CFHR1

Summary

CFHR1 (complement factor H related 1, HGNC:4888) is a protein-coding gene on chromosome 1q31.3, encoding Complement factor H-related protein 1 (Q03591). Involved in complement regulation.

This gene encodes a secreted protein belonging to the complement factor H protein family. It binds to Pseudomonas aeruginosa elongation factor Tuf together with plasminogen, which is proteolytically activated. It is proposed that Tuf acts as a virulence factor by acquiring host proteins to the pathogen surface, controlling complement, and facilitating tissue invasion. Mutations in this gene are associated with an increased risk of atypical hemolytic-uremic syndrome.

Source: NCBI Gene 3078 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dense deposit disease (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 152 total — 1 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 33
• MANE Select transcript: NM_002113

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4888
Approved symbol	CFHR1
Name	complement factor H related 1
Location	1q31.3
Locus type	gene with protein product
Status	Approved
Aliases	H36-1, FHR1, CFHL, H36-2
Ensembl gene	ENSG00000244414
Ensembl biotype	protein_coding
OMIM	134371
Entrez	3078

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 24 protein_coding, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000320493, ENST00000367424, ENST00000468079, ENST00000472961, ENST00000480960, ENST00000699454, ENST00000699455, ENST00000699456, ENST00000887399, ENST00000887400, ENST00000887401, ENST00000887402, ENST00000887403, ENST00000887404, ENST00000887405, ENST00000887406, ENST00000887407, ENST00000887408, ENST00000887409, ENST00000887410, ENST00000887411, ENST00000887412, ENST00000887413, ENST00000887414, ENST00000887415, ENST00000887416, ENST00000887417, ENST00000887418

RefSeq mRNA: 8 — MANE Select: NM_002113 NM_001379306, NM_001379307, NM_001379308, NM_001379309, NM_001379310, NM_001379311, NM_001379312, NM_002113

CCDS: CCDS1386, CCDS91131, CCDS91132

Canonical transcript exons

ENST00000320493 — 6 exons

Exon	Start	End
ENSE00001927163	196819731	196819902
ENSE00001938150	196831797	196832189
ENSE00002379624	196830500	196830682
ENSE00002381722	196828070	196828246
ENSE00003460082	196825477	196825671
ENSE00003542617	196826829	196827005

Expression profiles

Bgee: expression breadth ubiquitous, 125 present calls, max score 98.77.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.77	gold quality
liver	UBERON:0002107	98.73	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.63	gold quality
lymph node	UBERON:0000029	74.62	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.33	gold quality
spleen	UBERON:0002106	67.65	gold quality
tibial nerve	UBERON:0001323	64.87	gold quality
metanephros cortex	UBERON:0010533	64.71	gold quality
adult mammalian kidney	UBERON:0000082	62.23	gold quality
stromal cell of endometrium	CL:0002255	60.28	gold quality
kidney	UBERON:0002113	59.54	gold quality
vermiform appendix	UBERON:0001154	59.14	gold quality
right hemisphere of cerebellum	UBERON:0014890	58.80	gold quality
cerebellar hemisphere	UBERON:0002245	57.63	gold quality
lower esophagus mucosa	UBERON:0035834	57.08	gold quality
cerebellar cortex	UBERON:0002129	57.06	gold quality
cerebellum	UBERON:0002037	56.83	gold quality
subcutaneous adipose tissue	UBERON:0002190	56.18	gold quality
right coronary artery	UBERON:0001625	55.53	gold quality
mucosa of transverse colon	UBERON:0004991	55.41	gold quality
descending thoracic aorta	UBERON:0002345	54.92	gold quality
adipose tissue	UBERON:0001013	54.86	gold quality
cortex of kidney	UBERON:0001225	54.86	gold quality
left coronary artery	UBERON:0001626	53.81	gold quality
omental fat pad	UBERON:0010414	53.47	gold quality
left adrenal gland cortex	UBERON:0035825	53.40	gold quality
ascending aorta	UBERON:0001496	53.20	gold quality
tibial artery	UBERON:0007610	53.12	gold quality
popliteal artery	UBERON:0002250	52.88	gold quality
thoracic aorta	UBERON:0001515	52.87	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	30.53
E-ANND-3	no	7.92

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

14 targeting CFHR1, 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-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-4427	99.34	70.33	1854
HSA-MIR-148A-5P	99.30	68.27	1141
HSA-MIR-29A-5P	99.08	68.59	1813
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975
HSA-MIR-3907	96.76	65.04	662

Literature-anchored findings (GeneRIF, showing 40)

• This paper (PMID 10781834) was the first to describe the detailed structure of the human FHR1 gene. (PMID:10781834)
• Human complement regulatory factor H-like protein 1 (FHL-1) binds to Streptococcal pyogenes M18 surface protein Emm18. (PMID:15557185)
• the primary function of FHL-1 binding by T. denticola might be to facilitate adherence to FHL-1 present on anchorage-dependent cells and in the extracellular matrix (PMID:16239506)
• A common haplotype was associated with decreased risk of AMD. This haplotype carried a deletion of CFHR1 and CFHR3, and the proteins encoded by these genes were absent in serum of homozygotes. (PMID:16998489)
• Deletion of two closely related genes, complement factor H-related 1 (CFHR1) and complement factor H-related 3 (CFHR3), increases the risk of atypical hemolytic uremic syndrome. (PMID:17367211)
• we have identified factor H-related protein 1 (FHR-1) as a novel protein that binds to Borrelia burgdorferi via CRASP-3, -4, and -5. (PMID:17538892)
• either lacked the CFHR1/CFHR3 completely (n = 14) or showed extremely low CFHR1/CFHR3 plasma levels (n = 2) are positive for factor H (CFH) autoantibodies (PMID:18006700)
• The binding of factor H and factor H-like protein 1 (FHL-1) from human sera to Aspergillus fumigatus conidia was shown by adsorption assays and immunostaining. (PMID:18039838)
• Deletion of CFHR1 and CFHR3 may account for a small portion of the protection from age-related macular degeneration associated with particular haplotypes in complement factor H. (PMID:18084039)
• CFH/CFHL1 binding site within borrelial BbCRASP-2 and identified single amino acid residues potentially involved in the interaction with both complement regulators (PMID:18824548)
• Borrelia recurrentis HcpA binds human complement regulators, Factor H, CFHR-1, and simultaneously, the host protease plasminogen. (PMID:19308255)
• The number of CFHR1 alleles was quantified in patients with atypical haemolytic uraemic syndrome(aHUS) by multiplex ligation dependant probe amplification (MLPA). Frequency of the deleted allele was significantly higher in aHUS patients than in controls. (PMID:19435718)
• Results describe a correlation between the development of complement factor H autoantibodies and the deficiency of the CFH-related proteins, CFHR1 and CFHR3, in atypical hemolytic uremic syndrome. (PMID:19531976)
• Deletion of CFHR3 and CFHR1 protected against the development of AMD at least in part because the deletion tagged a protective haplotype and did not occur on the risk haplotype. (PMID:19553609)
• characterization of a novel CFHR1 polymorphism, resulting from a gene conversion event between CFH and CFHR1, which strongly associates with atypical hemolytic uremic syndrome (PMID:19745068)
• 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)
• CFH and CFHR1, when bound on the surface of C. albicans, enhance antimicrobial activity of human neutrophils. (PMID:20008295)
• Data from haplotype analysis demonstrates the relationship between the CFH rs10737680 association and the CFHR1-3Delta association in age-related macular degeneration. (PMID:20581873)
• deficiency of CFHR3 and CFHR1 results in a loss of complement control but enhances local regulation by factor H; alludes to critical balance between CFHR3, CFHR1 and factor H and emphasize role of complement regulation in age-related macular degeneration (PMID:20843825)
• Binding of the human complement regulators CFHR1 and factor H by streptococcal collagen-like protein 1 (Scl1) via their conserved C termini allows control of the complement cascade at multiple levels. (PMID:20855886)
• Studies indicated that atypical HUS was linked with a complement alternative pathway dysregulation due to genetic defects but also to development of autoantibodies to factor H (FH). (PMID:20865640)
• A change in gene dosage of the encoded proteins CFHR3 and CFHR1 might account for the increased systemic lupus erythematosus. risk (PMID:21637784)
• Anti-factor H autoantibodies in patients with autoimmune form of atypical hemolytic uremic syndrome crossreact with CFHR1. (PMID:21677636)
• Data show that 698 CNPs loci overlap with known disease-associated or pharmacogenetic-related genes such as CFHR3, CFHR1, GSTTI and UGT2B17. (PMID:21677662)
• Combined deletion of CFHR3 and CFHR1 is associated with a decreased risk of developing age-related macular degeneration. (PMID:21850184)
• In this matched subset of Age-Related Eye Disease Study (AREDS) subjects, after adjusting for 2 known risk variants in CFH, CNP147 deletion statistically associates with diminished risk for AMD. (PMID:21856016)
• Reduced expression of the CFHR1 allele has been associated with higher risk to atypical Haemolytic Uraemic Syndrome in Spanish patients. (PMID:22136554)
• Analysis of the CFHR1 genotypes provide sufficient information to delineate the individual risk of developing age-related macular degeneration. (PMID:22247456)
• A significant association with deletion of CFHR1-4 was identified in patients who presented with bilateral geographic atrophy. (PMID:22558131)
• A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. (PMID:22626820)
• we show that native factor H, factor H-like protein 1, and factor H-related protein 1 (CFHR1) bind to PTX3 (PMID:22786770)
• genetic variations in CFH and its related genes may contribute to hypertension risk in Chinese Hans (PMID:22848687)
• An average of 15.2% of factor H-autoantibody positive individuals with rheumatic diseases or hemolytic uremic syndrome had homozygous deficiency of CFHR1. (PMID:22894814)
• Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion. (PMID:23071278)
• Homozygous deletion in CFHR1 is strongly associated with occurrence of CFH antibodies in pediatric patients with atypical hemolytic uremic syndrome. (PMID:23243267)
• Identification and characterization of a unique CFHR1 mutation provides insights into the biology and pathogenic mechanisms underlying C3 glomerulopathy. (PMID:23728178)
• Results show non-coding CFH SNP (rs6677604) and the common deletion CNP147 were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations in patients with age-related macular degeneration. (PMID:23873044)
• The CFHR1/complement factor H hybrid gene fusion protein contains the first three short consensus repeats of CFHR1 (PMID:23880784)
• These results provide evidence for a role of CFH and FHL-1 in cutaneous squamous cell carcinoma progression and identify them as progression markers and potential therapeutic targets. (PMID:23938460)
• Prompt use of immunosuppressive agents and plasma exchanges are useful for improving outcomes in pediatric patients with anti-complement factor H-associated HUS. (PMID:24088957)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cfhr1	ENSMUSG00000057037
rattus_norvegicus	Cfhr1	ENSRNOG00000042901

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), CFHR5 (ENSG00000134389), 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)

Protein

Protein identifiers

Complement factor H-related protein 1 — Q03591 (reviewed: Q03591)

Alternative names: H factor-like protein 1, H36

All UniProt accessions (4): A0A8V8TNS5, A0A8V8TQ26, B1AKG0, Q03591

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. Can associate with lipoproteins and may play a role in lipid metabolism.

Subunit / interactions. Head-to-tail homodimer and heterodimer with CFHR2 or CFHR5. (Microbial infection) Interacts with C.albicans GPD2; the interaction is direct and leads to the degradation of C3.

Subcellular location. Secreted.

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

Post-translational modifications. N-glycosylated. Two forms are observed; one with a single side chain and the other with two.

Disease relevance. Hemolytic uremic syndrome, atypical, 1 (AHUS1) [MIM:235400] 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. A deletion encompassing CFHR1 and CFHR3 is associated with an increased risk of atypical hemolytic uremic syndrome, likely due to a defective regulation of complement activation. Some patients carrying the deletion have serum anti-CFH autoantibodies.

RefSeq proteins (8): NP_001366235, NP_001366236, NP_001366237, NP_001366238, NP_001366239, NP_001366240, NP_001366241, NP_002104* (*=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 (45 total): strand 17, disulfide bond 10, domain 5, sequence variant 4, helix 3, glycosylation site 2, signal peptide 1, chain 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3ZD2	X-RAY DIFFRACTION	1.99
4MUC	X-RAY DIFFRACTION	2.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03591-F1	89.21	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.

Disulfide bonds (10): 55–83, 87–129, 114–140, 147–190, 176–201, 208–251, 237–262, 266–317, 300–327, 23–72

Glycosylation sites (2): 126, 194

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-977606	Regulation of Complement cascade

MSigDB gene sets: 183 (showing top): LI_CISPLATIN_RESISTANCE_DN, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, JI_RESPONSE_TO_FSH_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PROTEIN_BINDING, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_1, HEIDENBLAD_AMPLICON_8Q24_DN, COUP_01, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_BINDING, GOBP_REGULATION_OF_IMMUNE_RESPONSE, MODULE_75, GOBP_COMPLEMENT_ACTIVATION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4

GO Biological Process (3): complement activation (GO:0006956), negative regulation of protein binding (GO:0032091), obsolete cytolysis by host of symbiont cells (GO:0051838)

GO Molecular Function (3): complement component C3b binding (GO:0001851), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), protein-containing complex (GO:0032991), blood microparticle (GO:0072562)

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

Protein interactions and networks

STRING

540 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CFHR1	C3	P01024	941
CFHR1	CFB	P00751	901
CFHR1	ADAMTS13	Q76LX8	832
CFHR1	CFI	P05156	812
CFHR1	DGKE	P52429	792
CFHR1	C2	P06681	739
CFHR1	MYBPH	Q13203	730
CFHR1	C4A	P01028	713
CFHR1	C4A	P01028	706
CFHR1	RBMS2	Q15434	691
CFHR1	C4BPB	P20851	690
CFHR1	PLG	P00747	670
CFHR1	THBD	P07204	655
CFHR1	CFP	P27918	645
CFHR1	ARMS2	P0C7Q2	625

IntAct

54 interactions, top by confidence:

A	B	Type	Score
CFH	CRP	psi-mi:“MI:0915”(physical association)	0.980
CFH	C3	psi-mi:“MI:0570”(protein cleavage)	0.870
CFI	C3	psi-mi:“MI:0407”(direct interaction)	0.850
CFHR1	CFHR1	psi-mi:“MI:0407”(direct interaction)	0.780
CFHR1	CFHR2	psi-mi:“MI:0915”(physical association)	0.780
CFHR1	CFHR2	psi-mi:“MI:0407”(direct interaction)	0.780
CFHR2	CFHR1	psi-mi:“MI:0915”(physical association)	0.780
PTX3	CFHR1	psi-mi:“MI:0407”(direct interaction)	0.720
	CFH	psi-mi:“MI:0914”(association)	0.700
CFHR1	CFH	psi-mi:“MI:0403”(colocalization)	0.640
CFHR1	ADGRE2	psi-mi:“MI:0407”(direct interaction)	0.630
CFHR1	ADGRE2	psi-mi:“MI:0915”(physical association)	0.630
CFHR1	ADGRE2	psi-mi:“MI:2364”(proximity)	0.630
CFHR1	C5	psi-mi:“MI:0407”(direct interaction)	0.610
C5	CFHR1	psi-mi:“MI:0915”(physical association)	0.610
C5	CFHR1	psi-mi:“MI:0407”(direct interaction)	0.610
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

BioGRID (5): CFHR1 (Affinity Capture-MS), CFHR1 (Affinity Capture-Western), CFHR1 (Affinity Capture-MS), CFHR1 (Affinity Capture-MS), PRDX4 (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: O62837, P05160, P06909, P08174, P08603, P14650, P15529, P36980, P49457, P68638, P68639, P79138, Q02985, Q03472, Q03591, Q26422, Q28085, Q53EL9, Q5R4D0, Q60401, Q9BXR6, Q01016, Q09101, Q501P1, A0JNA2, P17927, P19070, P28175, Q07968, Q29RN8, Q4LDE5, Q7TSK2, Q923L3, Q92496, A2AVA0, O02839, O08569, O19124, O62685, O88174

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CFHR1	“up-regulates activity”	C3	binding
CFHR1	“down-regulates activity”	CFH	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Regulation of Complement cascade	8	133.2×	4e-15

GO biological processes:

GO term	Partners	Fold	FDR
complement activation, alternative pathway	6	371.7×	3e-13
complement activation	6	234.1×	3e-12
inflammatory response	7	16.5×	2e-06

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	1
Uncertain significance	57
Likely benign	23
Benign	55

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
58538	GRCh38/hg38 1q31.3(chr1:196788148-196827586)x1	Pathogenic
1343371	NM_002113.3(CFHR1):c.887C>T (p.Ala296Val)	Likely pathogenic

SpliceAI

1009 predictions. Top by Δscore:

Variant	Effect	Δscore
1:196826850:T:TA	acceptor_gain	1.0000
1:196826851:G:A	acceptor_gain	1.0000
1:196828068:A:AG	acceptor_gain	1.0000
1:196828069:G:GG	acceptor_gain	1.0000
1:196830496:TTAG:T	acceptor_loss	1.0000
1:196830497:TAGAT:T	acceptor_loss	1.0000
1:196830498:A:AG	acceptor_gain	1.0000
1:196830498:A:C	acceptor_loss	1.0000
1:196830499:G:A	acceptor_loss	1.0000
1:196830499:G:GA	acceptor_gain	1.0000
1:196830499:G:GG	acceptor_gain	1.0000
1:196830683:G:GG	donor_gain	1.0000
1:196819899:GAAG:G	donor_gain	0.9900
1:196819900:AAGG:A	donor_loss	0.9900
1:196819901:AGGT:A	donor_loss	0.9900
1:196819902:GGT:G	donor_loss	0.9900
1:196819903:G:C	donor_loss	0.9900
1:196826828:GGACT:G	acceptor_gain	0.9900
1:196826848:T:TA	acceptor_gain	0.9900
1:196826857:T:TA	acceptor_gain	0.9900
1:196827003:CTG:C	donor_gain	0.9900
1:196827006:G:C	donor_loss	0.9900
1:196827006:G:GG	donor_gain	0.9900
1:196827007:T:TC	donor_loss	0.9900
1:196827008:AA:A	donor_loss	0.9900
1:196828064:A:AG	acceptor_gain	0.9900
1:196828065:CTCA:C	acceptor_loss	0.9900
1:196828066:TCAG:T	acceptor_loss	0.9900
1:196828067:CAGA:C	acceptor_loss	0.9900
1:196828068:A:AT	acceptor_loss	0.9900

AlphaMissense

2126 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:196828224:G:C	W195C	0.999
1:196828224:G:T	W195C	0.999
1:196830660:G:C	W256C	0.998
1:196830660:G:T	W256C	0.998
1:196826977:G:C	W134C	0.997
1:196826977:G:T	W134C	0.997
1:196828240:T:A	C201S	0.996
1:196828241:G:C	C201S	0.996
1:196828222:T:A	W195R	0.995
1:196828222:T:C	W195R	0.995
1:196826993:T:A	C140S	0.994
1:196826994:G:C	C140S	0.994
1:196828207:T:A	C190S	0.994
1:196828208:G:C	C190S	0.994
1:196830658:T:A	W256R	0.993
1:196830658:T:C	W256R	0.993
1:196825665:T:A	C83S	0.991
1:196825666:G:C	C83S	0.991
1:196826915:T:A	C114S	0.991
1:196826916:G:C	C114S	0.991
1:196825649:G:C	W77C	0.990
1:196825649:G:T	W77C	0.990
1:196826975:T:A	W134R	0.990
1:196826975:T:C	W134R	0.990
1:196830676:T:A	C262S	0.990
1:196830677:G:C	C262S	0.990
1:196826960:T:A	C129S	0.989
1:196826961:G:C	C129S	0.989
1:196828165:T:A	C176S	0.989
1:196828166:G:C	C176S	0.989

dbSNP variants (sampled 300 via entrez): RS1000643931 (1:196823542 T>C), RS1001189165 (1:196819523 T>C), RS1001262637 (1:196820225 C>T), RS1002887355 (1:196826434 G>A), RS1002918286 (1:196828527 G>A), RS1004431111 (1:196831145 C>T), RS1004804124 (1:196829324 T>G), RS1008073497 (1:196820873 CTT>C), RS1008520937 (1:196821480 A>C), RS1010356297 (1:196825912 T>G), RS1010619533 (1:196832578 ATATT>A), RS1010699349 (1:196823705 A>C,G), RS1014452912 (1:196819287 T>C), RS1016583330 (1:196819543 T>A), RS1018114136 (1:196821495 T>C)

Disease associations

OMIM: gene MIM:134371 | disease phenotypes: MIM:235400, MIM:603075, MIM:605714, MIM:614809

GenCC curated gene-disease

Disease	Classification	Inheritance
dense deposit disease	Supportive	Autosomal recessive
hemolytic uremic syndrome, atypical, susceptibility to, 1	Limited	Autosomal dominant
age related macular degeneration 1	Limited	Unknown

Mondo (9): hemolytic uremic syndrome, atypical, susceptibility to, 1 (MONDO:0009335), kidney disorder (MONDO:0005240), age related macular degeneration 1 (MONDO:0011285), primary ovarian failure (MONDO:0005387), cerebral amyloid angiopathy, APP-related (MONDO:0011583), C3 glomerulonephritis (MONDO:0013892), age-related macular degeneration (MONDO:0005150), chronic kidney disease (MONDO:0005300), dense deposit disease (MONDO:0019736)

Orphanet (12): Atypical hemolytic uremic syndrome (Orphanet:2134), Shiga toxin-associated hemolytic uremic syndrome (Orphanet:90038), ABeta amyloidosis, Dutch type (Orphanet:100006), ABetaL34V amyloidosis (Orphanet:324703), ABeta amyloidosis, Iowa type (Orphanet:324708), ABeta amyloidosis, Italian type (Orphanet:324713), ABetaA21G amyloidosis (Orphanet:324718), ABeta amyloidosis, Arctic type (Orphanet:324723), Hereditary cerebral amyloid angiopathy (Orphanet:85458), C3 glomerulonephritis (Orphanet:329931), NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619), NON RARE IN EUROPE: Age-related macular degeneration (Orphanet:279)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000529	Progressive visual loss
HP:0000608	Macular degeneration
HP:0000822	Hypertension
HP:0000979	Purpura
HP:0001250	Seizure
HP:0001259	Coma
HP:0001269	Hemiparesis
HP:0001873	Thrombocytopenia
HP:0001919	Acute kidney injury
HP:0001923	Reticulocytosis
HP:0001937	Microangiopathic hemolytic anemia
HP:0001945	Fever
HP:0001981	Schistocytosis
HP:0002014	Diarrhea
HP:0002381	Aphasia
HP:0003077	Hyperlipidemia
HP:0003138	Increased blood urea nitrogen
HP:0003259	Elevated circulating creatinine concentration
HP:0003584	Late onset
HP:0005356	Decreased circulating complement factor I concentration
HP:0005369	Decreased circulating complement factor H concentration
HP:0005416	Decreased circulating complement factor B concentration
HP:0005421	Decreased circulating complement C3 concentration
HP:0005575	Hemolytic-uremic syndrome
HP:0011506	Choroidal neovascularization
HP:0012643	Foveal hypopigmentation
HP:0025574	Macular hemorrhage
HP:0030499	Macular drusen

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001009_4	Nephropathy	3.000000e-10
GCST001679_9	Complement C3 and C4 levels	7.000000e-11
GCST001899_1	Age-related macular degeneration	1.000000e-16
GCST002655_5	IgA nephropathy	5.000000e-14
GCST003219_8	Advanced age-related macular degeneration	6.000000e-165
GCST005187_2	Matrix metalloproteinase-8 levels	2.000000e-35
GCST010284_2	Age-related macular degeneration (MTAG)	0.000000e+00
GCST90019042_1	Complement factor H-related protein 1 levels	1.000000e-57
GCST90019045_1	Complement factor H-related protein 4A levels	6.000000e-26

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004983	complement C3 measurement
EFO:1001492	atrophic macular degeneration
EFO:0600057	complement factor H-related protein 4A measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
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
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750
C566411	Macular Degeneration, Age-Related, 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases mutagenesis	3
methyleugenol	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	decreases expression	1
abrine	decreases expression	1
Air Pollutants	decreases expression	1
Cadmium	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	affects response to substance, increases expression, affects cotreatment	1
Progesterone	increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07403825	PHASE4	RECRUITING	Efficacy of Faricimab in Patients With Subretinal Hyper-reflective Material
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
NCT02761577	PHASE4	COMPLETED	A Prospective Study on Incidence and Prevention of Contrast-induced Nephropathy in Croatia