CFHR5

Summary

CFHR5 (complement factor H related 5, HGNC:24668) is a protein-coding gene on chromosome 1q31.3, encoding Complement factor H-related protein 5 (Q9BXR6). Involved in complement regulation.

This gene is a member of a small complement factor H (CFH) gene cluster on chromosome 1. Each member of this gene family contains multiple short consensus repeats (SCRs) typical of regulators of complement activation. The protein encoded by this gene has nine SCRs with the first two repeats having heparin binding properties, a region within repeats 5-7 having heparin binding and C reactive protein binding properties, and the C-terminal repeats being similar to a complement component 3 b (C3b) binding domain. This protein co-localizes with C3, binds C3b in a dose-dependent manner, and is recruited to tissues damaged by C-reactive protein. Allelic variations in this gene have been associated, but not causally linked, with two different forms of kidney disease: membranoproliferative glomerulonephritis type II (MPGNII) and hemolytic uraemic syndrome (HUS).

Source: NCBI Gene 81494 — RefSeq curated summary.

At a glance

• Gene–disease (curated): C3 glomerulonephritis (Strong, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 372 total — 2 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_030787

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24668
Approved symbol	CFHR5
Name	complement factor H related 5
Location	1q31.3
Locus type	gene with protein product
Status	Approved
Aliases	FHR5, FHR-5
Ensembl gene	ENSG00000134389
Ensembl biotype	protein_coding
OMIM	608593
Entrez	81494

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000256785, ENST00000699466, ENST00000699467, ENST00000699468, ENST00000699469, ENST00000699470, ENST00000699471, ENST00000875778, ENST00000875779, ENST00000875780

RefSeq mRNA: 1 — MANE Select: NM_030787 NM_030787

CCDS: CCDS1387

Canonical transcript exons

ENST00000256785 — 10 exons

Exon	Start	End
ENSE00000914601	196994080	196994256
ENSE00000914603	196995717	196995899
ENSE00000914605	196996022	196996201
ENSE00000914607	196998128	196998304
ENSE00000914609	197002482	197002664
ENSE00000959035	197004661	197004843
ENSE00002389135	196977556	196977722
ENSE00003976677	197008487	197009678
ENSE00003976679	196982885	196983079
ENSE00003976691	196983961	196984137

Expression profiles

Bgee: expression breadth broad, 15 present calls, max score 93.85.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.3413 / max 141.9657, expressed in 6 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7512	0.2041	6
7516	0.0848	6
7511	0.0159	6
7515	0.0142	6
7514	0.0138	6
7513	0.0085	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	93.85	gold quality
liver	UBERON:0002107	93.06	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.04	gold quality
oocyte	CL:0000023	52.66	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
quadriceps femoris	UBERON:0001377	48.41	gold quality
vastus lateralis	UBERON:0001379	48.25	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
upper arm skin	UBERON:0004263	48.06	gold quality
cervix epithelium	UBERON:0004801	48.04	gold quality
oviduct epithelium	UBERON:0004804	48.00	gold quality
tongue squamous epithelium	UBERON:0006919	47.92	gold quality
mucosa of urinary bladder	UBERON:0001259	47.80	gold quality
nasal cavity epithelium	UBERON:0005384	47.70	gold quality
epithelial cell of pancreas	CL:0000083	47.44	gold quality
thymus	UBERON:0002370	47.42	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
diaphragm	UBERON:0001103	47.05	gold quality
gluteal muscle	UBERON:0002000	47.03	gold quality
kidney epithelium	UBERON:0004819	47.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.26

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

51 targeting CFHR5, 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-4682	100.00	68.89	1258
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-548A-3P	99.76	70.58	3524
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-4667-3P	99.26	65.45	1608
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-5583-3P	99.06	65.68	1018
HSA-MIR-922	99.02	67.23	1838
HSA-MIR-6074	98.89	69.64	2187

Literature-anchored findings (GeneRIF, showing 29)

• Maps to between FHR-2 and the non-complement protein factor XIIIb at 1q32. (PMID:12041828)
• FHR-5 shares properties of binding heparin and C-reactive protein and lipoprotein association with one or more of the other FHRs, but is unique among this family of proteins in possessing independent complement-regulatory activity. (PMID:15879123)
• Identification of specific variants of variants of CFHR5 in membranoproliferative glomerulonephritis type II. (PMID:16299065)
• CFHR5 genetic alterations may play a secondary role in the pathogenesis of haemolytic uraemic syndrome. (PMID:17000000)
• No definitive pathogenic CFHR5 mutations have been found in any of 639 unrelated patients with age-related macular degeneration (AMD), indicating that sequence variations in CFHR5 do not play a major role in determining AMD susceptibility. (PMID:19365580)
• Study identified novel mutations in CFH, CFHR5, CFI, CFB and C3 in American patients with atypical hemolytic uremic syndrome. (PMID:20513133)
• evidence for an inherited renal disease, endemic in Cyprus, characterised by microscopic and synpharyngitic macroscopic haematuria, renal failure and C3 glomerulonephritis; affected individuals have an internal duplication within the gene for CFHR5 (PMID:20800271)
• Describe the clinical course, significant variable expressivity, and marked gender difference regarding the development of chronic renal failure in familial C3 glomerulopathy associated with CFHR5 mutations. (PMID:21566112)
• CFHR5 nephropathy is discussed. (PMID:22065842)
• A potentially pathogenic sequence variation was found in CFHR5 in the patients with atypical hemolytic uremic syndrome. (PMID:22622361)
• Recent investigations in London and Cyprus culminated in the identification of another autosomal dominant condition that presents with microscopic haematuria because of heterozygous mutations in the CFHR5 gene–{review} (PMID:23402027)
• At least two distinct intronic breakpoints within the CFHR5 gene can cause the same mutant CFHR5 protein and C3 glomerulopathy. (PMID:24067434)
• A hybrid CFHR2-CFHR5 plasma protein, arising from a chromosomal deletion mutation stabilizes the C3 convertase and reduces factor H-mediated convertase decay. (PMID:24334459)
• In this study, we identify pentraxin 3 (PTX3) as a novel ligand of CFHR5 (PMID:25855355)
• Studies indicate that complement factor H-related proteins (FHR1-5) may enhance complement activation, with important implications for the role of these proteins in disease. (PMID:25979655)
• Our study found that rare variants in CFHR5 may contribute to the genetic susceptibility to IgA Nephropathy, which suggests that CFHR5 is an IgA Nephropathy susceptibility gene (PMID:26825529)
• Next-generation sequencing of the CFH region identified putatively functional variants (missense, splice site and indel) on the four common haplotypes. We found no expression of any of the five CFH-related genes in the retina or RPE/Choroid/Sclera, in contrast to the liver, which is the main source of the circulating proteins. [CFHR5] (PMID:27196323)
• Higher serum FHR-5 levels were associated with a lack of response to immunosuppression, the presence of endocapillary hypercellularity, and histology scores of IgA nephropathy severity. (PMID:28673452)
• Novel genetic rearrangement generated from a heterozygous deletion spanning 146 Kbp involving multiple CFHR genes leading to a CFHR1-R5 hybrid protein. This deletion was found in four family members presenting with a familial dominant glomerulopathy. (PMID:28729035)
• Higher circulating FHR-5 levels in IgA nephropathy patients were associated with a lower estimated glomerular filtration rate, hypertension, and severe Oxford-T and Oxford-C scores. High FHR-5 levels were independently and significantly associated with a risk of developing either a 30% decline in the estimated glomerular filtration rate or end-stage renal disease. (PMID:29759419)
• The solution structure of the complement deregulator FHR5 reveals a compact dimer and provides new insights into CFHR5 nephropathy. (PMID:32928961)
• Gain-of-function factor H-related 5 protein impairs glomerular complement regulation resulting in kidney damage. (PMID:33753502)
• Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration. (PMID:34260947)
• Protective chromosome 1q32 haplotypes mitigate risk for age-related macular degeneration associated with the CFH-CFHR5 and ARMS2/HTRA1 loci. (PMID:34563268)
• FHR-5 Serum Levels and CFHR5 Genetic Variations in Patients With Immune Complex-Mediated Membranoproliferative Glomerulonephritis and C3-Glomerulopathy. (PMID:34566977)
• Complement Factor H-Related Proteins FHR1 and FHR5 Interact With Extracellular Matrix Ligands, Reduce Factor H Regulatory Activity and Enhance Complement Activation. (PMID:35392081)
• Elevated plasma complement factor H related 5 protein is associated with venous thromboembolism. (PMID:37286573)
• The complement factor H-related protein-5 (CFHR5) exacerbates pathological bone formation in ankylosing spondylitis. (PMID:38418621)
• Causal association between complement system FHR-5, CTRP9, and breast carcinoma in situ: a Mendelian randomization study. (PMID:38567599)

Cross-species orthologs

0 orthologs

Paralogs (39): CFH (ENSG00000000971), SELE (ENSG00000007908), C8B (ENSG00000021852), C6 (ENSG00000039537), SEZ6 (ENSG00000063015), CFHR2 (ENSG00000080910), APOH (ENSG00000091583), SEZ6L (ENSG00000100095), SUSD6 (ENSG00000100647), SRPX (ENSG00000101955), SRPX2 (ENSG00000102359), C7 (ENSG00000112936), C9 (ENSG00000113600), PAPPA2 (ENSG00000116183), CFHR3 (ENSG00000116785), CR2 (ENSG00000117322), CD46 (ENSG00000117335), CSMD2 (ENSG00000121904), C4BPA (ENSG00000123838), C4BPB (ENSG00000123843), CFHR4 (ENSG00000134365), F13B (ENSG00000143278), SUSD4 (ENSG00000143502), C8A (ENSG00000157131), SUSD3 (ENSG00000157303), CSMD3 (ENSG00000164796), SVEP1 (ENSG00000165124), C2 (ENSG00000166278), SELP (ENSG00000174175), SEZ6L2 (ENSG00000174938), PRF1 (ENSG00000180644), PAPPA (ENSG00000182752), CSMD1 (ENSG00000183117), SELL (ENSG00000188404), CD55 (ENSG00000196352), CR1L (ENSG00000197721), CR1 (ENSG00000203710), CFB (ENSG00000243649), CFHR1 (ENSG00000244414)

Protein

Protein identifiers

Complement factor H-related protein 5 — Q9BXR6 (reviewed: Q9BXR6)

All UniProt accessions (3): A0A8V8TNA3, Q9BXR6, A0A8V8TNF4

UniProt curated annotations — full annotation on UniProt →

Function. Involved in complement regulation. The dimerized forms have avidity for tissue-bound complement fragments and efficiently compete with the physiological complement inhibitor CFH.

Subunit / interactions. Head-to-tail homodimer and heterodimer with CFHR1 or CFHR2. Binds C3b in vitro.

Subcellular location. Secreted.

Tissue specificity. Expressed by the liver and secreted in plasma.

Disease relevance. Defects in CFHR5 have been found in patients with atypical hemolytic uremic syndrome and may contribute to the disease. Atypical hemolytic uremic syndrome 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. Susceptibility to the development of atypical hemolytic uremic syndrome can be conferred by mutations in various components of or regulatory factors in the complement cascade system. Other genes may play a role in modifying the phenotype. CFHR5 deficiency (CFHR5D) [MIM:614809] A progressive disease characterized by glomerulonephritis, hematuria, renal failure, end-stage renal disease, subendothelial and mesangial glomerular C3 deposits, mesangial matrix expansion, increased glomerular cellularity, and segmental capillary wall thickening. Hematuria may become apparent after respiratory infections. The disease is caused by variants affecting the gene represented in this entry.

RefSeq proteins (1): NP_110414* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000436	Sushi_SCR_CCP_dom	Domain
IPR035976	Sushi/SCR/CCP_sf	Homologous_superfamily
IPR051503	ComplSys_Reg/VirEntry_Med	Family

Pfam: PF00084

UniProt features (41 total): disulfide bond 18, sequence variant 10, domain 9, glycosylation site 2, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BXR6-F1	83.76	0.39

Functional residue map

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

Disulfide bonds (18): 23–72, 55–83, 87–129, 114–140, 147–189, 175–201, 208–251, 237–262, 269–311, 297–322, 331–370, 359–381, 389–431, 417–442, 449–492, 478–503, 507–558, 541–568

Glycosylation sites (2): 126, 400

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 88 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PROTEIN_BINDING, COUP_01, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_COMPLEMENT_ACTIVATION_ALTERNATIVE_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_MOLECULAR_FUNCTION, GOBP_HUMORAL_IMMUNE_RESPONSE, AACTTT_UNKNOWN, GOBP_IMMUNE_EFFECTOR_PROCESS, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_SYMBIONT, ACEVEDO_LIVER_CANCER_UP, GOBP_CELL_KILLING

GO Biological Process (4): complement activation (GO:0006956), complement activation, alternative pathway (GO:0006957), negative regulation of protein binding (GO:0032091), obsolete cytolysis by host of symbiont cells (GO:0051838)

GO Molecular Function (4): complement component C3b binding (GO:0001851), identical protein binding (GO:0042802), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), protein-containing complex (GO:0032991)

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
protein binding	2
immune effector process	1
activation of immune response	1
humoral immune response	1
protein activation cascade	1
complement activation	1
innate immune response	1
regulation of protein binding	1
negative regulation of binding	1
opsonin binding	1
complement binding	1
protein dimerization activity	1
binding	1
cellular anatomical structure	1
cellular_component	1

Protein interactions and networks

STRING

666 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFHR5	C3	P01024	979
CFHR5	PTX3	P26022	916
CFHR5	CFB	P00751	812
CFHR5	RAPGEF1	Q13905	806
CFHR5	DGKE	P52429	797
CFHR5	CRP	P02741	791
CFHR5	MYBPH	Q13203	781
CFHR5	CD46	P15529	720
CFHR5	C4A	P01028	684
CFHR5	C4A	P01028	669
CFHR5	ADAMTS13	Q76LX8	661
CFHR5	CFP	P27918	647
CFHR5	RBMS2	Q15434	646
CFHR5	MMACHC	Q9Y4U1	633
CFHR5	THBD	P07204	630

IntAct

79 interactions, top by confidence:

A	B	Type	Score
PTX3	CFH	psi-mi:“MI:0914”(association)	0.820
CFHR5	CREB3L1	psi-mi:“MI:0915”(physical association)	0.720
CREB3L1	CFHR5	psi-mi:“MI:0915”(physical association)	0.720
CFHR5	PTX3	psi-mi:“MI:0407”(direct interaction)	0.640
PTX3	CFHR5	psi-mi:“MI:0407”(direct interaction)	0.640
PTX3	CFHR5	psi-mi:“MI:0915”(physical association)	0.640
CFHR5	PTX3	psi-mi:“MI:0915”(physical association)	0.640
CFHR1	CFHR5	psi-mi:“MI:0407”(direct interaction)	0.600
CFHR1	CFHR5	psi-mi:“MI:0915”(physical association)	0.600
CFHR5	CFHR1	psi-mi:“MI:0915”(physical association)	0.600
CFHR5	CREB3	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	SLC10A1	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	PANX1	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	FFAR2	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	KCNK7	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	CISD2	psi-mi:“MI:0915”(physical association)	0.560
CFHR5	STOM	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (23): CREB3 (Two-hybrid), CREB3L1 (Two-hybrid), CFHR5 (Two-hybrid), CFHR5 (Two-hybrid), CFHR5 (Two-hybrid), CFHR5 (Two-hybrid), CFHR5 (Two-hybrid), CFHR5 (Two-hybrid), TMEM14B (Two-hybrid), CISD2 (Two-hybrid), EBAG9 (Two-hybrid), HIATL1 (Two-hybrid), STOM (Two-hybrid), TMEM237 (Two-hybrid), CREB3L1 (Two-hybrid)

ESM2 similar proteins: O02839, O08569, O19124, O62685, O62837, O88174, P02749, P04003, P05160, P06909, P08174, P08603, P08607, P15529, P16109, P17690, P19070, P20023, P26644, P33703, P36980, P42201, P49457, P70105, P79138, P98109, Q01339, Q02985, Q03472, Q03591, Q07968, Q22328, Q28065, Q28768, Q2VPA4, Q5R4D0, Q60401, Q60736, Q61475, Q61476

Diamond homologs: A0A1D5NSM8, E7FEC4, P08174, P0C6B8, P98110, Q09101, Q29RN8, Q4V9Z5, Q501P1, Q5R8M2, Q5VX71, Q6AX42, Q6P1D5, Q6UXD5, Q7Z407, Q80T79, Q8BGE4, Q8BH32, Q92537, Q9BXR6, Q9BYH1, A0JNA2, O02839, O08569, O19124, O62685, O62837, O88174, P04003, P08607, P10643, P15529, P17927, P33703, P49457, P68638, P68639, P70105, P79138, Q01016

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	1
Uncertain significance	236
Likely benign	46
Benign	22

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
37236	NM_030787.4(CFHR5):c.59-1806_430+3225dup	Pathogenic
988223	NM_030787.3:c.(58+1_59-1)_(430+1_431-1)dup	Pathogenic
633673	NM_030787.4(CFHR5):c.1303C>T (p.Arg435Ter)	Likely pathogenic

SpliceAI

1534 predictions. Top by Δscore:

Variant	Effect	Δscore
1:196983080:G:GG	donor_gain	1.0000
1:196984138:G:GG	donor_gain	1.0000
1:196994078:A:AG	acceptor_gain	1.0000
1:196994079:G:GG	acceptor_gain	1.0000
1:196994079:GAA:G	acceptor_gain	1.0000
1:197008481:TTTCA:T	acceptor_loss	1.0000
1:197008482:TTCA:T	acceptor_loss	1.0000
1:197008484:CAGA:C	acceptor_loss	1.0000
1:197008485:A:AG	acceptor_gain	1.0000
1:197008485:AGATC:A	acceptor_loss	1.0000
1:197008486:G:GG	acceptor_gain	1.0000
1:196982971:G:GT	donor_gain	0.9900
1:196984135:CTA:C	donor_gain	0.9900
1:196994075:TTTAG:T	acceptor_loss	0.9900
1:196994077:TA:T	acceptor_loss	0.9900
1:196994078:A:AC	acceptor_loss	0.9900
1:196994078:AGAAG:A	acceptor_gain	0.9900
1:196994079:GA:G	acceptor_gain	0.9900
1:196994079:GAAGG:G	acceptor_gain	0.9900
1:196994252:CAAAG:C	donor_loss	0.9900
1:196994253:AAAGG:A	donor_loss	0.9900
1:196994255:AGG:A	donor_loss	0.9900
1:196994257:GTC:G	donor_loss	0.9900
1:196994258:T:A	donor_loss	0.9900
1:196995258:G:GT	donor_gain	0.9900
1:196995277:GATA:G	donor_gain	0.9900
1:196995712:A:AG	acceptor_gain	0.9900
1:196995800:G:GT	donor_gain	0.9900
1:196995804:T:TA	donor_gain	0.9900
1:196995805:A:AA	donor_gain	0.9900

AlphaMissense

3720 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:197002642:G:C	W436C	0.996
1:197002642:G:T	W436C	0.996
1:197004821:G:C	W497C	0.996
1:197004821:G:T	W497C	0.996
1:196983057:G:C	W77C	0.995
1:196983057:G:T	W77C	0.995
1:196995877:G:C	W256C	0.995
1:196995877:G:T	W256C	0.995
1:196995875:T:A	W256R	0.994
1:196995875:T:C	W256R	0.994
1:196984109:G:C	W134C	0.993
1:196984109:G:T	W134C	0.993
1:196983073:T:A	C83S	0.992
1:196983074:G:C	C83S	0.992
1:196996179:G:C	W316C	0.992
1:196996179:G:T	W316C	0.992
1:196998282:G:C	W375C	0.992
1:196998282:G:T	W375C	0.992
1:196994231:G:C	W194C	0.991
1:196994231:G:T	W194C	0.991
1:197002640:T:A	W436R	0.991
1:197002640:T:C	W436R	0.991
1:196998265:T:A	C370S	0.990
1:196998266:G:C	C370S	0.990
1:196994229:T:A	W194R	0.989
1:196994229:T:C	W194R	0.989
1:196983055:T:A	W77R	0.988
1:196983055:T:C	W77R	0.988
1:196995860:T:A	C251S	0.988
1:196995861:G:C	C251S	0.988

dbSNP variants (sampled 300 via entrez): RS1000062371 (1:196999128 A>G), RS1000116534 (1:197004919 T>A,C), RS1000179903 (1:197004958 G>A), RS1000300289 (1:196998550 A>C), RS1000352033 (1:196973137 T>C), RS1000413766 (1:196998821 A>T), RS1000464138 (1:196979419 A>G), RS1000643380 (1:196984917 T>A), RS1000815013 (1:196979186 G>A,C), RS1000841227 (1:196987682 G>T), RS1000871731 (1:196978037 T>C), RS1001009214 (1:197009843 C>A), RS1001020549 (1:197000367 G>T), RS1001229638 (1:196998750 T>C), RS1001471479 (1:197000720 A>G)

Disease associations

OMIM: gene MIM:608593 | disease phenotypes: MIM:614809

GenCC curated gene-disease

Disease	Classification	Inheritance
C3 glomerulonephritis	Strong	Autosomal dominant

Mondo (4): C3 glomerulonephritis (MONDO:0013892), atypical hemolytic-uremic syndrome (MONDO:0016244), chronic kidney disease (MONDO:0005300), kidney disorder (MONDO:0005240)

Orphanet (2): C3 glomerulonephritis (Orphanet:329931), Atypical hemolytic uremic syndrome (Orphanet:2134)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000083	Renal insufficiency
HP:0000099	Glomerulonephritis
HP:0002907	Microscopic hematuria
HP:0003676	Progressive
HP:0003774	Stage 5 chronic kidney disease
HP:0004746	Glomerular subendothelial electron-dense deposits
HP:0012574	Mesangial hypercellularity
HP:0012576	Glomerular C3 deposition
HP:0025005	Thickening of glomerular capillary wall
HP:0033493	Mesangial matrix expansion

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001009_4	Nephropathy	3.000000e-10
GCST001899_1	Age-related macular degeneration	1.000000e-16
GCST001986_1	Age-related macular degeneration	1.000000e-31
GCST001987_2	Age-related macular degeneration (extreme sampling)	9.000000e-24
GCST002479_5	Lupus nephritis in systemic lupus erythematosus	5.000000e-06
GCST005187_2	Matrix metalloproteinase-8 levels	2.000000e-35
GCST005212_15	Asthma	9.000000e-06
GCST010284_3	Age-related macular degeneration (MTAG)	2.000000e-157

MeSH disease descriptors (3)

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
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression	2
methyleugenol	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
MT19c compound	decreases expression	1
Acetaminophen	decreases expression	1
Methotrexate	decreases expression	1
Valproic Acid	decreases expression, decreases methylation	1
Cyclosporine	decreases expression	1
Aflatoxin B1	decreases expression	1
Okadaic Acid	decreases expression	1

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
NCT00073710	PHASE4	COMPLETED	Study to Evaluate the Effects of Zemplar Injection and Calcijex on Intestinal Absorption of Calcium
NCT00125593	PHASE4	COMPLETED	Study of Heart and Renal Protection
NCT00132431	PHASE4	COMPLETED	START: Sensipar Treatment Algorithm to Reach K/DOQI Targets in Chronic Kidney Disease Subjects With Secondary Hyperparathyroidism
NCT00155246	PHASE4	COMPLETED	Efficacy of Pentoxifylline on Chronic Kidney Disease
NCT00175149	PHASE4	TERMINATED	Active Vitamin D Effect on Left Ventricular Hypertrophy
NCT00184769	PHASE4	COMPLETED	Growth Hormone Treatment in Infants Aged 1 to 2 Years With Chronic Renal Insufficiency (CRI) and Growth Retardation.
NCT00190580	PHASE4	COMPLETED	Kanagawa Valsartan Trial (KVT): Effects of Valsartan on Renal and Cardiovascular Disease
NCT00194961	PHASE4	TERMINATED	Effect of Growth Hormone on Leptin, Cytokines and Body Composition of Children With Growth Failure Due to Chronic Kidney Disease
NCT00239642	PHASE4	COMPLETED	Safety and Efficacy of Iron Sucrose in Children
NCT00324571	PHASE4	COMPLETED	Dialysis Clinical Outcomes Revisited (DCOR) Trial
NCT00364884	PHASE4	UNKNOWN	Keto-/Amino Acid Supplemented Low Protein Diet in Patients With Chronic Kidney Disease
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
NCT00384618	PHASE4	TERMINATED	Anti-Oxidant Therapy In Chronic Renal Insufficiency (ATIC) Study
NCT00478543	PHASE4	COMPLETED	Loop Diuretics in Chronic Kidney Disease
NCT00632125	PHASE4	COMPLETED	Post-authorization Safety Study in CKD Subjects Receiving HX575 i.v.
NCT00644046	PHASE4	COMPLETED	Chronic Kidney Disease Prevention of An-Lo District, Keelung
NCT00719316	PHASE4	UNKNOWN	Aliskiren and Muscle Sympathetic Nerve Activity
NCT00725517	PHASE4	COMPLETED	Efficacy and Safety of a 7.5% Icodextrin Peritoneal Dialysis Solution in Once-Daily Long Dwell Exchange
NCT00741585	PHASE4	COMPLETED	Prognostic Value of the Circadian Pattern of Ambulatory Blood Pressure for Multiple Risk Assessment
NCT00749736	PHASE4	COMPLETED	The Role of Vitamin D in Immune Function in Patients With Chronic Kidney Disease (CKD) Stages 3 and 4.
NCT00752102	PHASE4	COMPLETED	Vitamin D and Coronary Calcification Study
NCT00756145	PHASE4	COMPLETED	The Use of Low Molecular Weight Heparin in Hemodiafiltration
NCT00768638	PHASE4	COMPLETED	Study of Atorvastatin Dose Dependent Reduction of Proteinuria
NCT00786136	PHASE4	COMPLETED	Rosuvastatin Prevent Contrast Induced Acute Kidney Injury in Patients With Diabetes
NCT00803712	PHASE4	COMPLETED	20070360 Incident Dialysis
NCT00812123	PHASE4	COMPLETED	Calcineurin Free Immunosuppression in Renal Transplant Recipients
NCT00823303	PHASE4	COMPLETED	Paricalcitol Versus Calcitriol for Efficacy and Safety in Stage 3/4 Chronic Kidney Disease (CKD) With Secondary Hyperparathyroidism (SHPT)
NCT00830037	PHASE4	TERMINATED	A Clinical Trial of Oral Versus IV Iron in Patients With Chronic Kidney Disease
NCT00852969	PHASE4	COMPLETED	Niacin and Endothelial Function in Early CKD
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
NCT00860431	PHASE4	COMPLETED	Kremezin Study Against Renal Disease Progression in Korea
NCT00882401	PHASE4	COMPLETED	Vitamin D, Chronic Kidney Disease (CKD) and the Microcirculation
NCT00889629	PHASE4	COMPLETED	Pilot Study Evaluating Doxercalciferol Replacement Therapy in Kidney Transplant Recipients
NCT00892892	PHASE4	WITHDRAWN	Sympathetic Nerve Activity in Renal Failure
NCT00893425	PHASE4	COMPLETED	Effect of Renin Angiotensin System Blockade on the Fas Antigen (CD95) and Asymmetric Dimethylarginine (ADMA) Levels in Type-2 Diabetic Patients With Proteinuria