RNPEPL1

Summary

RNPEPL1 (arginyl aminopeptidase like 1, HGNC:10079) is a protein-coding gene on chromosome 2q37.3, encoding Aminopeptidase RNPEPL1 (Q9HAU8). Broad specificity aminopeptidase which preferentially hydrolyzes an N-terminal methionine, citrulline or glutamine.

Enables metalloaminopeptidase activity. Involved in proteolysis.

Source: NCBI Gene 57140 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 98 total
• Druggable target: yes
• MANE Select transcript: NM_018226

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10079
Approved symbol	RNPEPL1
Name	arginyl aminopeptidase like 1
Location	2q37.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000142327
Ensembl biotype	protein_coding
OMIM	605287
Entrez	57140

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 12 protein_coding, 6 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000270357, ENST00000437406, ENST00000451363, ENST00000460884, ENST00000464550, ENST00000471657, ENST00000481757, ENST00000486058, ENST00000493398, ENST00000498042, ENST00000885945, ENST00000885946, ENST00000885947, ENST00000885948, ENST00000885949, ENST00000920409, ENST00000920410, ENST00000971322, ENST00000971323

RefSeq mRNA: 1 — MANE Select: NM_018226 NM_018226

Canonical transcript exons

ENST00000270357 — 11 exons

Exon	Start	End
ENSE00000953532	240574113	240574348
ENSE00000953533	240574515	240574628
ENSE00001038855	240573775	240573891
ENSE00001260222	240568484	240569114
ENSE00001872415	240577599	240581372
ENSE00003582098	240575502	240575610
ENSE00003587572	240575030	240575142
ENSE00003600009	240573110	240573261
ENSE00003608709	240576535	240576765
ENSE00003619356	240576848	240576990
ENSE00003807076	240572423	240572563

Expression profiles

Bgee: expression breadth ubiquitous, 256 present calls, max score 98.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.6177 / max 918.7648, expressed in 1812 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
26426	23.8480	1806
26430	3.2041	1481
26427	2.9176	1156
26428	1.1355	470
26431	1.1115	683
26425	0.7462	484
26429	0.5959	306
26423	0.0590	24

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.50	gold quality
granulocyte	CL:0000094	98.15	gold quality
mucosa of transverse colon	UBERON:0004991	96.98	gold quality
lower esophagus mucosa	UBERON:0035834	96.84	gold quality
mucosa of stomach	UBERON:0001199	95.83	gold quality
body of stomach	UBERON:0001161	95.67	gold quality
body of pancreas	UBERON:0001150	95.62	gold quality
heart left ventricle	UBERON:0002084	95.24	gold quality
gastrocnemius	UBERON:0001388	95.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	95.01	gold quality
transverse colon	UBERON:0001157	94.92	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.92	gold quality
type B pancreatic cell	CL:0000169	94.79	silver quality
cardiac ventricle	UBERON:0002082	94.78	gold quality
lower esophagus	UBERON:0013473	94.59	gold quality
spleen	UBERON:0002106	94.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.58	gold quality
upper lobe of left lung	UBERON:0008952	94.47	gold quality
right coronary artery	UBERON:0001625	94.38	gold quality
olfactory bulb	UBERON:0002264	94.23	gold quality
leukocyte	CL:0000738	94.15	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.14	gold quality
right lung	UBERON:0002167	94.13	gold quality
esophagus	UBERON:0001043	94.02	gold quality
blood	UBERON:0000178	93.97	gold quality
left coronary artery	UBERON:0001626	93.97	gold quality
esophagus mucosa	UBERON:0002469	93.96	gold quality
metanephros cortex	UBERON:0010533	93.88	gold quality
monocyte	CL:0000576	93.84	gold quality
mononuclear cell	CL:0000842	93.81	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.20

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting RNPEPL1, 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-6825-5P	99.96	69.81	3431
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-3714	99.71	70.74	2671
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-6506-5P	99.04	65.66	1386
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-423-5P	98.69	67.48	1522

Literature-anchored findings (GeneRIF, showing 2)

• RT-PCR analysis of RNPEPL1 expression revealed a ubiquitous tissue distribution, consistent with a general housekeeping function, but also revealed alternative splicing of the mRNA in all tissues examined. (PMID:19508204)
• Characterization of the enzymatic properties of human RNPEPL1/aminopeptidase Z. (PMID:36545750)

Cross-species orthologs

17 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnpepl1	ENSDARG00000007813
mus_musculus	Rnpepl1	ENSMUSG00000026269
rattus_norvegicus	Rnpepl1	ENSRNOG00000045775
drosophila_melanogaster	CG7653	FBGN0028935
drosophila_melanogaster	CG9806	FBGN0030222
drosophila_melanogaster	CG2111	FBGN0030223
drosophila_melanogaster	CG6071	FBGN0036186
drosophila_melanogaster	CG5849	FBGN0038897
drosophila_melanogaster	CG3502	FBGN0046253
drosophila_melanogaster	CG31233	FBGN0051233
drosophila_melanogaster	CG31343	FBGN0051343
drosophila_melanogaster	CG31445	FBGN0051445
drosophila_melanogaster	SP1029	FBGN0263236
drosophila_melanogaster	CG46339	FBGN0285963
caenorhabditis_elegans	F49B2.6	WBGENE00009865
caenorhabditis_elegans		WBGENE00011587
caenorhabditis_elegans		WBGENE00012776

Paralogs (11): TRHDE (ENSG00000072657), LTA4H (ENSG00000111144), LNPEP (ENSG00000113441), ENPEP (ENSG00000138792), NPEPPS (ENSG00000141279), AOPEP (ENSG00000148120), ERAP1 (ENSG00000164307), ERAP2 (ENSG00000164308), ANPEP (ENSG00000166825), LVRN (ENSG00000172901), RNPEP (ENSG00000176393)

Protein

Protein identifiers

Aminopeptidase RNPEPL1 — Q9HAU8 (reviewed: Q9HAU8)

Alternative names: Arginyl aminopeptidase-like 1, Methionyl aminopeptidase

All UniProt accessions (3): Q9HAU8, C9JSI2, H7C200

UniProt curated annotations — full annotation on UniProt →

Function. Broad specificity aminopeptidase which preferentially hydrolyzes an N-terminal methionine, citrulline or glutamine.

Tissue specificity. Ubiquitously expressed. Expressed at relatively higher levels in heart and skeletal muscle.

Activity regulation. Inhibited by calcium but not affected by chloride ions. Inhibited by amastatin and to a lower extent by bestatin. Weakly inhibited by puromycin.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M1 family.

RefSeq proteins (1): NP_060696* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001930	Peptidase_M1	Family
IPR014782	Peptidase_M1_dom	Domain
IPR015211	Peptidase_M1_C	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR027268	Peptidase_M4/M1_CTD_sf	Homologous_superfamily
IPR034015	M1_LTA4H	Family
IPR038502	M1_LTA-4_hydro/amino_C_sf	Homologous_superfamily
IPR042097	Aminopeptidase_N-like_N_sf	Homologous_superfamily
IPR045357	Aminopeptidase_N-like_N	Domain
IPR049980	LTA4H_cat	Domain

Pfam: PF01433, PF09127, PF17900

UniProt features (11 total): binding site 4, chain 1, region of interest 1, sequence conflict 1, compositionally biased region 1, active site 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HAU8-F1	87.45	0.75

Functional residue map

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

Catalytic / active sites (2): 354 (proton acceptor); 442 (transition state stabilizer)

Ligand- & substrate-binding residues (4): 326–330; 353; 357; 376

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 97 (showing top): BENPORATH_ES_WITH_H3K27ME3, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOMF_METALLOPEPTIDASE_ACTIVITY, BLALOCK_ALZHEIMERS_DISEASE_UP, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_CDC25_DN, GOBP_PROTEOLYSIS, GOMF_METALLOEXOPEPTIDASE_ACTIVITY, GOMF_PEPTIDASE_ACTIVITY, GOMF_AMINOPEPTIDASE_ACTIVITY, GOMF_EXOPEPTIDASE_ACTIVITY, GSE13762_CTRL_VS_125_VITAMIND_DAY5_DC_UP, GOMF_METALLOAMINOPEPTIDASE_ACTIVITY, LI_INDUCED_T_TO_NATURAL_KILLER_DN, DCA_UP.V1_DN, FOXN3_TARGET_GENES

GO Biological Process (1): proteolysis (GO:0006508)

GO Molecular Function (8): initiator methionyl aminopeptidase activity (GO:0004239), zinc ion binding (GO:0008270), metalloaminopeptidase activity (GO:0070006), aminopeptidase activity (GO:0004177), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
aminopeptidase activity	2
protein metabolic process	1
transition metal ion binding	1
metalloexopeptidase activity	1
exopeptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
catalytic activity	1
cation binding	1

Protein interactions and networks

STRING

1208 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNPEPL1	CAPN10	Q9HC96	889
RNPEPL1	GPR35	Q9HC97	537
RNPEPL1	FAM98C	Q17RN3	493
RNPEPL1	JPT2	Q9H910	452
RNPEPL1	ZNF688	P0C7X2	396
RNPEPL1	ANKMY1	Q9P2S6	395
RNPEPL1	RTP5	Q14D33	393
RNPEPL1	MAB21L4	Q08AI8	370
RNPEPL1	OR7A5	Q15622	352
RNPEPL1	ALDH18A1	P54886	350
RNPEPL1	ZNF785	A8K8V0	348
RNPEPL1	FAM133B	Q5BKY9	347
RNPEPL1	THAP4	Q8WY91	346
RNPEPL1	RNF150	Q9ULK6	333
RNPEPL1	EML3	Q32P44	330

IntAct

11 interactions, top by confidence:

A	B	Type	Score
DKK4	LRP5	psi-mi:“MI:0914”(association)	0.530
RNPEPL1	USP11	psi-mi:“MI:0407”(direct interaction)	0.440
RNPEPL1	VDAC1	psi-mi:“MI:0915”(physical association)	0.400
XAGE3	PSMG1	psi-mi:“MI:0914”(association)	0.350
RIN3		psi-mi:“MI:0914”(association)	0.350
TMCC3	HSBP1	psi-mi:“MI:0914”(association)	0.350
dinB	RNPEPL1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-RNA), RNPEPL1 (Proximity Label-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-MS), RNPEPL1 (Affinity Capture-RNA), RNPEPL1 (Affinity Capture-RNA)

ESM2 similar proteins: A1A4I4, A5PKD8, A6NED2, A8MQ27, O35465, O60294, O75808, O94819, O95382, P70268, Q0MW30, Q14318, Q16512, Q2T9J0, Q32NY4, Q32P44, Q3B7U9, Q3MHW0, Q3U5Q7, Q3USL1, Q4R828, Q561R2, Q5EBM0, Q5EBP3, Q5PQP9, Q60806, Q63433, Q6PAT0, Q7T0L4, Q8BNW9, Q8BTU7, Q8BYR1, Q8IYL2, Q8N5A5, Q8NEP7, Q8VC03, Q8VHS5, Q8WXI3, Q91ZT7, Q96C12

Diamond homologs: A1CSI2, A1DG68, A2QKF8, A3LQI7, A3LRX6, A4QUC1, A5DGF3, A5DME6, A5DSS4, A6QPT7, A6RCT2, A6SAG8, A6ZS33, A7EJL9, A7THG7, G5E872, G5EFT4, O09175, O94544, P09960, P19602, P24527, P30349, P52922, Q0CFY9, Q0U653, Q10736, Q10740, Q1DVD1, Q2GY21, Q2TZ99, Q3SZH7, Q4X265, Q59NB8, Q5B0W8, Q6BW21, Q6C3E5, Q6CLD3, Q6FTM0, Q6IP81

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	78
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2074 predictions. Top by Δscore:

Variant	Effect	Δscore
2:240569112:GCC:G	donor_gain	1.0000
2:240569115:G:GG	donor_gain	1.0000
2:240572417:CCACA:C	acceptor_loss	1.0000
2:240572418:CACAG:C	acceptor_loss	1.0000
2:240572419:ACAGA:A	acceptor_loss	1.0000
2:240572420:CAGAT:C	acceptor_loss	1.0000
2:240572421:A:AC	acceptor_loss	1.0000
2:240572421:A:AG	acceptor_gain	1.0000
2:240572422:G:GA	acceptor_gain	1.0000
2:240572422:GATCT:G	acceptor_gain	1.0000
2:240572536:G:GT	donor_gain	1.0000
2:240572559:TCAAG:T	donor_loss	1.0000
2:240572560:CAAG:C	donor_loss	1.0000
2:240572561:AAGG:A	donor_loss	1.0000
2:240572562:AGG:A	donor_loss	1.0000
2:240572563:GGTC:G	donor_loss	1.0000
2:240572564:GTCAG:G	donor_loss	1.0000
2:240572600:G:GT	donor_gain	1.0000
2:240573258:CCAGG:C	donor_loss	1.0000
2:240573259:CAGGT:C	donor_loss	1.0000
2:240573261:GGTA:G	donor_loss	1.0000
2:240573262:G:GA	donor_loss	1.0000
2:240573262:G:GG	donor_gain	1.0000
2:240573263:T:G	donor_loss	1.0000
2:240574107:GTGCA:G	acceptor_loss	1.0000
2:240574108:TGCA:T	acceptor_loss	1.0000
2:240574109:GCA:G	acceptor_loss	1.0000
2:240574110:CA:C	acceptor_loss	1.0000
2:240574112:G:A	acceptor_loss	1.0000
2:240574112:GGTAC:G	acceptor_gain	1.0000

AlphaMissense

4674 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:240572501:C:A	R203S	1.000
2:240572523:A:T	D210V	1.000
2:240572559:T:A	V222D	1.000
2:240574160:A:T	E329V	1.000
2:240574231:C:G	H353D	1.000
2:240574265:T:A	V364D	1.000
2:240574279:T:A	W369R	1.000
2:240574279:T:C	W369R	1.000
2:240574281:G:C	W369C	1.000
2:240574281:G:T	W369C	1.000
2:240574291:T:A	W373R	1.000
2:240574291:T:C	W373R	1.000
2:240574301:A:T	E376V	1.000
2:240574302:G:C	E376D	1.000
2:240574302:G:T	E376D	1.000
2:240574303:G:C	G377R	1.000
2:240575074:G:C	G445R	1.000
2:240576552:T:A	W510R	1.000
2:240576552:T:C	W510R	1.000
2:240569091:T:G	Y169D	0.999
2:240572429:T:A	W179R	0.999
2:240572429:T:C	W179R	0.999
2:240572431:G:C	W179C	0.999
2:240572431:G:T	W179C	0.999
2:240572472:T:A	V193D	0.999
2:240572500:C:A	N202K	0.999
2:240572500:C:G	N202K	0.999
2:240572501:C:G	R203G	0.999
2:240572511:T:C	F206S	0.999
2:240572514:C:A	P207Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000027805 (2:240569934 G>A), RS1000261543 (2:240569776 T>A), RS1000463206 (2:240570239 C>A,T), RS1000653815 (2:240572885 A>C,G), RS1000684795 (2:240572759 A>G), RS1000811184 (2:240578008 C>A,T), RS1000856300 (2:240572931 C>T), RS1000873743 (2:240578896 C>G,T), RS1001069092 (2:240568036 C>T), RS1001158624 (2:240577149 C>T), RS1001437120 (2:240567800 C>T), RS1001534339 (2:240568743 G>A,C,T), RS1001570608 (2:240580837 A>G), RS1001601880 (2:240581056 G>C), RS1001758353 (2:240575775 A>G)

Disease associations

OMIM: gene MIM:605287 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST004599_289	Mean platelet volume	5.000000e-230
GCST004603_219	Platelet count	1.000000e-34
GCST004616_137	Platelet distribution width	3.000000e-44
GCST004630_111	Mean corpuscular hemoglobin	3.000000e-09
GCST90002383_352	Hematocrit	2.000000e-09
GCST90002385_467	High light scatter reticulocyte count	6.000000e-14
GCST90002386_537	High light scatter reticulocyte percentage of red cells	5.000000e-18
GCST90002387_65	Immature fraction of reticulocytes	2.000000e-12
GCST90002390_471	Mean corpuscular hemoglobin	5.000000e-16
GCST90002391_1	Mean corpuscular hemoglobin concentration	1.000000e-18
GCST90002395_363	Mean platelet volume	0.000000e+00
GCST90002396_184	Mean reticulocyte volume	3.000000e-20
GCST90002397_641	Mean spheric corpuscular volume	5.000000e-37
GCST90002400_349	Plateletcrit	1.000000e-15
GCST90002401_432	Platelet distribution width	8.000000e-38
GCST90002402_295	Platelet count	9.000000e-74
GCST90002403_127	Red blood cell count	6.000000e-14
GCST90002406_73	Reticulocyte fraction of red cells	8.000000e-14

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0007984	platelet component distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0004348	hematocrit
EFO:0007986	reticulocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0007985	platelet crit
EFO:0004305	erythrocyte count

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 — M1: Aminopeptidase N

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	increases abundance, decreases expression, affects expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression, increases abundance	1
cobaltous chloride	decreases expression	1
nickel sulfate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
MT19c compound	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Benzo(a)pyrene	increases methylation	1
Choline	affects expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
Dronabinol	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	decreases expression	1
Sodium Selenite	increases expression	1
Cadmium Chloride	increases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	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)

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