XPNPEP3

Summary

XPNPEP3 (X-prolyl aminopeptidase 3, HGNC:28052) is a protein-coding gene on chromosome 22q13.2, encoding Xaa-Pro aminopeptidase 3 (Q9NQH7). Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala.

The protein encoded by this gene belongs to the family of X-pro-aminopeptidases that utilize a metal cofactor, and remove the N-terminal amino acid from peptides with a proline residue in the penultimate position. This protein has been shown to localize to the mitochondria of renal cells, and have a role in ciliary function. Mutations in this gene are associated with nephronophthisis-like nephropathy-1. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene, however, expression of some of these isoforms in vivo is not known.

Source: NCBI Gene 63929 — RefSeq curated summary.

At a glance

• Gene–disease (curated): nephronophthisis-like nephropathy 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 10
• Clinical variants (ClinVar): 384 total — 7 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_022098

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28052
Approved symbol	XPNPEP3
Name	X-prolyl aminopeptidase 3
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	APP3, NPHPL1, ICP55
Ensembl gene	ENSG00000196236
Ensembl biotype	protein_coding
OMIM	613553
Entrez	63929

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 6 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 nonsense_mediated_decay

ENST00000357137, ENST00000417688, ENST00000428799, ENST00000465258, ENST00000482652, ENST00000614001, ENST00000904508, ENST00000904509, ENST00000926395, ENST00000950134

RefSeq mRNA: 2 — MANE Select: NM_022098 NM_001204827, NM_022098

CCDS: CCDS14007, CCDS74869

Canonical transcript exons

ENST00000357137 — 10 exons

Exon	Start	End
ENSE00001430265	40926269	40932815
ENSE00001811392	40857148	40857245
ENSE00003470762	40922333	40922513
ENSE00003485855	40907587	40907649
ENSE00003515949	40868999	40869115
ENSE00003518412	40881770	40882177
ENSE00003571075	40924362	40924482
ENSE00003602226	40914239	40914324
ENSE00003635120	40886313	40886515
ENSE00003682252	40909122	40909235

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 90.89.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.7688 / max 139.8894, expressed in 1808 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192433	11.8779	1789
192434	10.6565	1780
192432	0.2128	72
192435	0.0216	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	90.89	gold quality
bronchial epithelial cell	CL:0002328	89.46	gold quality
sperm	CL:0000019	89.02	gold quality
right testis	UBERON:0004534	88.98	gold quality
left testis	UBERON:0004533	88.81	gold quality
testis	UBERON:0000473	87.26	gold quality
male germ cell	CL:0000015	86.70	silver quality
epithelium of bronchus	UBERON:0002031	85.09	gold quality
adrenal tissue	UBERON:0018303	84.61	gold quality
bronchus	UBERON:0002185	84.56	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.24	gold quality
caput epididymis	UBERON:0004358	83.41	gold quality
tibia	UBERON:0000979	83.32	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.07	gold quality
liver	UBERON:0002107	82.66	gold quality
stromal cell of endometrium	CL:0002255	82.61	gold quality
colonic epithelium	UBERON:0000397	82.46	gold quality
muscle of leg	UBERON:0001383	82.31	gold quality
calcaneal tendon	UBERON:0003701	82.24	gold quality
gastrocnemius	UBERON:0001388	82.19	gold quality
parietal pleura	UBERON:0002400	82.01	gold quality
pituitary gland	UBERON:0000007	81.90	gold quality
germinal epithelium of ovary	UBERON:0001304	81.89	gold quality
right lobe of liver	UBERON:0001114	81.75	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.61	gold quality
adenohypophysis	UBERON:0002196	81.34	gold quality
left ovary	UBERON:0002119	81.20	gold quality
adrenal gland	UBERON:0002369	80.94	gold quality
left adrenal gland cortex	UBERON:0035825	80.88	gold quality
adrenal cortex	UBERON:0001235	80.75	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.35

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

231 targeting XPNPEP3, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 4)

• Individuals with mutations in XPNPEP3, which encodes a mitochondrial protein, develop a nephronophthisis-like nephropathy. (PMID:20179356)
• The findings reveal that APP3m is a new member of the TNF-TNFR2 signaling complex and characterize an APP3-mediated TNFR2 signal transduction mechanism that induces activation of JNK1 and JNK2. (PMID:25609706)
• Data suggest that human XPNPEP3, Ashbya gossypii Icp55, and Fusarium graminearum Icp55 exhibit structural and functional properties of genuine Xaa-Pro specific aminopeptidases; these enzymes appear to function in the previously observed mitochondrial role of Icp55 in processing of Nfs1 (mitochondrial cysteine desulfurase) substrate. [Icp55 = intermediate-cleavage metalloexopeptidases 55] (PMID:28476889)
• results therefore suggest XPNPEP3 to be a transcriptional target of Wnt/beta-catenin pathway with particular significance for CRC (PMID:29383790)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	xpnpep3	ENSDARG00000007916
mus_musculus	Xpnpep3	ENSMUSG00000022401
rattus_norvegicus	Xpnpep3	ENSRNOG00000019196
caenorhabditis_elegans	icpp-55	WBGENE00020088

Paralogs (7): XPNPEP1 (ENSG00000108039), METAP2 (ENSG00000111142), XPNPEP2 (ENSG00000122121), PEPD (ENSG00000124299), METAP1 (ENSG00000164024), PA2G4 (ENSG00000170515), METAP1D (ENSG00000172878)

Protein

Protein identifiers

Xaa-Pro aminopeptidase 3 — Q9NQH7 (reviewed: Q9NQH7)

Alternative names: Aminopeptidase P3

All UniProt accessions (3): Q9NQH7, A0A087X0Z2, F2Z316

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the removal of a penultimate prolyl residue from the N-termini of peptides, such as Leu-Pro-Ala. Also shows low activity towards peptides with Ala or Ser at the P1 position. Promotes TNFRSF1B-mediated phosphorylation of MAPK8/JNK1 and MAPK9/JNK2, suggesting a function as an adapter protein for TNFRSF1B; the effect is independent of XPNPEP3 peptidase activity. May inhibit apoptotic cell death induced via TNF-TNFRSF1B signaling.

Subunit / interactions. Homodimer. Isoform 1 interacts with TNFRSF1B/TNFR2 (activated) and TRAF2.

Subcellular location. Mitochondrion. Cytoplasm Cytoplasm.

Tissue specificity. Isoform 1 and isoform 2 are widely expressed, with isoform 1 being more abundant.

Disease relevance. Nephronophthisis-like nephropathy 1 (NPHPL1) [MIM:613159] An autosomal recessive disorder with features of nephronophthisis, a cystic kidney disease leading to end-stage renal failure. Nephronophthisis is histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts. Typical clinical manifestation are chronic renal failure, anemia, polyuria, polydipsia, isosthenuria, and growth retardation. Associations with extrarenal symptoms are frequent. In NPHPL1 patients, extrarenal symptoms include hypertension, essential tremor, sensorineural hearing loss and gout. Severely affected individuals can manifest a mitochondrial disorder with isolated complex I deficiency activity in muscle, seizures, intellectual disability and hypertrophic dilated cardiomyopathy. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 2 manganese ions per subunit.

Similarity. Belongs to the peptidase M24B family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9NQH7-1	1, m	yes
Q9NQH7-2	2, c
Q9NQH7-3	3
Q9NQH7-4	4
Q9NQH7-5	5

RefSeq proteins (2): NP_001191756, NP_071381* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000994	Pept_M24	Domain
IPR007865	Aminopep_P_N	Domain
IPR029149	Creatin/AminoP/Spt16_N	Homologous_superfamily
IPR036005	Creatinase/aminopeptidase-like	Homologous_superfamily
IPR052433	X-Pro_dipept-like	Family

Pfam: PF00557, PF05195

Enzyme classification (BRENDA):

• EC 3.4.11.9 — Xaa-Pro aminopeptidase (BRENDA: 34 organisms, 218 substrates, 171 inhibitors, 117 Km, 90 kcat entries)

Substrate kinetics (BRENDA)

47 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BRADYKININ	0.021–6.7	30
ARG-PRO-PRO	0.16–1.4	7
MET-PRO-ALA	1.9–9	7
L-ALA-L-PRO-4-NITROANILIDE	0.51–16.9	5
ARG-PRO-ALA	2.1–8.4	4
GLY-PRO-HYP	0.32–40.4	4
MET-ALA-ALA	0.15–0.46	3
MET-PRO	6.3–11.9	3
2-AMINOBENZOYL-L-LYS-L-PRO-L-PRO-4-NITROANILIDE	0.087–0.14	2
ABZ-L-LYS-L-PRO-L-PRO-4-NITROANILIDE	0.087–0.14	2
ARG-PRO-PRO-GLY-PHE	0.048–0.34	2
ARG-PRO-PRO-GLY-PHE-SER	0.032–0.15	2
ARG-PRO-PRO-GLY-PHE-SER-PRO	0.051–0.25	2
ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE	0.039–0.15	2
FPHFD	0.51–0.86	2

UniProt features (74 total): strand 21, helix 18, binding site 14, mutagenesis site 7, splice variant 6, sequence variant 2, sequence conflict 2, transit peptide 1, chain 1, region of interest 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5X49	X-RAY DIFFRACTION	1.65

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQH7-F1	92.09	0.87

Functional residue map

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

Ligand- & substrate-binding residues (14): 424; 431; 451; 451; 475; 475; 475; 300; 331; 331; 342; 342 …

Mutagenesis-validated functional residues (7):

Position	Phenotype
18	prevents cleavage of n-terminal transit peptide; when associated with a-29-30-a; a-39-40-a and a-44.
29–30	prevents cleavage of n-terminal transit peptide; when associated with a-18; a-39-40-a and a-44.
39–40	prevents cleavage of n-terminal transit peptide; when associated with a-18; a-29-30-a and a-44.
44	prevents cleavage of n-terminal transit peptide; when associated with a-18; a-29-30-a and a-39-40-a.
314	impairs catalytic activity.
342	impairs catalytic activity.
475	impairs catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 178 (showing top): RNGTGGGC_UNKNOWN, GOMF_METALLOPEPTIDASE_ACTIVITY, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, EFC_Q6, GOBP_PROTEIN_MATURATION, GRE_C, TGACATY_UNKNOWN, RYTTCCTG_ETS2_B, GRADE_COLON_AND_RECTAL_CANCER_DN, GOBP_RENAL_FILTRATION, ATF_01, TTCNRGNNNNTTC_HSF_Q6, CREBP1CJUN_01, GOBP_RENAL_SYSTEM_PROCESS, CREB_01

GO Biological Process (3): glomerular filtration (GO:0003094), proteolysis (GO:0006508), protein processing (GO:0016485)

GO Molecular Function (10): aminopeptidase activity (GO:0004177), manganese ion binding (GO:0030145), protein homodimerization activity (GO:0042803), metalloaminopeptidase activity (GO:0070006), protein binding (GO:0005515), peptidase activity (GO:0008233), metalloexopeptidase activity (GO:0008235), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (3): cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
exopeptidase activity	2
cellular anatomical structure	2
cytoplasm	2
renal filtration	1
protein metabolic process	1
proteolysis	1
protein maturation	1
transition metal ion binding	1
identical protein binding	1
protein dimerization activity	1
aminopeptidase activity	1
metalloexopeptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
metallopeptidase activity	1
peptidase activity	1
catalytic activity	1
cation binding	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
XPNPEP3	XPNPEP2	O43895	916
XPNPEP3	XPNPEP1	Q9NQW7	891
XPNPEP3	ALMS1	Q8TCU4	831
XPNPEP3	DNAAF1	Q8NEP3	767
XPNPEP3	CEP290	O15078	736
XPNPEP3	MIPEP	Q99797	725
XPNPEP3	NPHP1	O15259	653
XPNPEP3	PMPCA	Q10713	646
XPNPEP3	PMPCB	O75439	643
XPNPEP3	IMMP2L	Q96T52	587
XPNPEP3	LAP3	P28838	582
XPNPEP3	ATP23	Q9Y6H3	543
XPNPEP3	OMA1	Q96E52	523
XPNPEP3	DNPEP	Q9ULA0	521
XPNPEP3	LONP1	P36776	497

IntAct

86 interactions, top by confidence:

A	B	Type	Score
TP53	MDM4	psi-mi:“MI:0914”(association)	0.970
GFAP	NEFL	psi-mi:“MI:0914”(association)	0.850
VIM	NEFL	psi-mi:“MI:0914”(association)	0.840
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
BIRC7	HTRA2	psi-mi:“MI:0914”(association)	0.640
RELL1	TCAF2	psi-mi:“MI:0914”(association)	0.530
CHGA	DENR	psi-mi:“MI:0914”(association)	0.530
CST6	CTSV	psi-mi:“MI:0914”(association)	0.530
XPNPEP3	SEC16A	psi-mi:“MI:0914”(association)	0.510
CFTR	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
XPNPEP3	HNRNPA1L2	psi-mi:“MI:0915”(physical association)	0.400
XPNPEP3	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.400
Ubr5	UBR5	psi-mi:“MI:0915”(physical association)	0.400
Bub1b	NDC80	psi-mi:“MI:0915”(physical association)	0.400
JUN		psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
CFTR	SNHG32	psi-mi:“MI:0914”(association)	0.350
	TBKBP1	psi-mi:“MI:0914”(association)	0.350
ORF21	USP9Y	psi-mi:“MI:0914”(association)	0.350
ACBD3	BCKDHB	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350

BioGRID (101): XPNPEP3 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), MRPL57 (Affinity Capture-MS), NT5DC2 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), POLDIP2 (Affinity Capture-MS), ECH1 (Affinity Capture-MS), XPNPEP3 (Affinity Capture-MS), CHCHD2 (Affinity Capture-MS), C1QBP (Affinity Capture-MS), MRPL53 (Affinity Capture-MS), IDE (Affinity Capture-MS)

ESM2 similar proteins: A0JN95, A4IF87, A6NJ78, B5DEQ3, B7ZMP1, D3ZLY0, E9Q4Z2, F1QDI9, G1SPE9, O14717, O15228, O22268, O55055, O95453, O95671, P37287, P69341, P97770, Q05B63, Q08J23, Q0V8R7, Q0VGM9, Q10D00, Q1HFZ0, Q2T9W2, Q4G073, Q5R5T5, Q5R962, Q5R9W8, Q5RC51, Q5RJZ1, Q6GR37, Q6H1L8, Q6NYU2, Q6YJI5, Q7TNK6, Q7YS61, Q7Z4G4, Q8JZM0, Q8R2Y8

Diamond homologs: A0KEL3, A0KR51, A1CNW6, A1CSI0, A1D1S6, A1DG66, A1S1I9, A1TXT7, A2QAW7, A2QKF6, A3Q8U5, A4RAE9, A4RQ11, A4STF0, A6QYF6, A6SDE9, A6SL16, A7ENP9, A7EUB3, A7UWH7, A8FP64, B0XN37, B0XW47, B1KCZ4, B2AFW1, B2AW39, B2WKR4, B2WMQ2, B5DEQ3, B6H2M0, B6HAN0, B6Q8T5, B6QAW7, B7ZMP1, B8M0Z4, B8M2W9, B8MZI5, B8NC10, C0NF18, C0NIF0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	13
Uncertain significance	227
Likely benign	61
Benign	35

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1012365	NM_022098.4(XPNPEP3):c.1040G>A (p.Trp347Ter)	Pathogenic
1192531	NM_022098.4(XPNPEP3):c.720dup (p.Gln241fs)	Pathogenic
1415192	NM_022098.4(XPNPEP3):c.85C>T (p.Arg29Ter)	Pathogenic
2426715	NC_000022.10:g.(?41282297)(41282539_?)del	Pathogenic
2886078	NM_022098.4(XPNPEP3):c.250C>T (p.Gln84Ter)	Pathogenic
51	NM_022098.4(XPNPEP3):c.1357G>T (p.Gly453Cys)	Pathogenic
52	NM_022098.4(XPNPEP3):c.931_934del (p.Asn311fs)	Pathogenic
1012366	NM_022098.4(XPNPEP3):c.645del (p.Ser216fs)	Likely pathogenic
1497807	NM_022098.4(XPNPEP3):c.1055+2T>G	Likely pathogenic
1677907	NM_022098.4(XPNPEP3):c.970-1G>A	Likely pathogenic
2500236	NM_022098.4(XPNPEP3):c.658C>T (p.Gln220Ter)	Likely pathogenic
2500237	NM_022098.4(XPNPEP3):c.1194_1200del (p.Asp398fs)	Likely pathogenic
3383357	NM_022098.4(XPNPEP3):c.499C>T (p.Arg167Ter)	Likely pathogenic
3588056	NM_022098.4(XPNPEP3):c.97del (p.Leu33fs)	Likely pathogenic
3588059	NM_022098.4(XPNPEP3):c.130C>T (p.Arg44Ter)	Likely pathogenic
3588069	NM_022098.4(XPNPEP3):c.589+1G>T	Likely pathogenic
3588073	NM_022098.4(XPNPEP3):c.760C>T (p.Arg254Ter)	Likely pathogenic
3588077	NM_022098.4(XPNPEP3):c.855+1G>A	Likely pathogenic
3588082	NM_022098.4(XPNPEP3):c.937_938del (p.Leu313fs)	Likely pathogenic
3767168	NM_022098.4(XPNPEP3):c.466C>T (p.Arg156Ter)	Likely pathogenic

SpliceAI

2628 predictions. Top by Δscore:

Variant	Effect	Δscore
22:40868998:GGAT:G	acceptor_gain	1.0000
22:40869112:CCAGG:C	donor_loss	1.0000
22:40869113:CAGG:C	donor_loss	1.0000
22:40869114:AGGT:A	donor_loss	1.0000
22:40869116:G:T	donor_loss	1.0000
22:40869117:T:A	donor_loss	1.0000
22:40870034:T:A	acceptor_gain	1.0000
22:40870132:GCT:G	donor_gain	1.0000
22:40870135:GTAAG:G	donor_gain	1.0000
22:40870136:TAAGG:T	donor_loss	1.0000
22:40870137:AAGG:A	donor_loss	1.0000
22:40870138:AGGT:A	donor_loss	1.0000
22:40870140:GTAA:G	donor_loss	1.0000
22:40886296:C:CA	acceptor_gain	1.0000
22:40886310:AAGCT:A	acceptor_gain	1.0000
22:40886311:A:G	acceptor_gain	1.0000
22:40886511:CACAG:C	donor_loss	1.0000
22:40886512:ACAG:A	donor_loss	1.0000
22:40886513:CAGGT:C	donor_loss	1.0000
22:40886514:AGGT:A	donor_loss	1.0000
22:40886516:G:GC	donor_loss	1.0000
22:40886517:T:G	donor_loss	1.0000
22:40907582:TGCA:T	acceptor_loss	1.0000
22:40907583:GCA:G	acceptor_loss	1.0000
22:40907585:A:AC	acceptor_loss	1.0000
22:40909119:C:G	acceptor_gain	1.0000
22:40909120:A:AG	acceptor_gain	1.0000
22:40909121:G:GA	acceptor_gain	1.0000
22:40909232:CAAGG:C	donor_loss	1.0000
22:40909233:AAGG:A	donor_loss	1.0000

AlphaMissense

3323 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:40882075:T:A	W163R	0.998
22:40882075:T:C	W163R	0.998
22:40882077:G:C	W163C	0.998
22:40882077:G:T	W163C	0.998
22:40886464:G:C	K247N	0.998
22:40886464:G:T	K247N	0.998
22:40909180:C:A	A305D	0.998
22:40909206:C:G	H314D	0.998
22:40914308:T:A	W347R	0.998
22:40914308:T:C	W347R	0.998
22:40881982:A:C	S132R	0.997
22:40881984:C:A	S132R	0.997
22:40881984:C:G	S132R	0.997
22:40886462:A:G	K247E	0.997
22:40914261:A:T	D331V	0.997
22:40914290:A:C	S341R	0.997
22:40914292:T:A	S341R	0.997
22:40914292:T:G	S341R	0.997
22:40914294:A:T	D342V	0.997
22:40914303:G:C	R345P	0.997
22:40924395:C:G	H424D	0.997
22:40924419:G:C	D432H	0.997
22:40926335:A:T	E475V	0.997
22:40881811:C:A	R75S	0.996
22:40881816:A:C	R76S	0.996
22:40881816:A:T	R76S	0.996
22:40909208:C:A	H314Q	0.996
22:40909208:C:G	H314Q	0.996
22:40914255:T:C	L329P	0.996
22:40914262:T:A	D331E	0.996

dbSNP variants (sampled 300 via entrez): RS1000014107 (22:40858414 C>A), RS1000031535 (22:40864899 A>C,G), RS1000065015 (22:40913482 G>GT), RS1000097260 (22:40912411 T>C), RS1000135077 (22:40864674 A>G,T), RS1000157111 (22:40856615 C>A,G,T), RS1000157398 (22:40884002 T>G), RS1000171765 (22:40927538 A>G), RS1000249714 (22:40931124 G>C), RS1000250634 (22:40889674 T>A,C), RS1000258912 (22:40890389 A>G), RS1000342661 (22:40877822 C>T), RS1000368470 (22:40889974 T>G), RS1000397670 (22:40919860 G>A), RS1000407057 (22:40871569 AT>A,ATT)

Disease associations

OMIM: gene MIM:613553 | disease phenotypes: MIM:613159

GenCC curated gene-disease

Disease	Classification	Inheritance
nephronophthisis-like nephropathy 1	Strong	Autosomal recessive
late-onset nephronophthisis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
nephronophthisis-like nephropathy 1	Definitive	AR

Mondo (3): nephronophthisis-like nephropathy 1 (MONDO:0013163), kidney disorder (MONDO:0005240), late-onset nephronophthisis (MONDO:0019742)

Orphanet (1): Nephronophthisis (Orphanet:655)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000090	Nephronophthisis
HP:0000092	Renal tubular atrophy
HP:0000108	Renal corticomedullary cysts
HP:0000407	Sensorineural hearing impairment
HP:0000822	Hypertension
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001737	Pancreatic cysts
HP:0003774	Stage 5 chronic kidney disease
HP:0004719	Hyperechogenic kidneys
HP:0005583	Tubular basement membrane disintegration
HP:0006280	Chronic pancreatitis
HP:0030186	Kinetic tremor
HP:0100702	Arachnoid cyst

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004521_42	Autism spectrum disorder or schizophrenia	1.000000e-08
GCST004521_55	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST004946_20	Schizophrenia	1.000000e-12
GCST006944_42	Experiencing mood swings	2.000000e-10
GCST007615_50	C-reactive protein levels	1.000000e-08
GCST008103_42	Bipolar disorder	2.000000e-07
GCST008115_35	Bipolar I disorder	3.000000e-07
GCST010002_83	Refractive error	2.000000e-27
GCST010204_180	Low density lipoprotein cholesterol levels	6.000000e-13
GCST010243_145	Apolipoprotein B levels	8.000000e-09

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008475	mood instability measurement
EFO:0004458	C-reactive protein measurement
EFO:0009963	bipolar I disorder
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3831223 (PROTEIN FAMILY)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — M24: Methionyl aminopeptidase

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
chloropicrin	affects expression, increases expression	2
bisphenol S	affects expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
p-Chloromercuribenzoic Acid	affects cotreatment, decreases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
potassium chromate(VI)	increases expression	1
hydroquinone	decreases expression	1
mercuric bromide	decreases expression, affects cotreatment	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
Bortezomib	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	affects expression, increases abundance	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Lead	decreases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Quercetin	increases expression	1
Rotenone	increases expression	1
Tobacco Smoke Pollution	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4334276	ADMET	Stability in pH 2 HCl assessed as aminopeptidase (unknown origin)-mediated compound hydrolysis by measuring parent compound remaining at 200 uM up to 6 hrs by RP-HPLC analysis	Astratides: Insulin-Modulating, Insecticidal, and Antifungal Cysteine-Rich Peptides from Astragalus membranaceus. — J Nat Prod

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
NCT03029351	PHASE4	TERMINATED	GLP-1 Receptor Agonist Therapy and Albuminuria in Patients With Type 2 Diabetes