PREPL

Summary

PREPL (prolyl endopeptidase like, HGNC:30228) is a protein-coding gene on chromosome 2p21, encoding Prolyl endopeptidase-like (Q4J6C6). Serine peptidase whose precise substrate specificity remains unclear.

The protein encoded by this gene belongs to the prolyl oligopeptidase subfamily of serine peptidases. Mutations in this gene have been associated with hypotonia-cystinuria syndrome, also known as the 2p21 deletion syndrome. Several alternatively spliced transcript variants encoding either the same or different isoforms have been described for this gene.

Source: NCBI Gene 9581 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myasthenic syndrome, congenital, 22 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 981 total — 90 pathogenic, 22 likely-pathogenic
• Phenotypes (HPO): 36
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001171613

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30228
Approved symbol	PREPL
Name	prolyl endopeptidase like
Location	2p21
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0436
Ensembl gene	ENSG00000138078
Ensembl biotype	protein_coding
OMIM	609557
Entrez	9581

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 52 protein_coding, 2 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined

ENST00000260648, ENST00000378511, ENST00000378520, ENST00000409272, ENST00000409411, ENST00000409936, ENST00000409957, ENST00000410081, ENST00000420756, ENST00000425263, ENST00000426481, ENST00000438314, ENST00000444696, ENST00000477410, ENST00000540817, ENST00000541738, ENST00000906096, ENST00000906097, ENST00000906098, ENST00000906099, ENST00000906100, ENST00000906101, ENST00000906102, ENST00000906103, ENST00000906104, ENST00000906105, ENST00000906106, ENST00000906107, ENST00000906108, ENST00000906109, ENST00000906110, ENST00000906111, ENST00000906112, ENST00000906113, ENST00000906114, ENST00000906115, ENST00000906116, ENST00000906117, ENST00000906118, ENST00000939467, ENST00000939468, ENST00000939469, ENST00000939470, ENST00000939471, ENST00000939472, ENST00000939473, ENST00000939474, ENST00000939475, ENST00000939476, ENST00000959346, ENST00000959347, ENST00000959348, ENST00000959349, ENST00000959350, ENST00000959351, ENST00000959352

RefSeq mRNA: 10 — MANE Select: NM_001171613 NM_001042385, NM_001042386, NM_001171603, NM_001171606, NM_001171613, NM_001171617, NM_001374275, NM_001374276, NM_001374277, NM_006036

CCDS: CCDS33190, CCDS42675, CCDS42676, CCDS54353

Canonical transcript exons

ENST00000409411 — 14 exons

Exon	Start	End
ENSE00000000067	44317607	44321445
ENSE00000932609	44321827	44321900
ENSE00000932610	44322731	44322854
ENSE00000932611	44323262	44323411
ENSE00000932612	44326712	44326928
ENSE00000932613	44328937	44329112
ENSE00000932614	44332459	44332656
ENSE00000932615	44338351	44338536
ENSE00000932616	44339147	44339363
ENSE00000932617	44342417	44342552
ENSE00000932618	44343745	44343951
ENSE00000932619	44344520	44344586
ENSE00003648509	44346268	44346390
ENSE00003899696	44361380	44361494

Expression profiles

Bgee: expression breadth ubiquitous, 294 present calls, max score 99.93.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 75.6613 / max 4607.5102, expressed in 1809 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
28134	42.8667	1787
28136	12.5849	1655
28135	10.9961	1636
28139	4.2144	1319
28137	3.4543	1244
28138	1.3839	611
28125	0.1609	55

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.93	gold quality
endothelial cell	CL:0000115	99.84	gold quality
middle temporal gyrus	UBERON:0002771	99.69	gold quality
postcentral gyrus	UBERON:0002581	99.61	gold quality
substantia nigra pars compacta	UBERON:0001965	99.60	gold quality
parietal lobe	UBERON:0001872	99.56	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.54	gold quality
pons	UBERON:0000988	99.44	gold quality
lateral globus pallidus	UBERON:0002476	99.44	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.42	gold quality
entorhinal cortex	UBERON:0002728	99.40	gold quality
choroid plexus epithelium	UBERON:0003911	99.35	gold quality
superior vestibular nucleus	UBERON:0007227	99.33	gold quality
occipital lobe	UBERON:0002021	99.29	gold quality
orbitofrontal cortex	UBERON:0004167	99.28	gold quality
primary visual cortex	UBERON:0002436	99.25	gold quality
frontal pole	UBERON:0002795	99.23	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.20	gold quality
CA1 field of hippocampus	UBERON:0003881	99.15	gold quality
germinal epithelium of ovary	UBERON:0001304	99.14	gold quality
medulla oblongata	UBERON:0001896	99.14	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.95	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.92	gold quality
middle frontal gyrus	UBERON:0002702	98.92	gold quality
ventral tegmental area	UBERON:0002691	98.90	gold quality
superior frontal gyrus	UBERON:0002661	98.81	gold quality
inferior olivary complex	UBERON:0002127	98.80	gold quality
prefrontal cortex	UBERON:0000451	98.76	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.67	gold quality
paraflocculus	UBERON:0005351	98.65	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	48.68
E-ANND-3	yes	8.99
E-GEOD-84465	yes	6.66
E-MTAB-4850	no	226.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

140 targeting PREPL, 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-5692A	100.00	74.40	6850
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 12)

• description of L-leucine transport into bladder carcinoma cells (PMID:12225859)
• A 638-residue variant of PREPL, PREPL A, was identifiied, expressed in Escherichia coli and purified; its secondary structure was similar to that of oligopeptidase B. (PMID:16143824)
• Deletion of PREPL, a gene encoding a putative serine oligopeptidase, in patients with hypotonia-cystinuria syndrome. (PMID:16385448)
• Deletion of the gene results in hypotonia at birth, failure to thrive and growth hormone deficiency (PMID:16913837)
• a deletion of PREPL causes atypical hypotonia-cystinuria syndrome (PMID:18234729)
• Two key transcription factors, NRF-2 and YY-1, were further identified to coordinately participate in driving gene expressions of PREPL-C2ORF34 genes pairin an additive manner. (PMID:19575798)
• Two novel deletions encompassing the SLC3A1 and PREPL genes have been identified in unrelated hypotonia-cystinuria syndrome patients. (PMID:22796000)
• Deletion of PREPL is associated with Hypotonia-cystinuria syndrome. (PMID:23794250)
• we report the first homozygous PREPL point mutation in a girl with typical PREPL deficiency. This syndrome should be considered in the differential diagnosis of hypotonic neonates exhibiting myasthenic symptoms, hyperphagia, and various degrees of ID. (PMID:29483676)
• A Family Case of Congenital Myasthenic Syndrome-22 Induced by Different Combinations of Molecular Causes in Siblings. (PMID:32707643)
• Multiomics Analyses Identify Proline Endopeptidase-Like Protein As a Key Regulator of Protein Trafficking, a Pathway Underlying Alzheimer’s Disease Pathogenesis. (PMID:37147110)
• Missense variants in CMS22 patients reveal that PREPL has both enzymatic and nonenzymatic functions. (PMID:39078710)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	prepl	ENSDARG00000017853
mus_musculus	Prepl	ENSMUSG00000024127
rattus_norvegicus	Prepl	ENSRNOG00000007326
drosophila_melanogaster	CG5355	FBGN0032242
drosophila_melanogaster	CG2528	FBGN0032969

Paralogs (1): PREP (ENSG00000085377)

Protein

Protein identifiers

Prolyl endopeptidase-like — Q4J6C6 (reviewed: Q4J6C6)

Alternative names: Prolylendopeptidase-like

All UniProt accessions (4): C9JMT4, Q4J6C6, H7BZP6, H7C0M0

UniProt curated annotations — full annotation on UniProt →

Function. Serine peptidase whose precise substrate specificity remains unclear. Does not cleave peptides after a arginine or lysine residue. Regulates trans-Golgi network morphology and sorting by regulating the membrane binding of the AP-1 complex. May play a role in the regulation of synaptic vesicle exocytosis.

Subunit / interactions. Homodimer. Interacts with the AP-1 complex.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus. trans-Golgi network. Cytoskeleton. Nucleus.

Tissue specificity. Expressed in pyramidal neurons of the temporal cortex and neocortex (at protein level). Widely expressed. Expressed at higher level in brain, skeletal muscle, heart and kidney. Expressed at the endplates in the neuromuscular junction.

Disease relevance. Hypotonia-cystinuria syndrome (HCS) [MIM:606407] Characterized generalized hypotonia at birth, nephrolithiasis, growth hormone deficiency, minor facial dysmorphism, failure to thrive, followed by hyperphagia and rapid weight gain in late childhood. The gene represented in this entry is involved in disease pathogenesis. Hypotonia-cystinuria syndrome is a contiguous gene syndrome caused by a homozygous deletion on chromosome 2p21 that disrupts the gene represented in this entry and SLC3A1. A homozygous 77.4-kb deletion that disrupts the gene represented in this entry, SLC3A1 and CAMKMT, causes atypical hypotonia-cystinuria syndrome, characterized by mild to moderate intellectual disability and respiratory chain complex IV deficiency. Patient cells exhibit a larger trans-Golgi network and a reduced redistribution of AP-1 complex, which causes impairment in AP-1 mediated membrane-cytoplasm recycling and secretion. Myasthenic syndrome, congenital, 22 (CMS22) [MIM:616224] A form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre-synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features include easy fatigability and muscle weakness. CMS22 is an autosomal recessive form characterized by neonatal hypotonia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by PMSF and Prefabloc, as well as leupeptin at high concentrations. Partially inhibited by TPCK, a chymotrypsin inhibitor and E64, a cysteine protease inhibitor. Not affected by 4-amidinophenyl-methanesulfonyl fluoride (APMSF), pepstatin or EDTA. Inhibited by 1-isobutyl-3-oxo-3,5,6,7-tetrahydro-2H-cyclopenta[c]pyridine-4-carbonitrile.

Similarity. Belongs to the peptidase S9A family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q4J6C6-1	1	yes
Q4J6C6-2	2, D
Q4J6C6-3	3, E
Q4J6C6-4	4

RefSeq proteins (10): NP_001035844, NP_001035845, NP_001165074, NP_001165077, NP_001165084, NP_001165088, NP_001361204, NP_001361205, NP_001361206, NP_006027 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001375	Peptidase_S9_cat	Domain
IPR002470	Peptidase_S9A	Family
IPR023302	Pept_S9A_N	Domain
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR051543	Serine_Peptidase_S9A	Family

Pfam: PF00326, PF02897

Enzyme classification (BRENDA):

• EC 3.4.21.26 — prolyl oligopeptidase (BRENDA: 55 organisms, 511 substrates, 729 inhibitors, 161 Km, 156 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
L-LEU-4-NITROANILIDE	0.12–1.1	10
L-PHE-4-NITROANILIDE	0.063–6.2	10
BENZYLOXYCARBONYL-GLY-PRO-BETA-NAPHTHYLAMIDE	0.0054–0.14	5
CALCITONIN GENE-RELATED PEPTIDE	0.0012–0.0125	5
BENZYLOXYCARBONYL-GLY-PRO-P-NITROPHENOL	—	4
2-AMINOBENZOYL-GLY-PRO-GLN-N-(2,4-DINITROPHENYL)	0.0002–0.0022	3
BENZYLOXYCARBONYL-GLY-L-PRO-4-NITROANILIDE	0.0653–3.42	3
BENZYLOXYCARBONYL-GLY-PRO-SBZL	0.0015–0.016	3
Z-GLY-PRO-4-NITROANILIDE	0.0308–0.81	3
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0004–0.0008	2
2-AMINOBENZOYL-ARG-PRO-PRO-GLY-PHE-SER-PRO-PHE-A	0.0009–0.0011	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0003–0.0005	2
2-AMINOBENZOYL-GLY-PHE-SER-PRO-PHE-ARG-SER-SER-A	0.0008–0.0015	2
ABZ-GLY-L-PHE-L-ARG-L-PRO-L-PHE(NO2)-L-ARG-L-ALA	0.0008–0.0092	2
ARG-PRO-4-NITROANILIDE	0.0229–0.16	2

UniProt features (79 total): strand 38, helix 19, sequence conflict 6, mutagenesis site 4, active site 3, turn 3, splice variant 3, chain 1, sequence variant 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7OBM	X-RAY DIFFRACTION	3.1
8RFB	ELECTRON MICROSCOPY	4.01

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q4J6C6-F1	82.46	0.64

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 (3): 559 (charge relay system); 645 (charge relay system); 690 (charge relay system)

Post-translational modifications (1): 1

Mutagenesis-validated functional residues (4):

Position	Phenotype
690	loss of catalytic activity.
696	no effect on catalytic activity.
559	loss of catalytic activity.
645	loss of catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 281 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, GCM_MAP4K4, GCM_PTPRD, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, YY1_Q6, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_GOLGI_TO_PLASMA_MEMBRANE_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_REGULATION_OF_NEUROTRANSMITTER_TRANSPORT

GO Biological Process (4): proteolysis (GO:0006508), retrograde transport, endosome to Golgi (GO:0042147), Golgi to plasma membrane protein transport (GO:0043001), regulation of synaptic vesicle exocytosis (GO:2000300)

GO Molecular Function (4): serine-type endopeptidase activity (GO:0004252), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (7): nucleus (GO:0005634), mitochondrion (GO:0005739), Golgi apparatus (GO:0005794), trans-Golgi network (GO:0005802), cytosol (GO:0005829), cytoskeleton (GO:0005856), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
cytoplasm	3
cellular anatomical structure	2
protein metabolic process	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
Golgi to plasma membrane transport	1
protein transport	1
establishment of protein localization to plasma membrane	1
protein localization to plasma membrane	1
synaptic vesicle exocytosis	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
endopeptidase activity	1
serine-type peptidase activity	1
hydrolase activity	1
catalytic activity, acting on a protein	1
peptidase activity	1
serine hydrolase activity	1
catalytic activity	1
endomembrane system	1
Golgi apparatus subcompartment	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1226 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PREPL	CAMKMT	Q7Z624	977
PREPL	SLC3A1	Q07837	969
PREPL	PPM1B	O75688	966
PREPL	ALG14	Q96F25	661
PREPL	DPAGT1	Q9H3H5	581
PREPL	SURF2	Q15527	575
PREPL	COLQ	Q9Y215	522
PREPL	GMPPB	Q9Y5P6	489
PREPL	DOK7	Q18PE1	466
PREPL	APEH	P13798	464
PREPL	RBBP9	O75884	459
PREPL	MYNN	Q9NPC7	453
PREPL	GFPT1	Q06210	448
PREPL	RAPSN	Q13702	444
PREPL	DPP7	Q9UHL4	443

IntAct

87 interactions, top by confidence:

A	B	Type	Score
NDUFS6	NDUFS8	psi-mi:“MI:0914”(association)	0.640
CRYZ	MMUT	psi-mi:“MI:0914”(association)	0.560
ODAPH	TCAF2	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
MRPS34	ZZEF1	psi-mi:“MI:0914”(association)	0.530
NIPSNAP3A	CLUH	psi-mi:“MI:0914”(association)	0.530
TUFM	MTIF2	psi-mi:“MI:0914”(association)	0.530
PDHX	MTIF2	psi-mi:“MI:0914”(association)	0.530
SDHB	POLG	psi-mi:“MI:0914”(association)	0.530
COX5B	COX7A2L	psi-mi:“MI:0914”(association)	0.530
PREPL	H1-2	psi-mi:“MI:0915”(physical association)	0.400
NS	PREPL	psi-mi:“MI:0915”(physical association)	0.370
PREPL	NS2	psi-mi:“MI:0915”(physical association)	0.370
PREPL	NS	psi-mi:“MI:0915”(physical association)	0.370
LRRK2		psi-mi:“MI:0914”(association)	0.350
PREPL	BCKDHA	psi-mi:“MI:0914”(association)	0.350
PREPL	PMPCB	psi-mi:“MI:0914”(association)	0.350
PREPL	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
USP22	CNOT1	psi-mi:“MI:0914”(association)	0.350
ARHGAP36	HAX1	psi-mi:“MI:0914”(association)	0.350
IMMP2L	ANKHD1-EIF4EBP3	psi-mi:“MI:0914”(association)	0.350
ESR2		psi-mi:“MI:0914”(association)	0.350
MRM2	ZZEF1	psi-mi:“MI:0914”(association)	0.350

BioGRID (125): PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), GOT2 (Affinity Capture-MS), PMPCA (Affinity Capture-MS), C1QBP (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS), PREPL (Affinity Capture-MS)

ESM2 similar proteins: A5LFV8, A6NC97, B0JZ65, D3ZGS3, O12990, O19064, O23969, O60674, P23458, P42658, P42659, P46101, P52332, P97321, Q01968, Q06137, Q09178, Q13939, Q14BI7, Q16KN5, Q28068, Q2TBM9, Q32N48, Q4J6C6, Q5HZA6, Q5IS50, Q5RAK4, Q5RB23, Q5XI58, Q5ZKL5, Q62120, Q62689, Q6DNF3, Q6J5K9, Q6NVF0, Q6NXK7, Q6P5U7, Q6Q629, Q75R65, Q7JKY3

Diamond homologs: A0A1Q3EPF5, A0A4S8L6U5, A5LFV8, E2JFG1, E2JFG2, H2E7Q7, H2E7Q8, O07834, O70196, P23687, P48147, P55577, P81171, P9WEN5, Q06903, Q32N48, Q4J6C6, Q5RAK4, Q86AS5, Q8C167, Q9QUR6, Q9XTA2, P24555, Q5HZA6, Q5ZKL5, P55656, Q59536

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 105 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
Mitochondrial translation initiation	11	19.9×	1e-09
Mitochondrial translation elongation	11	19.9×	1e-09
Mitochondrial translation	10	19.7×	7e-09
Mitochondrial ribosome-associated quality control	10	17.5×	2e-08
Mitochondrial translation termination	10	15.7×	4e-08
Mitochondrial protein degradation	6	9.8×	1e-03
Translation	11	9.8×	7e-07
Respiratory electron transport	7	9.5×	3e-04

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	5	52.2×	9e-06
mitochondrial translation	12	21.9×	1e-10
translation	7	7.6×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	90
Likely pathogenic	22
Uncertain significance	441
Likely benign	309
Benign	54

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1064457	NM_000341.4(SLC3A1):c.1370dup (p.Leu457fs)	Pathogenic
1071553	NM_000341.4(SLC3A1):c.1699_1700del (p.Arg567fs)	Pathogenic
1073068	NC_000002.11:g.(?44527110)(44545243_?)dup	Pathogenic
1073815	NM_001171613.2(PREPL):c.-49+1802T>A	Pathogenic
1076230	NC_000002.11:g.(?44507855)(44549039_?)del	Pathogenic
1076231	NC_000002.11:g.(?44549870)(44556251_?)del	Pathogenic
1076232	NC_000002.11:g.(?44527090)(44556271_?)del	Pathogenic
1416920	NM_001171613.2(PREPL):c.1729G>T (p.Glu577Ter)	Pathogenic
1424295	NM_001171613.2(PREPL):c.1261C>T (p.Arg421Ter)	Pathogenic
1448058	NM_001171613.2(PREPL):c.196C>T (p.Gln66Ter)	Pathogenic
1452633	NM_001171613.2(PREPL):c.634del (p.Tyr212fs)	Pathogenic
1454890	NC_000002.11:g.(?44502646)(44586854_?)del	Pathogenic
1458585	NC_000002.11:g.(?44553841)(44566512_?)del	Pathogenic
1459037	NC_000002.11:g.(?44527110)(44550550_?)del	Pathogenic
1459197	NC_000002.11:g.(?44548495)(44586854_?)del	Pathogenic
145998	GRCh38/hg38 2p21(chr2:44303991-44325759)x1	Pathogenic
1950915	NM_001171613.2(PREPL):c.-49+1843_-49+1844del	Pathogenic
1976666	NM_001171613.2(PREPL):c.-49+1778C>A	Pathogenic
2422935	NC_000002.11:g.(?44547318)(44586854_?)del	Pathogenic
2425473	NC_000002.11:g.(?44565470)(44586854_?)del	Pathogenic
2425474	NC_000002.11:g.(?44547318)(44569711_?)del	Pathogenic
2425476	NC_000002.11:g.(?44565470)(44566522_?)del	Pathogenic
2425478	NC_000002.11:g.(?44547318)(44556271_?)del	Pathogenic
2730921	NM_001171613.2(PREPL):c.-49+1826dup	Pathogenic
2734176	NM_000341.4(SLC3A1):c.1640C>A (p.Ser547Ter)	Pathogenic
2734179	NM_000341.4(SLC3A1):c.1812_1813del (p.Leu605fs)	Pathogenic
2734181	NM_000341.4(SLC3A1):c.1975C>T (p.Gln659Ter)	Pathogenic
2792645	NM_001171613.2(PREPL):c.1250_1251del (p.Tyr417fs)	Pathogenic
3064482	NM_001171613.2(PREPL):c.71_72insCT (p.Glu25fs)	Pathogenic
3247123	NC_000002.11:g.(?44513151)(44586854_?)del	Pathogenic

SpliceAI

2306 predictions. Top by Δscore:

Variant	Effect	Δscore
2:44322727:CTA:C	donor_loss	1.0000
2:44322728:TA:T	donor_loss	1.0000
2:44322729:ACCT:A	donor_loss	1.0000
2:44322730:C:CT	donor_loss	1.0000
2:44322850:TAATG:T	acceptor_gain	1.0000
2:44322851:AATG:A	acceptor_gain	1.0000
2:44322852:ATG:A	acceptor_gain	1.0000
2:44322853:TG:T	acceptor_gain	1.0000
2:44322854:GC:G	acceptor_loss	1.0000
2:44322855:C:CC	acceptor_gain	1.0000
2:44322855:CTGAA:C	acceptor_loss	1.0000
2:44322856:T:G	acceptor_loss	1.0000
2:44323292:A:C	donor_gain	1.0000
2:44323306:T:TA	donor_gain	1.0000
2:44328933:TCA:T	donor_loss	1.0000
2:44328934:CAC:C	donor_loss	1.0000
2:44328935:A:AC	donor_gain	1.0000
2:44328935:ACC:A	donor_loss	1.0000
2:44328936:C:CC	donor_gain	1.0000
2:44329108:CCATC:C	acceptor_gain	1.0000
2:44329109:CATCC:C	acceptor_gain	1.0000
2:44329111:TCC:T	acceptor_loss	1.0000
2:44329113:C:CA	acceptor_loss	1.0000
2:44329114:T:C	acceptor_loss	1.0000
2:44339338:T:TC	acceptor_gain	1.0000
2:44339359:AGTAG:A	acceptor_gain	1.0000
2:44339361:TAG:T	acceptor_gain	1.0000
2:44339364:C:CC	acceptor_gain	1.0000
2:44342413:GTACC:G	donor_loss	1.0000
2:44342414:TA:T	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000021104 (2:44351623 G>A,T), RS1000095488 (2:44344845 T>C), RS1000115350 (2:44360394 T>C), RS1000119193 (2:44361271 A>C), RS1000158305 (2:44349142 G>A), RS1000231268 (2:44317724 T>C), RS1000240343 (2:44360518 C>A,T), RS1000252533 (2:44317560 C>T), RS1000262800 (2:44349413 C>A,G,T), RS1000281858 (2:44355759 A>T), RS1000349220 (2:44358838 A>T), RS1000375052 (2:44326386 T>A,C), RS1000423905 (2:44317746 C>G), RS1000475910 (2:44336374 T>C), RS1000502866 (2:44363280 A>C,T)

Disease associations

OMIM: gene MIM:609557 | disease phenotypes: MIM:220100, MIM:616224

GenCC curated gene-disease

Disease	Classification	Inheritance
myasthenic syndrome, congenital, 22	Strong	Autosomal recessive
hypotonia-cystinuria syndrome	Strong	Autosomal recessive

Mondo (6): cystinuria (MONDO:0009067), myasthenic syndrome, congenital, 22 (MONDO:0044299), intellectual disability (MONDO:0001071), kidney disorder (MONDO:0005240), premature menopause (MONDO:0001119), hypotonia-cystinuria syndrome (MONDO:0011669)

Orphanet (2): Cystinuria (Orphanet:214), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

36 total (30 of 36 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000135	Hypogonadism
HP:0000268	Dolichocephaly
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000358	Posteriorly rotated ears
HP:0000508	Ptosis
HP:0000527	Long eyelashes
HP:0000787	Nephrolithiasis
HP:0000824	Decreased response to growth hormone stimulation test
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001324	Muscle weakness
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001558	Decreased fetal movement
HP:0001611	Hypernasal speech
HP:0001943	Hypoglycemia
HP:0002007	Frontal bossing
HP:0002342	Moderate intellectual disability
HP:0002515	Waddling gait
HP:0002591	Polyphagia
HP:0002901	Hypocalcemia
HP:0003128	Lactic acidosis
HP:0003131	Cystinuria
HP:0003577	Congenital onset
HP:0003701	Proximal muscle weakness
HP:0004322	Short stature

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST003341_14	antipsychotic drug dosage in schizophrenia or schizoaffective disorder	5.000000e-06
GCST010002_389	Refractive error	3.000000e-26
GCST010121_4	Ceramide levels (C24:0)	5.000000e-06
GCST011494_93	Daytime nap	5.000000e-11
GCST012490_600	Femur bone mineral density x serum urate levels interaction	2.000000e-10
GCST012490_7	Femur bone mineral density x serum urate levels interaction	1.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007792	antipsychotic drug use measurement
EFO:0007828	daytime rest measurement
EFO:0004531	urate measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D003555	Cystinuria	C12.050.351.968.419.815.885.250; C12.200.777.419.815.885.250; C12.950.419.815.885.250; C16.320.831.885.250
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D007674	Kidney Diseases	C12.050.351.968.419; C12.200.777.419; C12.950.419
D008594	Menopause, Premature	C12.050.351.500.056.630.250; C12.100.250.056.630.250; G08.686.157.500.500; G08.686.841.249.500.500
C564710	Hypotonia-Cystinuria Syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2189128 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — S9: Prolyl oligopeptidase

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 8 [PMID: 21692504]	Inhibition	5.22	pIC50

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases expression	2
Hydrogen Peroxide	affects expression, increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases expression, increases abundance	1
bisphenol A	increases expression	1
salinomycin	decreases expression	1
trichostatin A	affects expression	1
methylparaben	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
nickel chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases abundance	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
entinostat	increases expression	1
K 7174	increases expression	1
nutlin 3	increases secretion, affects cotreatment	1
ICG 001	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	affects cotreatment, increases expression	1
jinfukang	decreases expression	1
NSC 689534	affects binding, increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases expression, increases abundance, affects cotreatment	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	affects methylation	1
Asbestos	affects expression	1
Benzo(a)pyrene	affects methylation	1
Carbamazepine	affects expression	1
Cocaine	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2209082	Binding	Inhibition of PREPL binding to FP-biotin in [12C][14N]-lysine, arginine and [13C6][15N2]-lysine, arginine labeled HEK293T cells at 20 uM after 1 hr by isotopic activity-based protein profiling-MudPIT assay	Discovery and optimization of sulfonyl acrylonitriles as selective, covalent inhibitors of protein phosphatase methylesterase-1. — J Med Chem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_TG57	HAP1 PREPL (-) 1	Cancer cell line	Male
CVCL_XR87	HAP1 PREPL (-) 2	Cancer cell line	Male
CVCL_XR88	HAP1 PREPL (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02125721	PHASE4	COMPLETED	Effect of Increasing Doses of Cystine Binding Thiol Drugs on Cystine Capacity in Patients With Cystinuria
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
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