CFI

Summary

CFI (complement factor I, HGNC:5394) is a protein-coding gene on chromosome 4q25, encoding Complement factor I (P05156). Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways.

This gene encodes a serine proteinase that is essential for regulating the complement cascade. The encoded preproprotein is cleaved to produce both heavy and light chains, which are linked by disulfide bonds to form a heterodimeric glycoprotein. This heterodimer can cleave and inactivate the complement components C4b and C3b, and it prevents the assembly of the C3 and C5 convertase enzymes. Defects in this gene cause complement factor I deficiency, an autosomal recessive disease associated with a susceptibility to pyogenic infections. Mutations in this gene have been associated with a predisposition to atypical hemolytic uremic syndrome, a disease characterized by acute renal failure, microangiopathic hemolytic anemia and thrombocytopenia. Primary glomerulonephritis with immune deposits and age-related macular degeneration are other conditions associated with mutations of this gene.

Source: NCBI Gene 3426 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atypical hemolytic-uremic syndrome (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 12
• Clinical variants (ClinVar): 831 total — 34 pathogenic, 38 likely-pathogenic
• Phenotypes (HPO): 86
• MANE Select transcript: NM_000204

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5394
Approved symbol	CFI
Name	complement factor I
Location	4q25
Locus type	gene with protein product
Status	Approved
Aliases	FI, C3b-INA, C3bINA, KAF
Ensembl gene	ENSG00000205403
Ensembl biotype	protein_coding
OMIM	217030
Entrez	3426

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 16 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined

ENST00000394634, ENST00000394635, ENST00000504853, ENST00000510800, ENST00000512148, ENST00000515512, ENST00000643384, ENST00000695844, ENST00000695845, ENST00000695846, ENST00000882815, ENST00000882816, ENST00000882817, ENST00000882818, ENST00000882819, ENST00000882820, ENST00000882821, ENST00000882822, ENST00000963330, ENST00000963331, ENST00000963332, ENST00000963333

RefSeq mRNA: 10 — MANE Select: NM_000204 NM_000204, NM_001318057, NM_001331035, NM_001375278, NM_001375279, NM_001375280, NM_001375281, NM_001375282, NM_001375283, NM_001375284

CCDS: CCDS34049, CCDS82945, CCDS82946

Canonical transcript exons

ENST00000394634 — 13 exons

Exon	Start	End
ENSE00003914976	109740695	109741110
ENSE00003965205	109749499	109749602
ENSE00003965206	109764537	109764690
ENSE00003965207	109742491	109742595
ENSE00003965208	109749218	109749321
ENSE00003965211	109761517	109761692
ENSE00003965212	109766554	109766824
ENSE00003965213	109760523	109760636
ENSE00003965215	109760270	109760380
ENSE00003965217	109757763	109757783
ENSE00003965218	109801915	109801999
ENSE00003965219	109752468	109752503
ENSE00003965222	109746222	109746502

Expression profiles

Bgee: expression breadth ubiquitous, 240 present calls, max score 99.30.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4514 / max 802.6298, expressed in 682 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
53604	3.4118	228
53607	1.4792	479
53608	0.8176	358
53609	0.4082	216
53606	0.2460	108
53605	0.0887	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
germinal epithelium of ovary	UBERON:0001304	99.30	gold quality
parietal pleura	UBERON:0002400	98.96	gold quality
right lobe of liver	UBERON:0001114	98.95	gold quality
liver	UBERON:0002107	98.59	gold quality
pleura	UBERON:0000977	98.09	gold quality
gall bladder	UBERON:0002110	97.38	gold quality
palpebral conjunctiva	UBERON:0001812	96.77	gold quality
visceral pleura	UBERON:0002401	96.72	gold quality
nephron tubule	UBERON:0001231	96.68	gold quality
adult mammalian kidney	UBERON:0000082	96.50	gold quality
metanephros cortex	UBERON:0010533	96.10	gold quality
right adrenal gland cortex	UBERON:0035827	95.78	gold quality
kidney epithelium	UBERON:0004819	95.34	gold quality
caput epididymis	UBERON:0004358	95.12	gold quality
left adrenal gland	UBERON:0001234	95.06	gold quality
right adrenal gland	UBERON:0001233	94.98	gold quality
left adrenal gland cortex	UBERON:0035825	94.77	gold quality
kidney	UBERON:0002113	94.36	gold quality
endometrium	UBERON:0001295	94.35	gold quality
renal glomerulus	UBERON:0000074	94.24	gold quality
right uterine tube	UBERON:0001302	94.17	gold quality
metanephric glomerulus	UBERON:0004736	93.95	gold quality
peritoneum	UBERON:0002358	93.84	gold quality
omental fat pad	UBERON:0010414	93.84	gold quality
adrenal cortex	UBERON:0001235	93.08	gold quality
cortex of kidney	UBERON:0001225	93.04	gold quality
corpus epididymis	UBERON:0004359	92.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.74	gold quality
left ovary	UBERON:0002119	92.58	gold quality
pericardium	UBERON:0002407	92.19	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-6	yes	1339.53
E-GEOD-81383	yes	702.86
E-HCAD-11	yes	39.44
E-MTAB-6701	yes	27.52
E-CURD-114	yes	22.92
E-MTAB-6678	yes	13.26
E-GEOD-130148	yes	6.73
E-CURD-112	yes	3.89
E-MTAB-10283	no	135.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, JUN, NFKB1, NFKB, RELA, TXK

miRNA regulators (miRDB)

17 targeting CFI, 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-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-186-5P	99.99	70.83	3707
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-580-3P	99.67	69.23	1841
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-6759-3P	96.94	68.31	823
HSA-MIR-769-5P	94.45	64.56	603

Literature-anchored findings (GeneRIF, showing 40)

• the last 45 amino acid of the heavy chain, including a disulfide bridge area, did not participate in the serine protease function of factor I (PMID:14967308)
• Human complement factor I does not require cofactors for cleavage of synthetic substrates. (PMID:15210795)
• fI and the serine protease domain were found to have similar amidolytic activities but strikingly different proteolytic activities on C3(NH(3)). (PMID:15835912)
• Mutations in the complement regulators factor H, membrane cofactor protein (MCP), and factor I are associated with atypical hemolytic uremic syndrome. (PMID:16386793)
• factor I in concert with CR1 on E and factor H in serum due to their cofactor activity are likely to be important contributors (PMID:16920989)
• both forms of factor I (fI) have very similar proteolytic activities against C3(NH(3)) indicating that the charged glycans of fI do not influence the fI-cofactor-substrate interactions (PMID:17055788)
• CFI precursor could aid in the diagnosis and indicate the advancement of gastric cancer (PMID:17067565)
• keratinocytes are capable of synthesizing factor I, and that this synthesis is regulated by IFN-gamma (PMID:17320177)
• Impairment of the mechanisms involved in the regulation of activation of complement system factor iC3b may be important in the pathogenesis of endometriosis and endometriosis-associated infertility. (PMID:17482181)
• Non-small cell lung cancer (NSCLC) cells produce soluble complement inhibitors factor I (FI) and C4b-binding protein (C4BP). (PMID:17548110)
• The nature of the functional defect in atypical hemolytic uremic syndrome-associated CFI mutations, is examined. (PMID:17597211)
• Age <3 mo at onset seems to be characteristic of CFH and IF mutation-associated atypical hemolytic uremic syndrome (PMID:17599974)
• The biochemical and genetic characterization in two Spanish families with complete Factor I deficiency, is described. (PMID:18374984)
• clumping factor A (ClfA) was identified as a specific protein bound by factor I; the shed ClfA fragment increased factor I cleavage of C3b into inactive C3b (PMID:18544012)
• Abeta activates the complement system within drusen by blocking the function of factor I leading to a low-grade, chronic inflammation in subretinal tissues (PMID:18566438)
• An abnormal control of the complement alternative pathway is a risk factor for the occurrence of HELLP syndrome. (PMID:18658028)
• This analysis identified a single nucleotide polymorphism just 3’ of complement factor I on chromosome 4 showing significant association (P<10(-7)) with age-related macular degeneration. (PMID:18685559)
• Pint mutations in patients with type 2 diabetes and their families were studied. mitochondrial genes including np3316, np3394 and np3426 in the ND1 region and np3243 in the tRNA(Leu(UUR))were screened. (PMID:18701018)
• renal transplant recipient developed recurrent hemolytic uremic syndrome 1 month after transplantation associated with factor I mutation (PMID:18805611)
• one of two polymorphic suballeles responsible for CFI A is Japanese-specific. (PMID:18825487)
• This is the first study that investigates, at the functional level, the consequences of molecular defects identified in patients with full complement factor I deficiency. (PMID:19065647)
• Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. (PMID:19861685)
• mutations in complement factor I affect both secretion and function of factor I, which leads to impaired regulation of the complement system in atypical hemolytic uremic syndrome. (PMID:19877009)
• In a large cohort of 202 patients with aHUS, we identified 23 patients carrying exonic mutations in CFI (PMID:20016463)
• the FIMAC domain appears to harbor the main binding sites important for the ability of FI to degrade C4b and C3b (PMID:20044478)
• Role of a common variant near the complement factor I gene in susceptibility to age-related macular degeneration. (PMID:20087399)
• Study identified novel mutations in CFH, CFHR5, CFI, CFB and C3 in American patients with atypical hemolytic uremic syndrome. (PMID:20513133)
• Study describes the molecular and functional consequences of two novel mutations of FI. (PMID:21316765)
• Data show that FI is in a proteolytically inactive form, demonstrating that it circulates in a zymogen-like state. (PMID:21768352)
• Forster resonance energy transfer was used to investigate the 10 muM K(D) (210 kD) complex between the N-terminal region of the soluble complement regulator, factor H (FH1-4), and the key activation-specific complement fragment, C3b. (PMID:21936007)
• Results question whether complement factor I autoantibodies per se predispose to atypical hemolytic uremic syndrome. (PMID:22223611)
• factor I were significantly diminished early after trauma. (PMID:22258234)
• all analyzed cofactors form similar trimolecular complexes with FI and C3b/C4b, and the accessibility of FIMAC and SP domains is crucial for the function of FI (PMID:22393059)
• Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. (PMID:22514678)
• The alternative pathway of complement may play a role in the pathogenesis of HELLP syndrome. (PMID:22594569)
• One SNP (rs10033900) in the CFI gene, which encodes a protein involved in the inflammatory pathway, was significantly associated with myopic choroidal neovascularization in multivariate analysis after correction for multiple testing. (PMID:22678500)
• we report four novel mutations and the first large gene deletion in the CFI locus. (PMID:22710145)
• Acute hemorrhagic leukoencephalitis (AHLE) is an unreported, rare phenotype for partial complement factor I deficiency. (PMID:22926405)
• Case Report: patient with atypical haemolytic uremic syndrome with combined membrane cofactor protein CD46 and complement factor I mutations undergoing successful kidney transplantation. (PMID:23519521)
• these findings demonstrate that rare, highly penetrant mutations in CFI contribute to the genetic burden of age-related macular degeneration. (PMID:23685748)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000099425
mus_musculus	Cfi	ENSMUSG00000058952
rattus_norvegicus	Cfi	ENSRNOG00000053400
drosophila_melanogaster	CG31266	FBGN0051266
drosophila_melanogaster	CG31267	FBGN0051267

Paralogs (16): F7 (ENSG00000057593), F11 (ENSG00000088926), F9 (ENSG00000101981), HGFAC (ENSG00000109758), F10 (ENSG00000126218), KLK10 (ENSG00000129451), F12 (ENSG00000131187), C1RL (ENSG00000139178), C1R (ENSG00000159403), KLKB1 (ENSG00000164344), C1S (ENSG00000182326), PRSS55 (ENSG00000184647), CFD (ENSG00000197766), PRSS51 (ENSG00000253649), HP (ENSG00000257017), HPR (ENSG00000261701)

Protein

Protein identifiers

Complement factor I — P05156 (reviewed: P05156)

Alternative names: C3B/C4B inactivator

All UniProt accessions (4): D6R9Z8, P05156, E7ETH0, G3XAM2

UniProt curated annotations — full annotation on UniProt →

Function. Trypsin-like serine protease that plays an essential role in regulating the immune response by controlling all complement pathways. Inhibits these pathways by cleaving three peptide bonds in the alpha-chain of C3b and two bonds in the alpha-chain of C4b thereby inactivating these proteins. Essential cofactors for these reactions include factor H and C4BP in the fluid phase and membrane cofactor protein/CD46 and CR1 on cell surfaces. The presence of these cofactors on healthy cells allows degradation of deposited C3b by CFI in order to prevent undesired complement activation, while in apoptotic cells or microbes, the absence of such cofactors leads to C3b-mediated complement activation and subsequent opsonization.

Subunit / interactions. Heterodimer of a light and heavy chains; disulfide-linked. The fully processed and mature protein circulates as a zymogen, and is allosterically activated by substrate-induced remodeling of the active site. Interacts with C3b. Interacts with complement factor H. (Microbial infection) Interacts with Staphylococcus aureus clumping factor A/ClfA; this interaction enhances cleavage of C3b into iC3b by CFI.

Subcellular location. Secreted. Extracellular space.

Tissue specificity. Expressed in the liver by hepatocytes. Also present in other cells such as monocytes, fibroblasts or keratinocytes.

Disease relevance. Hemolytic uremic syndrome, atypical, 3 (AHUS3) [MIM:612923] An atypical form of hemolytic uremic syndrome. It is a complex genetic disease characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal failure and absence of episodes of enterocolitis and diarrhea. In contrast to typical hemolytic uremic syndrome, atypical forms have a poorer prognosis, with higher death rates and frequent progression to end-stage renal disease. Disease susceptibility is associated with variants affecting the gene represented in this entry. Other genes may play a role in modifying the phenotype. Complement factor I deficiency (CFI deficiency) [MIM:610984] Autosomal recessive condition associated with a propensity to pyogenic infections. The disease is caused by variants affecting the gene represented in this entry. Macular degeneration, age-related, 13 (ARMD13) [MIM:615439] A form of age-related macular degeneration, a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch membrane. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the peptidase S1 family.

RefSeq proteins (10): NP_000195, NP_001304986, NP_001317964, NP_001362207, NP_001362208, NP_001362209, NP_001362210, NP_001362211, NP_001362212, NP_001362213 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR001254	Trypsin_dom	Domain
IPR001314	Peptidase_S1A	Family
IPR002172	LDrepeatLR_classA_rpt	Repeat
IPR002350	Kazal_dom	Domain
IPR003884	FacI_MAC	Domain
IPR009003	Peptidase_S1_PA	Homologous_superfamily
IPR018114	TRYPSIN_HIS	Active_site
IPR023415	LDLR_class-A_CS	Conserved_site
IPR033116	TRYPSIN_SER	Active_site
IPR036055	LDL_receptor-like_sf	Homologous_superfamily
IPR036058	Kazal_dom_sf	Homologous_superfamily
IPR036772	SRCR-like_dom_sf	Homologous_superfamily
IPR043504
IPR048719	CFAI_KAZAL	Domain
IPR048722	CFAI_FIMAC_N	Domain

Pfam: PF00057, PF00089, PF00530, PF21286, PF21287

Enzyme classification (BRENDA):

• EC 3.4.21.45 — complement factor I (BRENDA: 13 organisms, 57 substrates, 40 inhibitors, 20 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TERT-BUTYLOXYCARBONYL-ASP(BENZYL)-PRO-ARG-7-AMID	0.041–0.203	17
METHYLSULFONYL-D-PHE-GLY-ARG-4-METHYLCOUMARYL-7-	0.128	1
N-ALPHA-TERT-BUTYLOXYCARBONYL-VAL-PRO-ARG-4-METH	0.027	1
TERT-BUTYLOXYCARBONYL-ASP(BENZYL ESTER)-PRO-ARG-	0.0146	1

UniProt features (118 total): strand 36, disulfide bond 21, sequence variant 14, binding site 12, helix 11, glycosylation site 6, turn 5, domain 5, chain 3, active site 3, signal peptide 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2XRC	X-RAY DIFFRACTION	2.69
5O32	X-RAY DIFFRACTION	4.21

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05156-F1	84.50	0.58

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 (3): 429 (charge relay system); 525 (charge relay system); 380 (charge relay system)

Ligand- & substrate-binding residues (12): 239; 242; 244; 246; 252; 253; 276; 279; 281; 283; 289; 290

Disulfide bonds (21): 33–255, 43–54, 48–59, 61–93, 67–86, 75–106, 141–181, 154–214, 186–196, 229–247, 241–256, 259–271, 266–284, 278–293, 327–453, 365–381, 373–444, 453, 467–531, 495–510 …

Glycosylation sites (6): 70, 103, 177, 464, 494, 536

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 374 (showing top): MODULE_172, chr4q25, REACTOME_INNATE_IMMUNE_SYSTEM, MCLACHLAN_DENTAL_CARIES_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, LOPEZ_MESOTHELIOMA_SURVIVAL_OVERALL_UP, MODULE_64, HNF1_Q6, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, OUELLET_OVARIAN_CANCER_INVASIVE_VS_LMP_UP, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_PROTEIN_MATURATION

GO Biological Process (5): proteolysis (GO:0006508), complement activation, classical pathway (GO:0006958), innate immune response (GO:0045087), immune system process (GO:0002376), complement activation (GO:0006956)

GO Molecular Function (6): serine-type endopeptidase activity (GO:0004252), serine-type peptidase activity (GO:0008236), metal ion binding (GO:0046872), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), membrane (GO:0016020), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Complement cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
protein metabolic process	1
humoral immune response mediated by circulating immunoglobulin	1
complement activation	1
immune response	1
defense response to symbiont	1
biological_process	1
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
endopeptidase activity	1
serine-type peptidase activity	1
peptidase activity	1
serine hydrolase activity	1
cation binding	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
catalytic activity	1
extracellular vesicle	1

Protein interactions and networks

STRING

1070 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFI	CFH	P08603	981
CFI	C3	P01024	969
CFI	CFB	P00751	931
CFI	CD46	P15529	923
CFI	C4A	P01028	898
CFI	C4A	P01028	872
CFI	CFHR1	Q03591	812
CFI	CFHR3	Q02985	777
CFI	THBD	P07204	749
CFI	ADAMTS13	Q76LX8	719
CFI	DGKE	P52429	698
CFI	CD55	P08174	697
CFI	C2	P06681	696
CFI	CFP	P27918	695
CFI	CR1	P17927	687

IntAct

33 interactions, top by confidence:

A	B	Type	Score
CFH	C3	psi-mi:“MI:0570”(protein cleavage)	0.870
CFI	C3	psi-mi:“MI:0570”(protein cleavage)	0.850
CFI	C3	psi-mi:“MI:0407”(direct interaction)	0.850
CFI	GLP1R	psi-mi:“MI:0915”(physical association)	0.510
GLP1R	CFI	psi-mi:“MI:0915”(physical association)	0.510
ALB	C3	psi-mi:“MI:0570”(protein cleavage)	0.440
CFI	C3	psi-mi:“MI:0570”(protein cleavage)	0.440
PTX3	C3	psi-mi:“MI:0570”(protein cleavage)	0.440
CFI	ECM1	psi-mi:“MI:0915”(physical association)	0.400
CFI	JUP	psi-mi:“MI:0915”(physical association)	0.400
CFI	POTEI	psi-mi:“MI:0915”(physical association)	0.400
CFI		psi-mi:“MI:0915”(physical association)	0.370
AGPAT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
ATF2	ABLIM1	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): ECM1 (Affinity Capture-MS), ECM1 (Affinity Capture-MS), CFI (Synthetic Lethality), CFI (Proximity Label-MS), C3 (Biochemical Activity), C3 (Reconstituted Complex), JUP (Affinity Capture-MS), CFI (Affinity Capture-MS), CFI (Affinity Capture-MS), POTEI (Affinity Capture-MS), CFI (Affinity Capture-MS), S (Reconstituted Complex), CFI (Affinity Capture-MS), CFI (Positive Genetic), CFI (Proximity Label-MS)

ESM2 similar proteins: A0A182C2Z2, A0A1S4GMJ4, A6MFK8, B5G6G5, O15393, O60235, O70244, O96900, P00750, P05156, P11214, P19637, P25723, P29598, P79953, P81428, P82807, P83370, P86091, P97435, P98072, P98073, P98074, P98119, P98121, Q05589, Q14C59, Q17800, Q20176, Q4QXT9, Q58L93, Q58L94, Q5QSK2, Q5R5A4, Q5R8J0, Q61129, Q66TN7, Q6DIV5, Q6IE14, Q6ZMR5

Diamond homologs: F2YMG0, O15393, O35453, O60235, P00766, P00774, P03951, P03952, P05156, P05208, P05981, P08001, P08419, P0CW18, P10323, P14272, P15944, P20231, P21845, P23578, P26262, P27435, P29293, P35035, P35036, P35037, P35038, P48038, P50342, P56677, P57727, P69525, P69526, P83748, P86091, P97435, P98072, P98073, P98074, Q02844

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
NfKb-p65/p50	“up-regulates quantity by expression”	CFI	“transcriptional regulation”
JUN	“up-regulates quantity by expression”	CFI	“transcriptional regulation”
CFI	“down-regulates activity”	C3	cleavage
CFH	“up-regulates activity”	CFI	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 17 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
inflammatory response	5	11.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	34
Likely pathogenic	38
Uncertain significance	372
Likely benign	182
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1162967	NM_000204.5(CFI):c.786del (p.Gly263fs)	Pathogenic
1179031	NM_000204.5(CFI):c.763_772+9delinsGTATCCAC	Pathogenic
12122	NM_000204.5(CFI):c.1571A>T (p.Asp524Val)	Pathogenic
12123	NM_000204.5(CFI):c.1637G>A (p.Trp546Ter)	Pathogenic
12124	NM_000204.5(CFI):c.728G>A (p.Gly243Asp)	Pathogenic
1408529	NM_000204.5(CFI):c.760del (p.Leu254fs)	Pathogenic
1428093	NM_000204.5(CFI):c.1100dup (p.Ile368fs)	Pathogenic
1455043	NM_000204.5(CFI):c.267del (p.Ser90fs)	Pathogenic
1455473	NM_000204.5(CFI):c.265_266del (p.Lys89fs)	Pathogenic
2022339	NM_000204.5(CFI):c.1440_1441del (p.Arg480fs)	Pathogenic
2022570	NM_000204.5(CFI):c.76G>T (p.Glu26Ter)	Pathogenic
2030837	NM_000204.5(CFI):c.26del (p.Leu9fs)	Pathogenic
2100265	NM_000204.5(CFI):c.188dup (p.Pro64fs)	Pathogenic
2203560	NM_000204.5(CFI):c.1139A>G (p.His380Arg)	Pathogenic
2203565	NM_000204.5(CFI):c.434G>A (p.Trp145Ter)	Pathogenic
2422584	NC_000004.11:g.(?110662049)(110673679_?)del	Pathogenic
2577424	NM_000204.5(CFI):c.1149-1G>A	Pathogenic
2702129	NM_000204.5(CFI):c.296_297del (p.Lys99fs)	Pathogenic
2744663	NM_000204.5(CFI):c.310G>T (p.Gly104Ter)	Pathogenic
2792277	NM_000204.5(CFI):c.145C>T (p.Gln49Ter)	Pathogenic
280145	NM_000204.5(CFI):c.1176_1177dup (p.Trp393fs)	Pathogenic
2829643	NM_000204.5(CFI):c.1283del (p.Asn428fs)	Pathogenic
2881087	NM_000204.5(CFI):c.445G>T (p.Glu149Ter)	Pathogenic
2902474	NM_000204.5(CFI):c.1033C>T (p.Arg345Ter)	Pathogenic
3061879	NM_000204.5(CFI):c.79del (p.Asp27fs)	Pathogenic
3681538	NM_000204.5(CFI):c.308dup (p.Asn103fs)	Pathogenic
3690557	NM_000204.5(CFI):c.175_176insCAATGTTTGTAACTACCGTATCAGTGCCCAAAGTTTACAAACG (p.Cys59fs)	Pathogenic
4280435	NM_000204.5(CFI):c.739T>G (p.Cys247Gly)	Pathogenic
4280486	NM_000204.5(CFI):c.1045G>A (p.Gly349Arg)	Pathogenic
4280528	NM_000204.5(CFI):c.1610_1611insAT (p.Val537_Thr538insTer)	Pathogenic

SpliceAI

2063 predictions. Top by Δscore:

Variant	Effect	Δscore
4:109742489:AC:A	donor_loss	1.0000
4:109742490:C:A	donor_loss	1.0000
4:109742592:TTAT:T	acceptor_gain	1.0000
4:109742593:TAT:T	acceptor_gain	1.0000
4:109742595:TCTA:T	acceptor_loss	1.0000
4:109742596:C:CC	acceptor_gain	1.0000
4:109742596:CTAAA:C	acceptor_loss	1.0000
4:109742597:T:A	acceptor_loss	1.0000
4:109746320:CAAT:C	donor_gain	1.0000
4:109762448:T:TA	donor_gain	1.0000
4:109764535:A:AC	donor_gain	1.0000
4:109764536:C:CC	donor_gain	1.0000
4:109764574:C:A	donor_gain	1.0000
4:109742484:CACTT:C	donor_gain	0.9900
4:109742485:ACTTA:A	donor_gain	0.9900
4:109742486:CTTA:C	donor_gain	0.9900
4:109742487:TTACC:T	donor_gain	0.9900
4:109742488:TACCT:T	donor_gain	0.9900
4:109742489:A:AC	donor_gain	0.9900
4:109742489:A:C	donor_gain	0.9900
4:109742490:C:CC	donor_gain	0.9900
4:109742490:C:G	donor_gain	0.9900
4:109742490:CCTG:C	donor_gain	0.9900
4:109742591:GTTAT:G	acceptor_gain	0.9900
4:109742594:AT:A	acceptor_gain	0.9900
4:109742601:CAAAG:C	acceptor_gain	0.9900
4:109742605:G:C	acceptor_gain	0.9900
4:109742605:G:GC	acceptor_gain	0.9900
4:109742974:T:C	acceptor_gain	0.9900
4:109746501:CT:C	acceptor_gain	0.9900

AlphaMissense

3883 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:109740941:C:A	W568C	0.999
4:109740941:C:G	W568C	0.999
4:109741007:C:A	W546C	0.999
4:109741007:C:G	W546C	0.999
4:109741083:C:G	C521S	0.999
4:109741083:C:T	C521Y	0.999
4:109741084:A:T	C521S	0.999
4:109746360:C:G	A431P	0.999
4:109749223:A:C	C381W	0.999
4:109749224:C:G	C381S	0.999
4:109749224:C:T	C381Y	0.999
4:109749225:A:T	C381S	0.999
4:109740996:C:G	C550S	0.998
4:109740997:A:T	C550S	0.998
4:109741010:A:C	S545R	0.998
4:109741010:A:T	S545R	0.998
4:109741012:T:G	S545R	0.998
4:109741068:C:A	G526V	0.998
4:109741068:C:T	G526E	0.998
4:109741082:A:C	C521W	0.998
4:109741084:A:G	C521R	0.998
4:109742496:C:G	C510S	0.998
4:109742497:A:T	C510S	0.998
4:109746235:C:A	W472C	0.998
4:109746235:C:G	W472C	0.998
4:109746250:G:C	C467W	0.998
4:109746365:T:A	D429V	0.998
4:109746365:T:G	D429A	0.998
4:109746366:C:G	D429H	0.998
4:109749225:A:G	C381R	0.998

dbSNP variants (sampled 300 via entrez): RS10000072 (4:109795862 C>A,G), RS1000013460 (4:109803678 C>T), RS10000458 (4:109796087 G>A), RS1000066595 (4:109795580 C>G), RS1000121564 (4:109795334 A>G), RS1000145596 (4:109781537 G>A,T), RS1000195770 (4:109801298 G>A), RS10002034 (4:109751128 C>G,T), RS1000316769 (4:109738546 A>G), RS1000329053 (4:109732591 C>T), RS1000343163 (4:109762213 C>T), RS1000367796 (4:109790058 A>G), RS1000445252 (4:109732781 C>T), RS10004794 (4:109792376 G>A), RS1000486809 (4:109775211 C>A,T)

Disease associations

OMIM: gene MIM:217030 | disease phenotypes: MIM:610984, MIM:612923, MIM:615439, MIM:614809, MIM:614862

GenCC curated gene-disease

Disease	Classification	Inheritance
atypical hemolytic-uremic syndrome	Definitive	Autosomal dominant
atypical hemolytic-uremic syndrome with I factor anomaly	Strong	Autosomal dominant
complement factor I deficiency	Strong	Autosomal recessive
C3 glomerulonephritis	Moderate	Autosomal dominant
Doyne honeycomb retinal dystrophy	Supportive	Autosomal dominant
age related macular degeneration 13	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
atypical hemolytic-uremic syndrome	Definitive	AD
C3 glomerulonephritis	Moderate	AD

Mondo (12): complement factor I deficiency (MONDO:0012594), atypical hemolytic-uremic syndrome with I factor anomaly (MONDO:0013041), age related macular degeneration 13 (MONDO:0014189), atypical hemolytic-uremic syndrome (MONDO:0016244), C3 glomerulonephritis (MONDO:0013892), kidney disorder (MONDO:0005240), thrombotic microangiopathy (MONDO:0019737), focal segmental glomerulosclerosis (MONDO:0100313), chronic kidney disease (MONDO:0005300), kidney failure (MONDO:0001106), peroxisome biogenesis disorder 4A (Zellweger) (MONDO:0013930), Doyne honeycomb retinal dystrophy (MONDO:0007471)

Orphanet (6): Immunodeficiency with factor I anomaly (Orphanet:200418), Atypical hemolytic uremic syndrome (Orphanet:2134), C3 glomerulonephritis (Orphanet:329931), Thrombotic microangiopathy (Orphanet:93573), Zellweger syndrome (Orphanet:912), OBSOLETE: Atypical hemolytic uremic syndrome with I factor anomaly (Orphanet:93580)

HPO phenotypes

86 total (30 of 86 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000083	Renal insufficiency
HP:0000093	Proteinuria
HP:0000099	Glomerulonephritis
HP:0000403	Recurrent otitis media
HP:0000529	Progressive visual loss
HP:0000572	Visual loss
HP:0000608	Macular degeneration
HP:0000613	Photophobia
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0001058	Poor wound healing
HP:0001342	Cerebral hemorrhage
HP:0001581	Recurrent skin infections
HP:0001873	Thrombocytopenia
HP:0001878	Hemolytic anemia
HP:0001903	Anemia
HP:0001919	Acute kidney injury
HP:0001937	Microangiopathic hemolytic anemia
HP:0002013	Vomiting
HP:0002018	Nausea
HP:0002027	Abdominal pain
HP:0002202	Pleural effusion
HP:0002315	Headache
HP:0002615	Hypotension
HP:0002633	Vasculitis
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003095	Septic arthritis

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000652_3	Age-related macular degeneration	3.000000e-07
GCST000653_4	Age-related macular degeneration	9.000000e-09
GCST001100_2	Age-related macular degeneration	4.000000e-10
GCST001578_8	Age-related macular degeneration (geographic atrophy)	4.000000e-06
GCST001884_4	Age-related macular degeneration	7.000000e-11
GCST002248_6	Fasting insulin (dietary factor interaction)	9.000000e-06
GCST002253_4	Homeostasis model assessment of insulin resistance (dietary factor interaction)	5.000000e-06
GCST003219_19	Advanced age-related macular degeneration	5.000000e-17
GCST003219_20	Advanced age-related macular degeneration	6.000000e-10
GCST003265_336	Post bronchodilator FEV1/FVC ratio in COPD	5.000000e-06
GCST006585_2558	Blood protein levels	4.000000e-34
GCST011353_39	Serum alkaline phosphatase levels	1.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0008111	diet measurement
EFO:0004501	HOMA-IR
EFO:0004713	FEV/FVC ratio
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D065766	Atypical Hemolytic Uremic Syndrome	C12.050.351.968.419.936.463.500; C12.200.777.419.936.463.500; C12.950.419.936.463.500; C15.378.050.141.610.500; C15.378.140.855.925.500.500; C15.378.243.937.925.500.500
D005923	Glomerulosclerosis, Focal Segmental	C12.050.351.968.419.570.363.640; C12.200.777.419.570.363.660; C12.950.419.570.363.640
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D007676	Kidney Failure, Chronic	C12.050.351.968.419.780.750.500; C12.200.777.419.780.750.500; C12.950.419.780.750.500; C23.550.291.500.906.500
D051437	Renal Insufficiency	C12.050.351.968.419.780; C12.200.777.419.780; C12.950.419.780
D057049	Thrombotic Microangiopathies	C15.378.140.855.925; C15.378.243.937.925
C572568	Complement Factor I Deficiency (supp.)
C563301	Peroxisome Biogenesis Disorder, Complementation Group 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs10033900	CFI		0.00	0

CTD chemical–gene interactions

48 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression	4
Valproic Acid	decreases expression, increases expression	3
Benzo(a)pyrene	decreases expression, decreases methylation, increases methylation	2
Cadmium	decreases expression, increases abundance, affects binding	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
propionaldehyde	decreases expression	1
bisphenol A	affects expression	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
pentanal	decreases expression	1
cylindrospermopsin	decreases expression	1
K 7174	decreases expression	1
abrine	decreases expression	1
MRK 003	decreases expression	1
bisphenol S	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	increases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression	1
Aldehydes	decreases expression	1
Allergens	increases expression	1
Atrazine	increases expression	1

Cellosaurus cell lines

4 cell lines: 4 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_B5T9	SCTCi015-A	Induced pluripotent stem cell	Female
CVCL_B5TA	SCTCi014-A	Induced pluripotent stem cell	Male
CVCL_C0FS	SCTCi015-A-1	Induced pluripotent stem cell	Female
CVCL_C0FT	SCTCi014-A-1	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02574403	PHASE4	COMPLETED	Study Assessing an Algorithm-based Strategy of Eculizumab Discontinuation in Children and Adults With aHUS
NCT07308574	PHASE4	RECRUITING	Post-Marketing Clinical Study of Ravulizumab in Participants With Clinical aHUS
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00117078	PHASE4	COMPLETED	Aranesp® Monthly Preference Study - 2
NCT00117130	PHASE4	COMPLETED	Study to Evaluate Effectiveness of Aranesp®
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00140985	PHASE4	COMPLETED	Antiproteinuric Efficacy of Losartan Potassium in Patients With Non-Diabetic Proteinuric Renal Diseases (0954-213)
NCT00246129	PHASE4	COMPLETED	CamTac Trial:Campath-Tacrolimus vs IL2R MoAb/Tacrolimus/MMF in Renal Transplantation
NCT00275535	PHASE4	COMPLETED	The Comparison of Tacrolimus and Sirolimus Immunosuppression Based Drug Regimens in Kidney Transplant Recipients
NCT00282217	PHASE4	COMPLETED	Study Evaluating Sirolimus in the Treatment of Kidney Transplant
NCT00289614	PHASE4	COMPLETED	Patients With Renal Impairment and Diabetes Undergoing Computed Tomography (CT)
NCT00290069	PHASE4	UNKNOWN	Renal Function Optimization With Mycophenolate Mofetil (MMF) Immunosuppressor Regimes (ALHAMBRA)
NCT00338468	PHASE4	TERMINATED	A Study to Assess Disability in Anemic Elderly Patients With Kidney Disease Receiving PROCRIT (Epoetin Alfa)
NCT00368901	PHASE4	COMPLETED	STAAR-2 Clinical Study
NCT00369733	PHASE4	COMPLETED	STAAR-3 Clinical Study
NCT00369772	PHASE4	COMPLETED	STAAR-1 Clinical Study
NCT00379899	PHASE4	COMPLETED	ADVANCE: Study to Evaluate Cinacalcet Plus Low Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Hemodialysis
NCT00443508	PHASE4	UNKNOWN	Reduction or Discontinuation of CNI’s With Conversion to Everolimus-Based Immunosuppresion
NCT00452478	PHASE4	TERMINATED	Conversion From Standard Phosphate Binder Therapy to Fosrenol® (Lanthanum Carbonate) in Chronic Kidney Disease Stage 5
NCT00492518	PHASE4	COMPLETED	Acetylcysteine, Theophylline, and a Combination of Both in the Prophylaxis of Contrast-Induced Nephropathy
NCT00505102	PHASE4	UNKNOWN	Safe Renal Function In Long Term Heart Transplanted Patients
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00688480	PHASE4	COMPLETED	Do Xanthine Oxidase Inhibitors Reduce Both Left Ventricular Hypertrophy and Endothelial Dysfunction in Cardiovascular Patients With Renal Dysfunction?
NCT00863707	PHASE4	COMPLETED	A Study of the Safety and Tolerance of Regadenoson in Subjects With Renal Impairment
NCT01101698	PHASE4	UNKNOWN	Vitamin K2 and Vessel Calcification in Chronic Kidney Disease Patients
NCT01150201	PHASE4	COMPLETED	Aliskiren Combined With Losartan in Proteinuric, Non-diabetic Chronic Kidney Disease
NCT01155141	PHASE4	COMPLETED	Idiopathic Focal Segmental Glomerulosclerosis (FSGS) and Treatment With ACTH
NCT01228279	PHASE4	COMPLETED	Sympathetic Activity in Patients With End-stage Renal Disease on Peritoneal Dialysis
NCT01334333	PHASE4	COMPLETED	Comparison of Medication Adherence Between Once and Twice Daily Tacrolimus in Stable Renal Transplant Recipients
NCT01437943	PHASE4	TERMINATED	Effect of Short Term Aliskiren Treatment in Kidney Transplant Patients
NCT01545479	PHASE4	COMPLETED	Increased Renal Oxygenation and Angiotensin Converting Enzyme Inhibition
NCT01614431	PHASE4	COMPLETED	N Acetyl Cysteine for Cystinosis Patients
NCT01631149	PHASE4	COMPLETED	Effect of Deep BLock on Intraoperative Surgical Conditions
NCT01722513	PHASE4	UNKNOWN	Efficacy and Safety of Alprostadil Prevent Contrast Induced Nephropathy
NCT01985360	PHASE4	COMPLETED	ISCHEMIA-Chronic Kidney Disease Trial
NCT02311010	PHASE4	UNKNOWN	Practical Use of Advagraf de Novo After Kidney Transplantation According to Recipient Genetic Polymorphism
NCT02413073	PHASE4	COMPLETED	Whole Body Vibration in Kidney Disease
NCT02444013	PHASE4	UNKNOWN	Folic Acid for Prevention of Contrast Induced Nephropathy
NCT02663713	PHASE4	COMPLETED	A Randomized, Pharmacodynamic Comparison of Low Dose Ticagrelor to Clopidogrel in Patients With Prior Myocardial Infarction
NCT02707809	PHASE4	COMPLETED	Effects of Dexmedetomidine on Microcirculation of Kidney Transplant Recipient