1
signaling receptor activity	1
cation binding	1
protein-containing complex	1
plasma membrane	1
cell surface	1
side of membrane	1
extracellular region	1
other organism part	1

Protein interactions and networks

STRING

878 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FCN3	F8W876	F8W876	996
FCN3	MASP2	O00187	965
FCN3	MBL2	P11226	965
FCN3	COLEC11	Q9BWP8	862
FCN3	COLEC10	Q9Y6Z7	859
FCN3	KIR3DL1	P43629	803
FCN3	FCN2	Q15485	766
FCN3	C1S	P09871	711
FCN3	ALB	P02768	674
FCN3	C3	P01024	664
FCN3	FCN1	O00602	659
FCN3	C1R	P00736	651
FCN3	CR1	P17927	637
FCN3	APCS	P02743	630
FCN3	C4A	P01028	609

IntAct

43 interactions, top by confidence:

A	B	Type	Score
MASP1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.760
MASP1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.710
MASP1	FCN3	psi-mi:“MI:0915”(physical association)	0.710
FCN2	FCN3	psi-mi:“MI:0915”(physical association)	0.700
FCN3	FCN2	psi-mi:“MI:0915”(physical association)	0.700
fbpB	FCN3	psi-mi:“MI:0407”(direct interaction)	0.650
FCN3	fbpB	psi-mi:“MI:0915”(physical association)	0.650
FN1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.540
FN1	FCN3	psi-mi:“MI:0915”(physical association)	0.540
PTX3	FCN3	psi-mi:“MI:0407”(direct interaction)	0.440
DMBT1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.440
fbpA	FCN3	psi-mi:“MI:0407”(direct interaction)	0.440
CR1	FCN3	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (47): METTL15 (Affinity Capture-MS), COL14A1 (Affinity Capture-MS), FCN3 (Co-purification), TUBB3 (Affinity Capture-MS), XRCC3 (Affinity Capture-MS), PC (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), HOXD13 (Affinity Capture-MS), TUBB8 (Affinity Capture-MS), TUBA4A (Affinity Capture-MS), SAR1B (Affinity Capture-MS), DDX19B (Affinity Capture-MS), IL17RA (Affinity Capture-MS), DERL2 (Affinity Capture-MS), CRLF1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8C2MDK8, A0PJX2, A2ACG1, D3ZBP4, E2RDP2, F1MH07, O08644, O75038, O75064, O75636, P0C0K7, P0DPD7, P0DPE0, P0DPE1, P52824, Q00653, Q0IID2, Q1LWV7, Q3SYT1, Q3U1Y4, Q4KM32, Q4R380, Q5NCQ5, Q5RKI3, Q62137, Q684M2, Q68DD2, Q6ZSI9, Q86TL0, Q86XP0, Q8BGV9, Q8BX80, Q8C9V1, Q8NFF5, Q8NFI3, Q8R5G7, Q8TDZ2, Q8VDP3, Q8WWN8, Q91ZJ0

Diamond homologs: A0A8J8, A2AV25, D8VNS7, D8VNS8, D8VNS9, D8VNT0, E2IYB3, E9PV24, O00602, O08538, O15123, O18920, O35460, O35462, O35608, O43827, O70165, O70497, O75636, O77802, O93526, O95841, P02671, P02675, P02676, P02678, P02679, P02680, P04115, P06399, P10039, P12799, P12804, P14448, P14480, P17634, P19477, P21520, P22105, P24821

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
FCN3	“up-regulates activity”	MASP1	binding
PAMPs	“up-regulates activity”	FCN3	binding
FCN3	“up-regulates activity”	MASP2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	3
Uncertain significance	54
Likely benign	9
Benign	0

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
3337104	NM_003665.4(FCN3):c.230del (p.Pro77fs)	Likely pathogenic
4813073	NM_003665.4(FCN3):c.219del (p.Lys74fs)	Likely pathogenic
4845898	NM_003665.4(FCN3):c.74_77dup (p.His26fs)	Likely pathogenic

SpliceAI

1105 predictions. Top by Δscore:

Variant	Effect	Δscore
1:27370728:TAC:T	acceptor_gain	1.0000
1:27370729:AC:A	acceptor_gain	1.0000
1:27370730:CC:C	acceptor_gain	1.0000
1:27370731:C:CA	acceptor_loss	1.0000
1:27370731:C:CC	acceptor_gain	1.0000
1:27370841:AC:A	donor_gain	1.0000
1:27370842:CC:C	donor_gain	1.0000
1:27373961:TCA:T	donor_loss	1.0000
1:27373964:C:CG	donor_loss	1.0000
1:27374010:C:CA	acceptor_loss	1.0000
1:27374010:C:CC	acceptor_gain	1.0000
1:27370589:CACT:C	donor_loss	0.9900
1:27370590:ACTC:A	donor_loss	0.9900
1:27370592:TCACC:T	donor_loss	0.9900
1:27370593:CACCT:C	donor_loss	0.9900
1:27370595:C:CA	donor_loss	0.9900
1:27370618:G:A	donor_gain	0.9900
1:27370726:GTTAC:G	acceptor_gain	0.9900
1:27370727:TTAC:T	acceptor_gain	0.9900
1:27370838:CTCA:C	donor_loss	0.9900
1:27370839:TCACC:T	donor_loss	0.9900
1:27370840:CACCC:C	donor_loss	0.9900
1:27370841:A:AG	donor_loss	0.9900
1:27370842:C:CA	donor_loss	0.9900
1:27373959:A:AC	donor_gain	0.9900
1:27373960:C:CC	donor_gain	0.9900
1:27373960:CTCA:C	donor_gain	0.9900
1:27373964:CCTGG:C	donor_gain	0.9900
1:27374006:GGCC:G	acceptor_gain	0.9900
1:27374007:GCC:G	acceptor_gain	0.9900

AlphaMissense

1932 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:27369443:A:C	F231L	0.992
1:27369443:A:T	F231L	0.992
1:27369445:A:G	F231L	0.992
1:27370904:A:C	F154L	0.992
1:27370904:A:T	F154L	0.992
1:27370906:A:G	F154L	0.992
1:27369293:C:A	W281C	0.991
1:27369293:C:G	W281C	0.991
1:27369444:A:C	F231C	0.989
1:27369444:A:G	F231S	0.989
1:27370937:G:C	F143L	0.989
1:27370937:G:T	F143L	0.989
1:27370939:A:G	F143L	0.989
1:27369376:A:G	W254R	0.988
1:27369376:A:T	W254R	0.988
1:27369374:C:A	W254C	0.985
1:27369374:C:G	W254C	0.985
1:27370960:G:T	R136S	0.985
1:27369295:A:G	W281R	0.984
1:27369295:A:T	W281R	0.984
1:27369344:A:C	N264K	0.984
1:27369344:A:T	N264K	0.984
1:27370883:G:C	F161L	0.984
1:27370883:G:T	F161L	0.984
1:27370885:A:G	F161L	0.984
1:27373167:C:G	C121S	0.981
1:27373168:A:T	C121S	0.981
1:27369377:C:A	W253C	0.980
1:27369377:C:G	W253C	0.980
1:27369379:A:G	W253R	0.980

dbSNP variants (sampled 300 via entrez): RS1000151649 (1:27372761 C>T), RS1001720221 (1:27371951 G>C), RS1001864708 (1:27376272 C>T), RS1002052355 (1:27370625 G>A), RS1002145682 (1:27370289 A>T), RS1002219149 (1:27371705 C>A,G), RS1002294395 (1:27376068 C>T), RS1002450773 (1:27372244 C>T), RS1003566962 (1:27374656 G>A), RS1003725297 (1:27369265 A>C), RS1003779089 (1:27368658 C>T), RS1003820330 (1:27368893 C>T), RS1003940911 (1:27374941 G>A,C,T), RS1004276918 (1:27375813 G>A), RS1004389165 (1:27369509 G>A,T)

Disease associations

OMIM: gene MIM:604973 | disease phenotypes: MIM:613860

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency due to ficolin3 deficiency	Moderate	Autosomal recessive

Mondo (3): immunodeficiency due to ficolin3 deficiency (MONDO:0013467), microcephaly (MONDO:0001149), rheumatic heart disease (MONDO:0006955)

Orphanet (1): Immunodeficiency due to ficolin3 deficiency (Orphanet:331190)

HPO phenotypes

6 total (7 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002722	Recurrent abscess formation
HP:0002726	Recurrent Staphylococcus aureus infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0033165	Necrotizing enterocolitis
HP:0200043	Verrucae
HP:0000252	Microcephaly

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006585_2187	Blood protein levels	1.000000e-48
GCST006585_2317	Blood protein levels	4.000000e-42

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D012214	Rheumatic Heart Disease	C01.150.252.410.890.731.649; C14.280.874

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
Valproic Acid	affects expression, increases methylation	2
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	increases expression	1
clothianidin	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Atrazine	increases expression	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	affects binding	1
Catechin	affects cotreatment, increases expression	1
Fluorocarbons	affects cotreatment, increases expression	1
Hydrocarbons, Chlorinated	affects cotreatment, increases expression	1
Metals	affects cotreatment, increases expression	1
Pentachlorophenol	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Polychlorinated Biphenyls	affects cotreatment, increases expression	1
Teratogens	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Zinc	affects binding	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02832531	PHASE3	WITHDRAWN	INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Superiority
NCT02832544	PHASE3	COMPLETED	INVestIgation of rheumatiC AF Treatment Using Vitamin K Antagonists, Rivaroxaban or Aspirin Studies, Non-Inferiority
NCT03926156	PHASE3	TERMINATED	RIvoraxaban in Mitral Stenosis
NCT03991910	PHASE3	UNKNOWN	The Effect of Ramipril in Suppressing ST2 Expression in Rheumatic Mitral Stenosis Patients
NCT05618223	PHASE3	UNKNOWN	Dapagliflozin Effect on Rheumatic Mitral Stenosis
NCT07146048	PHASE3	NOT_YET_RECRUITING	A Non-Inferiority Trial of Stopping Penicillin in Early Rheumatic Heart Disease: GOAL-Stop
NCT01794884	PHASE2	COMPLETED	Validity Study of Glutamine to Improve Cardiac Function in Cardiac Surgery
NCT03346525	PHASE2	UNKNOWN	Determining the Impact of Penicillin in Latent RHD: The GOAL Trial
NCT05693545	PHASE2	ACTIVE_NOT_RECRUITING	GOALIE: Intramuscular vs. Enteral Penicillin Prophylaxis to Prevent Progression of Latent RHD Trial
NCT00482573	PHASE1	COMPLETED	Dental Anesthesia in Pregnant Women With Rheumatic Heart Disease
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT00001639	Not specified	COMPLETED	Evaluation of Patients With Unresolved Chromosome Abnormalities
NCT01151462	Not specified	WITHDRAWN	Postnatal HCMV Infection in Very Preterm Infants. Implications, Morbidity, Growth and Neurodevelopmental Outcomes.
NCT01565005	Not specified	COMPLETED	Microcephaly Genetic Deficiency in Neural Progenitors
NCT02510170	Not specified	COMPLETED	Fetal and Maternal Head Circumference During Pregnancy in Israeli Population
NCT02741882	Not specified	COMPLETED	Zika and Microcephaly: Case-control Study
NCT02943304	Not specified	COMPLETED	Neurodevelopment Outcome of Newborns Exposed to Zika Virus (ZIKV) in Utero
NCT03255369	Not specified	UNKNOWN	Vertical Exposure to Zika Virus and Its Consequences for Child Neurodevelopment (ZIKVIRUSIFF)
NCT03325946	Not specified	RECRUITING	The FBRI VTC Neuromotor Research Clinic
NCT03330600	Not specified	COMPLETED	Efficacy of Aquatic Physiotherapy in Children With Microcephaly by Zika Virus Congenital Syndrome
NCT03548779	Not specified	COMPLETED	North Carolina Genomic Evaluation by Next-generation Exome Sequencing, 2
NCT03651687	Not specified	COMPLETED	Guangzhou Surveillance and Clinical Study in Microcephaly (GSCSM)
NCT03922594	Not specified	TERMINATED	Surveillance of Zika-related Microcephaly in Sub-Saharan Africa and Asia
NCT04816175	Not specified	COMPLETED	Intensive Therapy for Children With Microcephaly, Hyperkinetic Movements, or Global Developmental Delay
NCT05322980	Not specified	COMPLETED	Summary of Infants Weighing 500 Grams or Less
NCT06019182	Not specified	RECRUITING	MEHMO Natural History and Biomarkers
NCT06566066	Not specified	RECRUITING	Register for Patients With Thyroid Hormone Resistance.
NCT02881398	PHASE2/PHASE3	COMPLETED	Mobile Health in Structural Heart Disease
NCT07078357	PHASE1/PHASE2	NOT_YET_RECRUITING	Clinical Trial Phase I/IIa to Evaluate the Safety and Immunogenicity of StreptInCor
NCT00264524	Not specified	COMPLETED	DNA Typing of HLA-DR/DQ Alleles in Taiwan Chinese With Rheumatic Heart Disease
NCT00779662	Not specified	UNKNOWN	The Prevalence of Rheumatic Heart Disease in School Children in Fiji
NCT01178710	Not specified	COMPLETED	Effect of Simvastatin on Cardiac Function
NCT01550068	Not specified	COMPLETED	Rheumatic Heart Disease School Project
NCT02118818	Not specified	COMPLETED	RhEumatiC Heart diseAse Genetics
NCT02124109	Not specified	COMPLETED	The Genetic Basis of Acquired Heart Disease in Africa
NCT02188862	Not specified	COMPLETED	Genetic Susceptibility to Rheumatic Heart Disease in the Pacific Region
NCT02353663	Not specified	COMPLETED	Rheumatic Heart Disease in Peru: Prevalence and Cardiovascular Outcomes Among Schoolchildren
NCT02474108	Not specified	COMPLETED	Surgical Prevention of Atrial Fibrillation in Patients With Rheumatic Mitral Valve Lesion and Left Atrium Enlargement
NCT02661763	Not specified	COMPLETED	Rheumatic Heart Disease Study in Lusaka
NCT03156972	Not specified	UNKNOWN	Speckle Tracking for Timing of Surgical Operation in Severe Mitral Regurge