APOL1

Summary

APOL1 (apolipoprotein L1, HGNC:618) is a protein-coding gene on chromosome 22q12.3, encoding Apolipoprotein L1 (O14791). May play a role in lipid exchange and transport throughout the body.

This gene encodes a secreted high density lipoprotein which binds to apolipoprotein A-I. Apolipoprotein A-I is a relatively abundant plasma protein and is the major apoprotein of HDL. It is involved in the formation of most cholesteryl esters in plasma and also promotes efflux of cholesterol from cells. This apolipoprotein L family member may play a role in lipid exchange and transport throughout the body, as well as in reverse cholesterol transport from peripheral cells to the liver. Several different transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 8542 — RefSeq curated summary.

At a glance

• Gene–disease (curated): focal segmental glomerulosclerosis 4, susceptibility to (Definitive, ClinGen)
• GWAS associations: 7
• Clinical variants (ClinVar): 216 total — 1 pathogenic
• Phenotypes (HPO): 18
• Druggable target: yes
• MANE Select transcript: NM_003661

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:618
Approved symbol	APOL1
Name	apolipoprotein L1
Location	22q12.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000100342
Ensembl biotype	protein_coding
OMIM	603743
Entrez	8542

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 7 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000319136, ENST00000397278, ENST00000422471, ENST00000426053, ENST00000427990, ENST00000431184, ENST00000433768, ENST00000438034, ENST00000439680, ENST00000475519, ENST00000949540, ENST00000949541

RefSeq mRNA: 5 — MANE Select: NM_003661 NM_001136540, NM_001136541, NM_001362927, NM_003661, NM_145343

CCDS: CCDS13925, CCDS13926, CCDS46702

Canonical transcript exons

ENST00000397278 — 6 exons

Exon	Start	End
ENSE00000653597	36257319	36257407
ENSE00001909014	36265151	36267525
ENSE00003571060	36254937	36254999
ENSE00003572739	36261596	36261722
ENSE00003622803	36257083	36257136
ENSE00003901084	36253133	36253219

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 96.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.3214 / max 714.2223, expressed in 1274 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192036	8.5039	1054
192035	5.8175	1141

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	96.89	gold quality
right lobe of liver	UBERON:0001114	96.22	gold quality
liver	UBERON:0002107	94.65	gold quality
smooth muscle tissue	UBERON:0001135	94.51	gold quality
olfactory bulb	UBERON:0002264	94.50	silver quality
vermiform appendix	UBERON:0001154	94.35	gold quality
pericardium	UBERON:0002407	94.16	gold quality
upper lobe of left lung	UBERON:0008952	94.12	gold quality
caecum	UBERON:0001153	94.04	gold quality
upper lobe of lung	UBERON:0008948	93.82	gold quality
apex of heart	UBERON:0002098	93.52	gold quality
decidua	UBERON:0002450	93.25	gold quality
nasal cavity epithelium	UBERON:0005384	93.00	gold quality
right lung	UBERON:0002167	92.96	gold quality
omental fat pad	UBERON:0010414	92.70	gold quality
peritoneum	UBERON:0002358	92.69	gold quality
palpebral conjunctiva	UBERON:0001812	92.43	gold quality
urinary bladder	UBERON:0001255	92.37	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.23	gold quality
type B pancreatic cell	CL:0000169	91.93	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.93	gold quality
right uterine tube	UBERON:0001302	91.85	gold quality
pylorus	UBERON:0001166	91.66	gold quality
cardia of stomach	UBERON:0001162	91.63	gold quality
spleen	UBERON:0002106	91.60	gold quality
mucosa of urinary bladder	UBERON:0001259	91.41	gold quality
monocyte	CL:0000576	91.12	gold quality
rectum	UBERON:0001052	90.92	gold quality
mucosa of stomach	UBERON:0001199	90.90	gold quality
metanephros cortex	UBERON:0010533	90.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-53	no	1753.83
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting APOL1, 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-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-136-5P	99.50	67.26	1153
HSA-MIR-548AV-3P	99.43	68.50	1721
HSA-MIR-584-3P	99.35	67.69	1082
HSA-MIR-3199	99.17	65.19	696
HSA-MIR-8052	99.17	65.01	719
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-3152-3P	99.10	66.35	678
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-6749-3P	99.00	65.73	1443
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-326	98.25	66.44	1565
HSA-MIR-6787-3P	97.75	66.17	1233
HSA-MIR-7154-3P	97.65	65.02	985
HSA-MIR-3144-5P	97.64	65.45	646
HSA-MIR-6886-3P	96.96	66.36	844
HSA-MIR-6857-3P	96.70	65.43	915
HSA-MIR-597-3P	96.46	68.03	1035
HSA-MIR-541-3P	96.07	66.11	1271

Literature-anchored findings (GeneRIF, showing 40)

• APOL1 has been found only in humans and African green monkeys (PMID:11944986)
• ApoL-I is the trypanosome lytic factor of normal human serum, and serum resistance associated protein confers resistance to lysis by interaction with apoL-I in the lysosome (PMID:12621437)
• APOL1 is a senescence-associated gene in normal human oral keratinocytes. (PMID:12837283)
• identified as component of trypanosome lytic factor 1 (TLF1); apoL-I alone is not sufficient for optimal trypanosome lytic activity in human TLF1. (PMID:15500911)
• The Apolipoprotein L-I (apoL-I) is present on a subset of HDL particles and is positively correlated with plasma triglycerides (TGs). (PMID:15604524)
• contains a membrane pore-forming domain; APOL1 was targeted to the lysosomal membrane of Trypanosoma brucei & triggered depolarization of the membrane, continuous influx of chloride & subsequent osmotic swelling of the lysosome until the trypanosome lysed (PMID:16020735)
• apoL-I is responsible for the trypanolytic activity of normal human serum, whereas Hpr allows fast uptake of the carrier HDL particles in trypanolysis (PMID:17360487)
• Infection by Trypanosoma brucei brucei causes hemolysis that triggers activation of trypanosome lytic factor by formation of haptoglobin-related protein-hemoglobin complexes, enhancing binding, trypanolytic activity, and clearance of parasites (PMID:17845074)
• Apolipoprotein L1 is a novel Bcl-2 homology domain 3-only lipid-binding protein, induces autophagic cell death (PMID:18505729)
• An association of APOL1, 2 and 4 with schizophrenia was establised. (PMID:18632255)
• APOL1 is the first BH3-only protein with lipid binding activity that, when overproduced intracellularly, induces autophagic cell death. (PMID:18927493)
• The Lys166Glu and Ile244Met polymorphisms in apoL-I gene are associated with TG levels in subjects with endogenous hypertriglyceridemia in Chinese. However, these polymorphisms were not associated with the risk of HTG in the population. (PMID:19239905)
• at low pH. Trypanosome lytic factor, apoL-1, and apoA-1 exhibit specificity for anionic membranes, whereas Hpr permeabilizes both anionic and zwitterionic membranes. (PMID:19324878)
• This study did not find DAOA significant associations with schizophrenia. Thus, APOL1 genes do not fit the antagonistic pleiotropy model. (PMID:20483474)
• Coding region mutations in the APOL1 gene are highly associated with end stage kidney disease in African and Hispanic Americans. (PMID:20635188)
• missense mutations with predicted functional effects in the APOL1 gene are significantly more associated with ESKD than all previously reported SNPs in MYH9 (PMID:20635188)
• in African Americans, focal segmental glomerulosclerosis and hypertension-attributed end-stage kidney disease are associated with 2 independent sequence variants in APOL1 gene; only kidney disease-associated ApoL1 variants lysed Trypanosoma rhodesiense (PMID:20647424)
• A risk allele for focal segmental glomerulosclerosis in African Americans is located within a region containing APOL1 and MYH9. (PMID:20668430)
• show that trypanosome lytic factor-1 resistance in Trypanosoma brucei brucei is caused by reduced expression of the Hp/Hb receptor gene. (PMID:20805508)
• Susceptibility of African-Americans to nondiabetic chronic kidney disease is likely due to functional variants of APOL1 that have been selected for because of their ability to protect from parasital infection (PMID:21080072)
• APOL1 genotype has a role in failure of kidney after renal transplantation in African American deceased donors (PMID:21486385)
• The powerful evolutionary selection pressure of an infectious pathogen in West Africa favored the spread of APOL1 variants that protect against a lethal form of African sleeping sickness but are highly associated with an increased risk of kidney disease (PMID:21537348)
• type 2 diabetic nephropathy-associated FRMD3 SNPs were detectable in African Americans only after accounting for MYH9, with differential effects for APOL1 (PMID:21698141)
• Data provide insight into the pathobiology of renal dysfunction in SCD, suggesting that MYH9 and APOL1 are both associated with risk. (PMID:21910715)
• Coding variants in the apolipoprotein L1 gene are strongly associated with non-diabetic nephropathy in African Americans. (PMID:21931123)
• The coinciding absence of HIVAN and the APOL1 risk variants among HIV-infected individuals of Ethiopian ancestry support a Western rather than Pan-African ancestry risk for end-stage kidney disease. (PMID:21968148)
• Comparing the renal distribution of APOL1 in nondiabetic kidney disease to normal kidney suggests that a previously unrecognized arteriopathy may contribute to disease pathogenesis in patients of African ancestry. (PMID:21997392)
• African Americans carrying two APOL1 risk alleles have a greatly increased risk for glomerular disease, and APOL1-associated focal segmental glomerulosclerosis occurs earlier and progresses to kidney failure more rapidly. (PMID:21997394)
• Our data suggest that more than 3 million African Americans likely have the high-risk genotype and are at markedly increased risk for nondiabetic chronic kidney disease. (PMID:21997396)
• These data further support the strong association of genetic variants in APOL1 with susceptibility to focal segmental glomerulosclerosis and HIV nephropathy among African Americans. (PMID:21997397)
• Genetic variations in APOL1 identify African Americans that initiate chronic hemodialysis at a younger age. (PMID:21997398)
• A genome-wide association study provides additional and independent evidence that APOL1 variants contribute to nondiabetic nephropathy in African Americans. (PMID:22119407)
• an association between APOL1 variants and renal outcomes in non-HIVAN kidney disease, suggesting a possible use for APOL1 genotyping to help guide the care of HIV-infected patients. (PMID:22135313)
• The current study has provided evidence that genetic variations of polymorphic sites in apoL-I gene might affect plasma TG variability in nonobese Chinese subjects, but are not associated with obesity in the population. (PMID:22239288)
• APOL1 allelic variants are associated with lower age of dialysis initiation and thereby increased dialysis vintage in African and Hispanic Americans with non-diabetic end-stage kidney disease. (PMID:22357707)
• conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation (PMID:22487534)
• There were no differences in the pathological findings of HIV-associated nephropathy and the number of APOL1 risk alleles. (PMID:22495294)
• discussion of role of ApoL1 in renal cell carcinoma and chronic kidney disease: Intracellularly, elevated ApoL1 can induce autophagy and autophagy-associated cell death, which may be critical in maintenance of cellular homeostasis in kidney. [REVIEW] (PMID:22569246)
• APOL1 expression is likely induced by bloodborne Trypanosoma brucei gambiense, but is not related to resistance/susceptibility in its human host. (PMID:22691369)
• Report association of APOL1 variants with mild kidney disease in the first-degree relatives of African American patients with non-diabetic end-stage renal disease. (PMID:22695330)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
danio_rerio	apol	ENSDARG00000073718
mus_musculus	Apol10b	ENSMUSG00000050014
mus_musculus	Apol10a	ENSMUSG00000050982
mus_musculus	Apol9a	ENSMUSG00000057346
mus_musculus	Apol9b	ENSMUSG00000068246
mus_musculus	Apol11a	ENSMUSG00000091650
mus_musculus	Apol11b	ENSMUSG00000091694
rattus_norvegicus	Apol9a	ENSRNOG00000023410
rattus_norvegicus	Apol3l1	ENSRNOG00000042771
rattus_norvegicus	LOC120093819	ENSRNOG00000069032
rattus_norvegicus		ENSRNOG00000081988
caenorhabditis_elegans		WBGENE00017219
caenorhabditis_elegans		WBGENE00017220

Paralogs (6): APOL4 (ENSG00000100336), APOL3 (ENSG00000128284), APOL5 (ENSG00000128313), APOL2 (ENSG00000128335), APOLD1 (ENSG00000178878), APOL6 (ENSG00000221963)

Protein

Protein identifiers

Apolipoprotein L1 — O14791 (reviewed: O14791)

Alternative names: Apolipoprotein L, Apolipoprotein L-I

All UniProt accessions (4): O14791, B1AH94, B1AH95, B1AH96

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in lipid exchange and transport throughout the body. May participate in reverse cholesterol transport from peripheral cells to the liver. A component of trypanosome lytic factor of human serum; plays a crucial role in killing Trypanosoma brucei by forming pores in parasite lysosomal membranes and sensitizing T.brucei to oxidation-stimulated osmotic lysis.

Subunit / interactions. In plasma, interacts with APOA1 and mainly associated with large high density lipoprotein particles. (Microbial infection) Interacts (via C-terminus) with serum resistance-associated protein from Trypanosoma brucei rhodesiense; the interaction results in inactivation of APOL1 pore-forming activity and T.brucei rhodesiense resistance to lysis by normal human serum.

Subcellular location. Secreted.

Tissue specificity. Plasma. Found on APOA-I-containing high density lipoprotein (HDL3). Expressed in pancreas, lung, prostate, liver, placenta and spleen.

Post-translational modifications. Phosphorylated by FAM20C in the extracellular medium.

Disease relevance. Focal segmental glomerulosclerosis 4 (FSGS4) [MIM:612551] A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. Major isoform.

Similarity. Belongs to the apolipoprotein L family.

Isoforms (3)

UniProt ID	Names	Canonical?
O14791-1	1, A	yes
O14791-2	2, B
O14791-3	3

RefSeq proteins (5): NP_001130012, NP_001130013, NP_001349856, NP_003652, NP_663318 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008405	ApoL	Family

Pfam: PF05461

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

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
7LFA	X-RAY DIFFRACTION	1.86
7LFB	X-RAY DIFFRACTION	1.91
7LF7	X-RAY DIFFRACTION	2.03
7LFD	X-RAY DIFFRACTION	2.16
7L6K	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14791-F1	52.94	0.02

Antibody-complex structures (SAbDab): 4 — 7LF7, 7LFA, 7LFB, 7LFD

Functional residue map

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

Post-translational modifications (2): 311, 314

Glycosylation sites (1): 261

Mutagenesis-validated functional residues (14):

Position	Phenotype
249	results in the loss of trypanolytic activity; when associated with k-253 and k-256.
253	results in the loss of trypanolytic activity; when associated with k-249 and k-256.
256	results in the loss of trypanolytic activity; when associated with k-249 and k-253.
345	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense.
352	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense.
354	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense.
378	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense and trypanolytic but no
382	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense and trypanolytic but no
385	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense and trypanolytic but no
386–389	reduces interaction with serum resistance-associated protein from trypanosoma brucei rhodesiense. results in the ability

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-2168880	Scavenging of heme from plasma
R-HSA-381426	Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)
R-HSA-8957275	Post-translational protein phosphorylation
R-HSA-2173782	Binding and Uptake of Ligands by Scavenger Receptors
R-HSA-392499	Metabolism of proteins
R-HSA-5653656	Vesicle-mediated transport
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 236 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_LIPOPROTEIN_METABOLIC_PROCESS, GOZGIT_ESR1_TARGETS_DN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_CHLORIDE_TRANSPORT, GOBP_LIPID_METABOLIC_PROCESS, BROWN_MYELOID_CELL_DEVELOPMENT_UP, MODULE_88, GOBP_BIOLOGICAL_PROCESS_INVOLVED_IN_INTERACTION_WITH_SYMBIONT, MODULE_236

GO Biological Process (8): lipid transport (GO:0006869), cholesterol metabolic process (GO:0008203), lipoprotein metabolic process (GO:0042157), innate immune response (GO:0045087), obsolete cytolysis by host of symbiont cells (GO:0051838), chloride transmembrane transport (GO:1902476), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202)

GO Molecular Function (3): chloride channel activity (GO:0005254), lipid binding (GO:0008289), protein binding (GO:0005515)

GO Cellular Component (7): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), endoplasmic reticulum lumen (GO:0005788), membrane (GO:0016020), very-low-density lipoprotein particle (GO:0034361), high-density lipoprotein particle (GO:0034364), blood microparticle (GO:0072562)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Metabolism of proteins	2
Binding and Uptake of Ligands by Scavenger Receptors	1
Post-translational protein modification	1
Vesicle-mediated transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
binding	2
transport	1
lipid localization	1
sterol metabolic process	1
secondary alcohol metabolic process	1
protein metabolic process	1
immune response	1
defense response to symbiont	1
chloride transport	1
monoatomic anion transmembrane transport	1
primary metabolic process	1
lipid metabolic process	1
monoatomic anion channel activity	1
chloride transmembrane transporter activity	1
endoplasmic reticulum	1
intracellular organelle lumen	1
triglyceride-rich plasma lipoprotein particle	1
plasma lipoprotein particle	1
extracellular region	1

Protein interactions and networks

STRING

1202 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APOL1	HPR	P00739	998
APOL1	APOA1	P02647	993
APOL1	MYH9	P35579	898
APOL1	APOE	P02649	881
APOL1	APOF	Q13790	854
APOL1	INF2	Q27J81	831
APOL1	NPHS2	Q9NP85	821
APOL1	CD2AP	Q9Y5K6	806
APOL1	NPHS1	O60500	791
APOL1	PLCE1	Q9P212	775
APOL1	APOA4	P06727	755
APOL1	APOA2	P02652	747
APOL1	APOC3	P02656	740
APOL1	APOM	O95445	740
APOL1	TRPC6	Q9Y210	733

IntAct

9 interactions, top by confidence:

A	B	Type	Score
APOL1	CDC23	psi-mi:“MI:0915”(physical association)	0.560
CDC23	APOL1	psi-mi:“MI:0915”(physical association)	0.560
APOL1	FAM20C	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
IGHM	APOL1	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (5): CDC23 (Two-hybrid), APOA1 (Co-purification), APOL1 (Affinity Capture-MS), MYH7 (Cross-Linking-MS (XL-MS)), VLDLR (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0A140LIF8, A0A2P1BRP3, A0A386CAB9, A0JN92, A1A4Y4, O14791, P27473, P59045, P86448, P86449, Q0GUM3, Q13075, Q3B7D9, Q3T9E4, Q3TL54, Q53G44, Q5NCI0, Q5RFJ8, Q60766, Q62293, Q66X01, Q66X03, Q66X05, Q66X22, Q6AYC2, Q6ZSC3, Q7Z745, Q84WJ0, Q86W28, Q8BV66, Q8BVM9, Q8C6J9, Q8CBA2, Q8CCN1, Q8TCB0, Q8TCY9, Q8TD90, Q90597, Q99388, Q99J64

Diamond homologs: O14791, O95236, Q9BPW4, Q9BQE5, Q9BWW8, Q9BWW9, Q96LR9

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	102
Likely benign	46
Benign	39

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
221996	GRCh37/hg19 22q12.3-13.1(chr22:35680095-38098981)x1	Pathogenic

SpliceAI

922 predictions. Top by Δscore:

Variant	Effect	Δscore
22:36257316:AAG:A	acceptor_gain	1.0000
22:36261719:CCAGG:C	donor_loss	1.0000
22:36261721:AGGT:A	donor_loss	1.0000
22:36261722:GGTA:G	donor_loss	1.0000
22:36261723:GT:G	donor_loss	1.0000
22:36261724:T:G	donor_loss	1.0000
22:36265150:GGAAT:G	acceptor_gain	1.0000
22:36253219:GGTA:G	donor_loss	0.9900
22:36253220:G:GG	donor_gain	0.9900
22:36253220:G:T	donor_loss	0.9900
22:36253221:TAAGT:T	donor_loss	0.9900
22:36257317:A:G	acceptor_gain	0.9900
22:36261590:A:AG	acceptor_gain	0.9900
22:36261591:A:G	acceptor_gain	0.9900
22:36261593:TA:T	acceptor_loss	0.9900
22:36261594:A:AG	acceptor_gain	0.9900
22:36261594:A:G	acceptor_loss	0.9900
22:36261595:G:GG	acceptor_gain	0.9900
22:36261595:GA:G	acceptor_gain	0.9900
22:36261595:GAG:G	acceptor_loss	0.9900
22:36261595:GAGA:G	acceptor_gain	0.9900
22:36261723:G:GG	donor_gain	0.9900
22:36265145:GTGCA:G	acceptor_loss	0.9900
22:36265148:CA:C	acceptor_loss	0.9900
22:36265149:A:AG	acceptor_gain	0.9900
22:36265149:A:AT	acceptor_loss	0.9900
22:36265150:G:GG	acceptor_gain	0.9900
22:36265150:GGA:G	acceptor_gain	0.9900
22:36253216:CTTG:C	donor_gain	0.9800
22:36253217:TTG:T	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000027871 (22:36267781 A>T), RS1000211287 (22:36263418 T>G), RS1000304612 (22:36263235 G>A), RS1000331769 (22:36254301 A>C), RS1000441417 (22:36267568 C>T), RS1000932100 (22:36253144 G>A,C), RS1001043408 (22:36266715 C>A,T), RS1001057990 (22:36262519 C>A,T), RS1001363426 (22:36253389 A>G), RS1001543997 (22:36267275 G>A), RS1001669005 (22:36263179 T>A), RS1001673333 (22:36257784 C>A), RS1001842903 (22:36253296 T>C), RS1001914693 (22:36267163 G>A), RS1001942563 (22:36267292 T>C)

Disease associations

OMIM: gene MIM:603743 | disease phenotypes: MIM:612551

GenCC curated gene-disease

Disease	Classification	Inheritance
focal segmental glomerulosclerosis 4, susceptibility to	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
focal segmental glomerulosclerosis 4, susceptibility to	Definitive	AR

Mondo (5): focal segmental glomerulosclerosis 4, susceptibility to (MONDO:0012931), glomerulonephritis (MONDO:0002462), proteinuria (MONDO:0003634), steroid-resistant nephrotic syndrome (MONDO:0044765), focal segmental glomerulosclerosis (MONDO:0100313)

Orphanet (1): Sporadic idiopathic steroid-resistant nephrotic syndrome (Orphanet:84271)

HPO phenotypes

18 total (19 of 18 shown, HPO-id order):

HPO	Term
HP:0000093	Proteinuria
HP:0000097	Focal segmental glomerulosclerosis
HP:0000707	Abnormality of the nervous system
HP:0000737	Irritability
HP:0000969	Edema
HP:0001945	Fever
HP:0001967	Diffuse mesangial sclerosis
HP:0002027	Abdominal pain
HP:0002315	Headache
HP:0002586	Peritonitis
HP:0003073	Hypoalbuminemia
HP:0003774	Stage 5 chronic kidney disease
HP:0010982	Polygenic inheritance
HP:0011947	Respiratory tract infection
HP:0012579	Minimal change glomerulonephritis
HP:0012622	Chronic kidney disease
HP:0031504	Foamy urine
HP:0100539	Periorbital edema
HP:0000099	Glomerulonephritis

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST000741_1	Glomerulosclerosis	5.000000e-13
GCST003098_36	Diabetic kidney disease	2.000000e-06
GCST003098_7	Diabetic kidney disease	5.000000e-07
GCST006585_672	Blood protein levels	6.000000e-06
GCST006585_991	Blood protein levels	1.000000e-19
GCST006814_7	End-stage renal disease	6.000000e-76
GCST008395_15	End-stage kidney disease	2.000000e-09

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D005921	Glomerulonephritis	C12.050.351.968.419.570.363; C12.200.777.419.570.363; C12.950.419.570.363
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
D011507	Proteinuria	C12.050.351.968.934.734; C12.200.777.934.734; C12.950.934.734; C23.888.942.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680021 (SINGLE PROTEIN)

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

ChEMBL bioactivities

139 potent at pChembl≥5 of 139 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.60	IC50	0.25	nM	CHEMBL5087702
9.60	IC50	0.25	nM	CHEMBL5077676
9.60	IC50	0.25	nM	CHEMBL5076950
9.60	IC50	0.25	nM	CHEMBL5080571
9.60	IC50	0.25	nM	CHEMBL5093385
9.60	IC50	0.25	nM	CHEMBL5094500
9.60	IC50	0.25	nM	CHEMBL5081620
9.60	IC50	0.25	nM	CHEMBL5089988
9.60	IC50	0.25	nM	CHEMBL5080245
9.60	IC50	0.25	nM	CHEMBL5087854
9.60	IC50	0.25	nM	CHEMBL5093715
9.60	IC50	0.25	nM	CHEMBL5084952
9.60	IC50	0.25	nM	CHEMBL5076369
9.60	IC50	0.25	nM	CHEMBL5091210
9.60	IC50	0.25	nM	CHEMBL5086503
9.60	IC50	0.25	nM	CHEMBL5091964
9.60	IC50	0.25	nM	CHEMBL5093734
9.60	IC50	0.25	nM	CHEMBL5080929
9.60	IC50	0.25	nM	CHEMBL5082430
9.60	IC50	0.25	nM	CHEMBL5082742
9.60	IC50	0.25	nM	CHEMBL5085955
9.60	IC50	0.25	nM	CHEMBL5085019
9.60	IC50	0.25	nM	CHEMBL5082103
9.60	IC50	0.25	nM	CHEMBL5092511
9.60	IC50	0.25	nM	CHEMBL5081854
9.60	IC50	0.25	nM	CHEMBL5092615
9.60	IC50	0.25	nM	CHEMBL5093063
9.60	IC50	0.25	nM	CHEMBL5080254
9.60	IC50	0.25	nM	CHEMBL5094600
9.60	IC50	0.25	nM	CHEMBL5074357
9.60	IC50	0.25	nM	CHEMBL5094544
9.60	IC50	0.25	nM	CHEMBL5081065
9.60	IC50	0.25	nM	CHEMBL5070651
9.60	IC50	0.25	nM	CHEMBL5076729
9.60	IC50	0.25	nM	CHEMBL5070196
9.60	IC50	0.25	nM	CHEMBL5090454
9.60	IC50	0.25	nM	CHEMBL5088723
9.60	IC50	0.25	nM	CHEMBL5080712
9.60	IC50	0.25	nM	CHEMBL5079082
9.60	IC50	0.25	nM	CHEMBL5083779
9.60	IC50	0.25	nM	CHEMBL5091162
9.60	IC50	0.25	nM	CHEMBL5084244
9.60	IC50	0.25	nM	CHEMBL5087672
9.60	IC50	0.25	nM	CHEMBL5094530
9.60	IC50	0.25	nM	CHEMBL5078098
9.60	IC50	0.25	nM	CHEMBL5082503
9.60	IC50	0.25	nM	CHEMBL5086262
9.60	IC50	0.25	nM	CHEMBL5089404
9.60	IC50	0.25	nM	CHEMBL5082754
9.60	IC50	0.25	nM	CHEMBL5089252

PubChem BioAssay actives

12 with measured affinity, of 12 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
3-[5-(2-chloro-4,6-difluorophenyl)-2-(4-chlorophenyl)-1H-pyrrol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0005	uM
3-[5-tert-butyl-2-[4-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0016	uM
3-[2-(4-chlorophenyl)-4-fluoro-5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0020	uM
3-[2-(4-chlorophenyl)-5-[1-(trifluoromethyl)cyclopropyl]-1H-pyrrol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0025	uM
N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]-3-[5-[1-(trifluoromethyl)cyclopropyl]-2-[4-(trifluoromethyl)phenyl]-1H-pyrrol-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0025	uM
3-[2-(4-chlorophenyl)-5-(2,4,6-trifluorophenyl)-1H-pyrrol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	2022015: Inhibition of wild type APOL1 containing G0 in human U2OS cells incubated for 80 mins by thallium flux based FLIPR assay	ic50	0.0032	uM
3-[2-(4-cyanophenyl)-5,7-difluoro-1H-indol-3-yl]-N-[(3S)-2-oxopyrrolidin-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM
3-[5,7-difluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4S)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM
N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]-3-[2-(4-methoxyphenyl)-1H-indol-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM
3-[7-cyano-5-fluoro-2-(4-fluorophenyl)-1H-indol-3-yl]-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM
3-(7-fluoro-2-phenyl-1H-indol-3-yl)-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM
3-(5,6-difluoro-2-phenyl-1H-indol-3-yl)-N-[(3S,4R)-4-hydroxy-2-oxopyrrolidin-3-yl]propanamide	1678545: Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	ic50	0.2500	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	3
Cyclosporine	decreases expression, increases expression	3
bisphenol A	affects expression, increases expression	2
Acetaminophen	decreases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	2
Nickel	affects binding, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	decreases expression	2
aristolochic acid I	decreases expression	1
sotorasib	affects cotreatment, increases expression	1
TL8-506	affects cotreatment, increases expression	1
quinone	increases expression, increases reaction	1
triphenyl phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases expression	1
sulindac sulfide	decreases expression	1
ochratoxin A	decreases expression	1
ciglitazone	affects binding, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression, increases reaction	1
trametinib	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Air Pollutants	increases abundance, decreases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4672961	Binding	Inhibition of APOL1 (unknown origin) in HEK293 cells assessed as thallium influx incubated for 30 mins by FLIPR based thallium influx assay	Novel APOL1 Inhibitors for Treating Kidney Diseases. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00426348	PHASE4	COMPLETED	A Study of the Antioxidant Probucol Combined With Valsartan in Patients With IgA Nephropathy
NCT00862693	PHASE4	UNKNOWN	Calcitriol in the Treatment of Immunoglobulin A Nephropathy
NCT02063100	PHASE4	UNKNOWN	Efficacy and Safety of Shenyankangfu Tablets for Primary Glomerulonephritis
NCT02523768	PHASE4	TERMINATED	Prevention in Recipients With Primary IgA Nephropathy of Recurrence After Kidney Transplantation: ATG-F Versus Basiliximab as Induction Immunosuppressive Treatment
NCT04349683	PHASE4	UNKNOWN	Efficacy and Safety of Jinshuibao for Patients With Chronic Kidney Disease Due to Glomerulonephritis
NCT04662723	PHASE4	RECRUITING	Multicentre Clinical Study to Evaluate the Effect of Personalized Therapy on Patients With Immunoglobulin A Nephropathy.
NCT00067990	PHASE4	COMPLETED	Angiotensin II Blockade for Chronic Allograft Nephropathy
NCT00234871	PHASE4	COMPLETED	Tarka® vs. Lotrel® in Hypertensive, Diabetic Subjects With Renal Disease (TANDEM)
NCT00241085	PHASE4	COMPLETED	Effect of Valsartan on Proteinuria in Patients With Hypertension and Diabetes Mellitus
NCT00369538	PHASE4	SUSPENDED	Specific Blockage of Angiotensine 2 and Podocyturia in Glomerular Nephropathies With Hypertension and Proteinuria
NCT00508898	PHASE4	WITHDRAWN	The Efficacy and Safety of Calcitriol for the Treatment of Lupus Nephritis and Persistent Proteinuria
NCT00550095	PHASE4	COMPLETED	To Assess the Effects of Valsartan on Albuminuria/Proteinuria in Hypertensive Patients With Type 2 Diabetes Mellitus
NCT00674596	PHASE4	COMPLETED	The Effect of Renin Angiotensin System Blockage (RAS) Blockade On PTX3 Levels In Diabetic Patients With Proteinuria
NCT00858299	PHASE4	UNKNOWN	The Change of Urinary Angiotensinogen Excretion After Valsartan Treatment in Patients With Persistent Proteinuria
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
NCT00921570	PHASE4	COMPLETED	The Effects of Renin Angiotensin System Blockage (RAS), Calcium Channel Blocker and Combined Drugs on TWEAK, PTX3 and FMD Levels in Diabetic Proteinuric Patients With Hypertension
NCT00961207	PHASE4	TERMINATED	Triple Blockade of the Renin Angiotensin Aldosterone System in Diabetic (Type 1&2) Proteinuric Patients
NCT01169857	PHASE4	WITHDRAWN	Velcade for Proliferative Lupus Nephritis
NCT01219413	PHASE4	COMPLETED	Influence of Aliskiren on Proteinuria
NCT01386554	PHASE4	COMPLETED	Acthar for Treatment of Proteinuria in Membranous Nephropathy Patients
NCT01512862	PHASE4	UNKNOWN	Anti-proteinuric Effect of Calcitriol in Non-diabetic Kidney Disease Patients
NCT01541267	PHASE4	COMPLETED	The Effect of Various Types of the Renin-angiotensin-aldosterone System Blockade on Proteinuria
NCT01637259	PHASE4	COMPLETED	MARCH Renal Substudy
NCT01703234	PHASE4	COMPLETED	FGF-23 and Endothelial Dysfunction in Diabetic Proteinuric Patients
NCT01820832	PHASE4	UNKNOWN	Oral Calcitriol for Reduction of Mild Proteinuria in Patients With CKD
NCT01827202	PHASE4	COMPLETED	RAS Quantification in Patients With Aliskiren or Candesartan
NCT02057523	PHASE4	TERMINATED	Acthar as Rescue Therapy for Transplant Glomerulopathy in Kidney Transplant Recipients
NCT02382523	PHASE4	WITHDRAWN	Acthar on Proteinuria in IgA Nephropathy Patients
NCT02522650	PHASE4	UNKNOWN	A Crossover Pilot Study of the Effect of Amiloride on Proteinuria
NCT03195023	PHASE4	UNKNOWN	Effect of RAS Blockers on CKD Progression in Elderly Patients With Non Proteinuric Nephropathies (PROERCAN01)
NCT03550859	PHASE4	UNKNOWN	HMG-CoA Reductase add-on in Chronic Kidney Disease Patients With Proteinuria
NCT03983551	PHASE4	COMPLETED	Comparing the Renal Effect of Dipeptidyl-peptidase 4 Inhibitors and Sulfonylureas
NCT04531397	PHASE4	WITHDRAWN	Efficacy and Safety of Dapagliflozin in Children With Proteinuric Chronic Kidney Disease
NCT04534270	PHASE4	COMPLETED	Efficacy and Safety of Dapagliflozin in Children With Proteinuria
NCT06374043	PHASE4	COMPLETED	Decentralized N=1 Study: A Feasible Approach to Evaluate Individual Therapy Response to Dapagliflozin.
NCT07030894	PHASE4	RECRUITING	Nefecon and Ambrisentan in IgA Nephropathy
NCT07219121	PHASE4	RECRUITING	Sparsentan in Posttransplant Immunoglobulin A Nephropathy or Focal Segmental Glomerulosclerosis
NCT07358520	PHASE4	NOT_YET_RECRUITING	Clinical Study on the Use of Huaier Granules for the Treatment of Proteinuria Related to Bevacizumab and Anlotinib in Lung Cancer Patients
NCT03408405	PHASE4	WITHDRAWN	ACTHAR Gel for Drug REsistant Nephrotic Syndrome in Children
NCT01129557	PHASE4	TERMINATED	Aldosterone Breakthrough During Diovan, Tekturna, and Combination Therapy in Patients With Proteinuric Kidney Disease