PARL

Summary

PARL (presenilin associated rhomboid like, HGNC:18253) is a protein-coding gene on chromosome 3q27.1, encoding Presenilin-associated rhomboid-like protein, mitochondrial (Q9H300). Required for the control of apoptosis during postnatal growth. It is a selective cancer dependency (DepMap: 10.3% of cell lines).

This gene encodes a member of the rhomboid family of intramembrane serine proteases that is localized to the inner mitochondrial membrane. The encoded protein regulates mitochondrial remodeling and apoptosis through regulated substrate proteolysis. Proteolytic processing of the encoded protein results in the release of a small peptide, P-beta, which may transit to the nucleus. Mutations in this gene may be associated with Parkinson’s disease.

Source: NCBI Gene 55486 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 77 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 10.3% of screened cell lines
• MANE Select transcript: NM_018622

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18253
Approved symbol	PARL
Name	presenilin associated rhomboid like
Location	3q27.1
Locus type	gene with protein product
Status	Approved
Aliases	PRO2207, PSARL1, RHBDS1
Ensembl gene	ENSG00000175193
Ensembl biotype	protein_coding
OMIM	607858
Entrez	55486

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 13 protein_coding, 3 nonsense_mediated_decay, 2 retained_intron

ENST00000311101, ENST00000317096, ENST00000417784, ENST00000418450, ENST00000421484, ENST00000435888, ENST00000449306, ENST00000450375, ENST00000469056, ENST00000488202, ENST00000638817, ENST00000639100, ENST00000639900, ENST00000870311, ENST00000870312, ENST00000931664, ENST00000931665, ENST00000931666

RefSeq mRNA: 5 — MANE Select: NM_018622 NM_001037639, NM_001324436, NM_001324437, NM_001324438, NM_018622

CCDS: CCDS3248, CCDS33897, CCDS82878

Canonical transcript exons

ENST00000317096 — 10 exons

Exon	Start	End
ENSE00000000143	183884722	183884880
ENSE00001276172	183862753	183862801
ENSE00003508162	183833492	183833589
ENSE00003541661	183842298	183842447
ENSE00003568714	183844231	183844326
ENSE00003602497	183866625	183866765
ENSE00003652772	183840570	183840640
ENSE00003674704	183867865	183868060
ENSE00003688290	183833724	183833825
ENSE00003900005	183829271	183829709

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 96.37.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.1918 / max 94.3440, expressed in 1812 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45849	17.1918	1812

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	96.37	gold quality
leukocyte	CL:0000738	96.28	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.20	gold quality
thymus	UBERON:0002370	95.48	gold quality
apex of heart	UBERON:0002098	95.46	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.33	gold quality
body of pancreas	UBERON:0001150	95.32	gold quality
mucosa of stomach	UBERON:0001199	95.03	gold quality
putamen	UBERON:0001874	94.90	gold quality
mucosa of transverse colon	UBERON:0004991	94.89	gold quality
tibial artery	UBERON:0007610	94.88	gold quality
popliteal artery	UBERON:0002250	94.87	gold quality
rectum	UBERON:0001052	94.73	gold quality
substantia nigra	UBERON:0002038	94.67	gold quality
pancreas	UBERON:0001264	94.65	gold quality
granulocyte	CL:0000094	94.63	gold quality
cortex of kidney	UBERON:0001225	94.57	gold quality
cardiac atrium	UBERON:0002081	94.53	gold quality
right atrium auricular region	UBERON:0006631	94.53	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.49	gold quality
lower esophagus	UBERON:0013473	94.48	gold quality
colon	UBERON:0001155	94.46	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.43	gold quality
heart left ventricle	UBERON:0002084	94.40	gold quality
hypothalamus	UBERON:0001898	94.39	gold quality
prostate gland	UBERON:0002367	94.39	gold quality
caudate nucleus	UBERON:0001873	94.28	gold quality
nerve	UBERON:0001021	94.27	gold quality
tibial nerve	UBERON:0001323	94.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	885.79
E-ANND-3	yes	6.10

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting PARL, 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-4283	100.00	66.42	2097
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-501-3P	99.33	66.12	651
HSA-MIR-502-3P	99.33	66.12	651
HSA-MIR-28-3P	96.42	67.18	579
HSA-MIR-4462	95.10	66.27	172

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 10.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 29)

• PARL might mediate a developmentally regulated mitochondria-to-nuclei signaling through regulated proteolysis of its N terminus and release of the Pbeta peptide (PMID:14732705)
• Variation in PSARL sequence and/or expression may be an important new risk factor for type 2 diabetes and other components of the metabolic syndrome. (PMID:15729572)
• The Leu262Val variant is unlikely to be an important contributor to insulin resistance. (PMID:17019603)
• the PARL rs3732581 genetic variant may have a role in insulin levels, metabolic syndrome and coronary artery disease (PMID:18758826)
• Genetic variation of PARL may indicate earlier onset of type 2 diabetes and increased susceptibility to nephropathy and cardiovascular complications. (PMID:19185381)
• results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing. (PMID:19680265)
• Results suggest that genetic variation within PARL influences mitochondrial abundance and integrity. (PMID:19862556)
• variants of PARL are suggested to influence cell death by apoptosis which has long been believed to intrigue the neurodegeneration of LHON. (PMID:20407791)
• Data show that no association between PARL gene SNPs and LHON in Chinese patients with m.11778G>A. (PMID:20711738)
• Mitochondrial protease PARL cleaves PINK1 at position A103. (PMID:21138942)
• PARL deficiency impairs PARKIN recruitment to mitochondria. (PMID:21355049)
• work provides unexpected insights into the structural determinants regulating Parl stability and activity in vivo, and reveals a complex cascade of proteolytic events controlling the function of the protease in the mitochondrion (PMID:21415861)
• the PARL-catalyzed removal of the Pink1 signal sequence in the canonical import pathway acts as a cellular checkpoint for mitochondrial integrity (PMID:21426348)
• p.S77N variant, and, possibly, mutations in the PARL protein overall, are not a frequent cause of autosomal recessive early-onset Parkinson’s disease (PMID:21953724)
• Rhomboid protease PARL mediates the mitochondrial membrane potential loss-induced cleavage of PGAM5. (PMID:22915595)
• the frequency of the haplotype AAC, and AAT were significantly higher in the unaffected cases and the frequencies of haplotype GGT were significantly higher in LHON cases (PMID:23973714)
• Common genetic variants of the PINK1 and PARL genes are unlikely to be involved in schizophrenia. (PMID:25354644)
• pathogenic PINK1 mutants which are not cleaved by PARL affect PINK1 kinase activity and the ability to induce PARK2-mediated mitophagy. (PMID:26101826)
• Its mutations are a rare cause of PD and genetic variants are neither strong nor common risk factors in Parkinson disease. (PMID:26778534)
• Study confirmed that common variants in PARL and PINK1 were associated with leprosy. Furthermore, PARL and PINK1 could physically interact with each other and were involved in the highly connected network formed by reported leprosy susceptibility genes. (PMID:27876828)
• PDK2/PARL senses defects in mitochondrial bioenergetics. (PMID:28178523)
• These results reveal a pro-apoptotic function of PARL and identify PARL-mediated Smac processing and cytochrome c release facilitated by OPA1-dependent cristae remodelling as two independent pro-apoptotic pathways in mitochondria. (PMID:28288130)
• Adipogenic process can be dissected into 3 stages according to the participation of PARL-PINK1-Parkin system. Findings reveal the sequential adipogenic events directed by PARL-PINK1-Parkin system, add more evidence supporting the convergence of pathogenesis leading to neurodegenerative and metabolic disease (PMID:28641777)
• These findings enrich the allelic spectrum of ABCC5 in PACG. We identified no tagging SNP responsible for the association of the whole region. (PMID:28813580)
• PARL preserves mitochondrial membrane homeostasis via STARD7 processing and is emerging as a critical regulator of protein localization between mitochondria and the cytosol (PMID:29301859)
• Proapoptotic Mitochondrial Carrier Homolog Protein PSAP Mediates Death Receptor 6 Induced Apoptosis. (PMID:32144986)
• PARL Protease: A Glimpse at Intramembrane Proteolysis in the Inner Mitochondrial Membrane. (PMID:32320686)
• Accumulation of HAX-1 and PARL in brainstem- and cortical-type Lewy bodies in Parkinson’s disease and dementia with Lewy bodies. (PMID:32470650)
• Cleavage of mitochondrial homeostasis regulator PGAM5 by the intramembrane protease PARL is governed by transmembrane helix dynamics and oligomeric state. (PMID:35921890)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	parlb	ENSDARG00000020891
danio_rerio	parla	ENSDARG00000039310
mus_musculus	Parl	ENSMUSG00000033918
rattus_norvegicus	Parl	ENSRNOG00000023271
drosophila_melanogaster	rho-7	FBGN0033672
caenorhabditis_elegans	rom-5	WBGENE00004404

Paralogs (5): RHBDF1 (ENSG00000007384), RHBDL1 (ENSG00000103269), RHBDF2 (ENSG00000129667), RHBDL3 (ENSG00000141314), RHBDL2 (ENSG00000158315)

Protein

Protein identifiers

Presenilin-associated rhomboid-like protein, mitochondrial — Q9H300 (reviewed: Q9H300)

Alternative names: Mitochondrial intramembrane cleaving protease PARL

All UniProt accessions (9): A0A1W2PP66, A0A1W2PS40, C9JNP8, F8WCQ4, Q9H300, H7C045, H7C0U0, H7C122, H7C1V6

UniProt curated annotations — full annotation on UniProt →

Function. Required for the control of apoptosis during postnatal growth. Essential for proteolytic processing of an antiapoptotic form of OPA1 which prevents the release of mitochondrial cytochrome c in response to intrinsic apoptotic signals. Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP). Promotes cleavage of serine/threonine-protein phosphatase PGAM5 in damaged mitochondria in response to loss of mitochondrial membrane potential. Mediates differential cleavage of PINK1 and PGAM5 depending on the health status of mitochondria, disassociating from PINK1 and associating with PGAM5 in response to mitochondrial membrane potential loss. Required for processing of CLPB into a form with higher protein disaggregase activity by removing an autoinhibitory N-terminal peptide. Promotes processing of DIABLO/SMAC in the mitochondrion which is required for DIABLO apoptotic activity. Also required for cleavage of STARD7 and TTC19. Promotes changes in mitochondria morphology regulated by phosphorylation of P-beta domain.

Subunit / interactions. Interacts with PSEN1 and PSEN2. Binds OPA1.

Subcellular location. Mitochondrion inner membrane Nucleus.

Post-translational modifications. P-beta is proteolytically processed (beta-cleavage) in a PARL-dependent manner. The cleavage is inhibited when residues Ser-65, Thr-69 and Ser-70 are all phosphorylated.

Similarity. Belongs to the peptidase S54 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H300-1	1	yes
Q9H300-2	2

RefSeq proteins (5): NP_001032728, NP_001311365, NP_001311366, NP_001311367, NP_061092* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR022764	Peptidase_S54_rhomboid_dom	Domain
IPR035952	Rhomboid-like_sf	Homologous_superfamily
IPR050925	Rhomboid_protease_S54	Family

Pfam: PF01694

Enzyme classification (BRENDA):

• EC 3.4.21.105 — rhomboid protease (BRENDA: 42 organisms, 229 substrates, 68 inhibitors, 19 Km, 19 kcat entries)

Substrate kinetics (BRENDA)

4 substrates with measured Km, best-characterized 4. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
BODIPY FL CASEIN	0.0007–0.0029	12
FL-CASEIN	0.0018–0.0065	3
TATA	0.0076–0.119	3
CYPET-TATA-YPET	0.0039	1

UniProt features (37 total): mutagenesis site 11, topological domain 8, transmembrane region 7, modified residue 3, active site 2, sequence variant 2, transit peptide 1, chain 1, peptide 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H300-F1	77.67	0.57

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): 277 (nucleophile); 335

Post-translational modifications (3): 65, 69, 70

Mutagenesis-validated functional residues (11):

Position	Phenotype
65	strongly reduces the beta cleavage; when associated with d-69 and d-70.
69	strongly reduces the beta cleavage; when associated with d-65 and d-70.
70	strongly reduces the beta cleavage; when associated with d-65 and d-69.
76	abolishes the beta cleavage.
77	abolishes the beta cleavage.
78	abolishes the beta cleavage.
79	abolishes the beta cleavage.
277	loss of cleavage of clpb, diablo, stard7 and ttc19.
277	loss of pgam5 cleavage.
335	loss of pgam5 cleavage.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8949664	Processing of SMDT1

MSigDB gene sets: 157 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, AAGCCAT_MIR135A_MIR135B, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MACROAUTOPHAGY, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_REGULATION_OF_MITOCHONDRION_ORGANIZATION, GOBP_PROTEIN_MATURATION, GOBP_NEGATIVE_REGULATION_OF_INTRINSIC_APOPTOTIC_SIGNALING_PATHWAY, GOBP_APOPTOTIC_SIGNALING_PATHWAY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_REGULATION_OF_RELEASE_OF_CYTOCHROME_C_FROM_MITOCHONDRIA, GOBP_RELEASE_OF_CYTOCHROME_C_FROM_MITOCHONDRIA, GOBP_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_METABOLIC_PROCESS

GO Biological Process (12): obsolete signal peptide processing (GO:0006465), proteolysis (GO:0006508), mitochondrial fusion (GO:0008053), regulation of mitochondrion organization (GO:0010821), protein processing (GO:0016485), regulation of proteolysis (GO:0030162), membrane protein proteolysis (GO:0033619), negative regulation of release of cytochrome c from mitochondria (GO:0090201), regulation of mitophagy (GO:1901524), obsolete regulation of protein targeting to mitochondrion (GO:1903214), regulation of reactive oxygen species metabolic process (GO:2000377), negative regulation of intrinsic apoptotic signaling pathway (GO:2001243)

GO Molecular Function (6): endopeptidase activity (GO:0004175), serine-type endopeptidase activity (GO:0004252), protein binding (GO:0005515), peptidase activity (GO:0008233), serine-type peptidase activity (GO:0008236), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Mitochondrial calcium ion transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
proteolysis	3
mitochondrion organization	2
negative regulation of apoptotic signaling pathway	2
peptidase activity	2
intracellular membrane-bounded organelle	2
protein metabolic process	1
organelle fusion	1
regulation of organelle organization	1
protein maturation	1
regulation of protein metabolic process	1
release of cytochrome c from mitochondria	1
negative regulation of organelle organization	1
regulation of release of cytochrome c from mitochondria	1
mitophagy	1
regulation of macroautophagy	1
regulation of autophagy of mitochondrion	1
regulation of metabolic process	1
reactive oxygen species metabolic process	1
intrinsic apoptotic signaling pathway	1
negative regulation of intracellular signal transduction	1
regulation of intrinsic apoptotic signaling pathway	1
endopeptidase activity	1
serine-type peptidase activity	1
binding	1
hydrolase activity	1
catalytic activity, acting on a protein	1
serine hydrolase activity	1
catalytic activity	1
cytoplasm	1
organelle inner membrane	1
mitochondrial membrane	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1524 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PARL	PINK1	Q9BXM7	928
PARL	HTRA2	O43464	910
PARL	YME1L1	Q96TA2	903
PARL	OPA1	O60313	883
PARL	HAX1	O00165	822
PARL	PHB2	Q99623	818
PARL	OMA1	Q96E52	779
PARL	PGAM5	Q96HS1	770
PARL	PRKN	O60260	765
PARL	MFN1	Q8IWA4	763
PARL	MFN2	O95140	741
PARL	RHBDL1	O75783	687
PARL	FUNDC1	Q8IVP5	686
PARL	AFG3L2	Q9Y4W6	685
PARL	SPG7	Q9UQ90	677

IntAct

40 interactions, top by confidence:

A	B	Type	Score
SLC7A1	TMEM223	psi-mi:“MI:0914”(association)	0.530
VSIG4	TCAF2	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
SYP	APBB1	psi-mi:“MI:0914”(association)	0.530
ITGB8	GET1	psi-mi:“MI:0914”(association)	0.530
CHST10	B4GAT1	psi-mi:“MI:0914”(association)	0.530
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
ERGIC3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CD80	POTEF	psi-mi:“MI:0914”(association)	0.350
C5AR1	TCAF2	psi-mi:“MI:0914”(association)	0.350
BSG	METTL15	psi-mi:“MI:0914”(association)	0.350
KIR2DS5	METTL15	psi-mi:“MI:0914”(association)	0.350
GLMP	RTL8C	psi-mi:“MI:0914”(association)	0.350
SLC22A4	RTL8C	psi-mi:“MI:0914”(association)	0.350
RAMP3	GOLIM4	psi-mi:“MI:0914”(association)	0.350
CD79B	GOLIM4	psi-mi:“MI:0914”(association)	0.350
TACR3	TCAF2	psi-mi:“MI:0914”(association)	0.350
GPR12	TLCD2	psi-mi:“MI:0914”(association)	0.350
CPQ	COX7A2L	psi-mi:“MI:0914”(association)	0.350
RBFOX2	PRMT5	psi-mi:“MI:0914”(association)	0.350
FAM131B	UQCRQ	psi-mi:“MI:0914”(association)	0.350
GAA	ENTPD6	psi-mi:“MI:0914”(association)	0.350
PARL	CCDC92	psi-mi:“MI:0914”(association)	0.350
FFAR1	SLC12A8	psi-mi:“MI:0914”(association)	0.350
GPR182	SLC12A8	psi-mi:“MI:0914”(association)	0.350
SLC2A1	SLC33A1	psi-mi:“MI:0914”(association)	0.350
RAMP3	MGST3	psi-mi:“MI:0914”(association)	0.350
RAMP3	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (254): PARL (Affinity Capture-MS), ENAH (Affinity Capture-MS), EEF2KMT (Affinity Capture-MS), CA10 (Affinity Capture-MS), HIST2H2AB (Affinity Capture-MS), PARL (Affinity Capture-MS), PARL (Affinity Capture-MS), PARL (Affinity Capture-MS), EEF2KMT (Affinity Capture-MS), CA10 (Affinity Capture-MS), PARL (Affinity Capture-MS), ENAH (Affinity Capture-MS), PARL (Affinity Capture-MS), PARL (Affinity Capture-MS), PARL (Affinity Capture-MS)

ESM2 similar proteins: A2RVP7, A2VDV9, A4IFL0, O14925, O35093, O35094, O35857, O43615, O60830, P0CR88, P0CR89, P59670, Q02921, Q2HJE9, Q2KHV4, Q2UAP8, Q38820, Q3B8P0, Q3ZBE6, Q4V8S3, Q5BIN4, Q5M7K0, Q5R5H4, Q5RDD0, Q5REX0, Q5SRD1, Q5U4F4, Q5U4U5, Q5XH94, Q5XJY4, Q5ZLL0, Q6BZY4, Q6GQ39, Q6INU6, Q6NWD4, Q7T2P6, Q86UB9, Q9C1E8, Q9CQ85, Q9CYV5

Diamond homologs: A1Z8R8, O14364, Q2KHV4, Q3B8P0, Q58EK4, Q5R5H4, Q5XJY4, Q9H300, P53259, F4ICF4, P54493, Q9FZ81

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
PARL	“down-regulates quantity by destabilization”	PINK1	cleavage
PDK2	“up-regulates activity”	PARL	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	56
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1778 predictions. Top by Δscore:

Variant	Effect	Δscore
3:183833485:AACTT:A	donor_loss	1.0000
3:183833486:ACTT:A	donor_loss	1.0000
3:183833487:CTT:C	donor_loss	1.0000
3:183833488:TTA:T	donor_loss	1.0000
3:183833489:TA:T	donor_loss	1.0000
3:183833490:A:AC	donor_gain	1.0000
3:183833490:A:AG	donor_loss	1.0000
3:183833490:ACATT:A	donor_gain	1.0000
3:183833491:C:CG	donor_gain	1.0000
3:183833491:CA:C	donor_gain	1.0000
3:183833491:CAT:C	donor_gain	1.0000
3:183833491:CATT:C	donor_gain	1.0000
3:183833491:CATTC:C	donor_gain	1.0000
3:183833494:T:A	donor_gain	1.0000
3:183833590:C:CA	acceptor_loss	1.0000
3:183833590:C:CC	acceptor_gain	1.0000
3:183833599:A:T	acceptor_gain	1.0000
3:183833722:A:AC	donor_gain	1.0000
3:183833722:ACATT:A	donor_gain	1.0000
3:183833723:C:CC	donor_gain	1.0000
3:183833723:CATT:C	donor_gain	1.0000
3:183833723:CATTC:C	donor_gain	1.0000
3:183833821:CCAGA:C	acceptor_gain	1.0000
3:183833822:CAGA:C	acceptor_gain	1.0000
3:183833822:CAGAC:C	acceptor_gain	1.0000
3:183833824:GA:G	acceptor_gain	1.0000
3:183833826:C:CC	acceptor_gain	1.0000
3:183833840:A:T	acceptor_gain	1.0000
3:183840564:ACTT:A	donor_loss	1.0000
3:183840565:CTTA:C	donor_gain	1.0000

AlphaMissense

2473 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:183833495:C:T	G342E	1.000
3:183833565:C:G	D319H	1.000
3:183842372:A:T	V228D	1.000
3:183842394:G:C	H221D	1.000
3:183829648:A:G	W364R	0.999
3:183829648:A:T	W364R	0.999
3:183829667:C:A	R357S	0.999
3:183829667:C:G	R357S	0.999
3:183829668:C:A	R357M	0.999
3:183829676:C:A	W354C	0.999
3:183829676:C:G	W354C	0.999
3:183829678:A:G	W354R	0.999
3:183829678:A:T	W354R	0.999
3:183829692:C:T	G349D	0.999
3:183833496:C:G	G342R	0.999
3:183833496:C:T	G342R	0.999
3:183833507:C:A	G338V	0.999
3:183833507:C:T	G338E	0.999
3:183833508:C:G	G338R	0.999
3:183833508:C:T	G338R	0.999
3:183833510:C:T	G337E	0.999
3:183833511:C:G	G337R	0.999
3:183833511:C:T	G337R	0.999
3:183833513:A:G	L336P	0.999
3:183833515:A:C	H335Q	0.999
3:183833515:A:T	H335Q	0.999
3:183833517:G:C	H335D	0.999
3:183833517:G:T	H335N	0.999
3:183833528:T:A	D331V	0.999
3:183833541:A:G	W327R	0.999

dbSNP variants (sampled 300 via entrez): RS1000053611 (3:183881397 C>T), RS1000102627 (3:183844170 T>C), RS1000124261 (3:183869026 A>G), RS1000127779 (3:183878070 C>A,G,T), RS1000137458 (3:183840828 C>T), RS1000218406 (3:183882629 AT>A,ATT), RS1000266938 (3:183876338 T>C), RS1000322783 (3:183842049 G>A,T), RS1000332384 (3:183829902 C>A,T), RS1000410947 (3:183878245 G>A,C), RS1000462129 (3:183836038 A>C,G), RS1000462723 (3:183876899 C>T), RS1000496012 (3:183859407 G>A), RS1000510591 (3:183859471 G>A), RS1000568931 (3:183882825 A>G)

Disease associations

OMIM: gene MIM:607858 | disease phenotypes: MIM:609888

GenCC curated gene-disease

Mondo (1): leprosy, susceptibility to, 1 (MONDO:0012358)

Orphanet (1): Leprosy (Orphanet:548)

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002383_1	Anterior chamber depth	8.000000e-09
GCST005312_9	Menopause (age at onset)	3.000000e-09
GCST008473_21	Visceral fat	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879516 (SINGLE PROTEIN)

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

ChEMBL bioactivities

35 potent at pChembl≥5 of 36 total, top 34 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.35	Kd	4.508	nM	CHEMBL3752910
8.35	ED50	4.508	nM	CHEMBL3752910
7.55	IC50	28	nM	CHEMBL5419931
7.46	IC50	35	nM	CHEMBL5405012
7.38	IC50	42	nM	CHEMBL5590380
7.33	IC50	47	nM	CHEMBL5593588
7.30	IC50	50	nM	CHEMBL5595990
7.28	IC50	52	nM	CHEMBL5591199
7.28	EC50	52	nM	CHEMBL5591199
7.23	IC50	59	nM	CHEMBL5590363
7.10	IC50	80	nM	CHEMBL5428186
6.82	IC50	150	nM	CHEMBL5419931
6.82	IC50	150	nM	CHEMBL6078250
6.80	IC50	160	nM	CHEMBL6091763
6.58	IC50	260	nM	CHEMBL6101903
6.57	EC50	270	nM	CHEMBL5595990
6.42	IC50	380	nM	CHEMBL6101800
6.39	IC50	410	nM	CHEMBL5419931
6.35	EC50	445	nM	CHEMBL5419931
6.32	IC50	480	nM	CHEMBL6120267
6.31	IC50	490	nM	CHEMBL6102809
6.25	IC50	560	nM	CHEMBL6142517
6.16	IC50	700	nM	CHEMBL4859980
6.05	IC50	900	nM	CHEMBL4854450
6.05	IC50	890	nM	CHEMBL6078142
6.00	IC50	1000	nM	CHEMBL6134377
5.98	IC50	1042	nM	CHEMBL5432932
5.84	IC50	1430	nM	CHEMBL6082935
5.72	IC50	1900	nM	CHEMBL4855230
5.71	IC50	1930	nM	CHEMBL6078466
5.58	IC50	2600	nM	CHEMBL6134131
5.50	IC50	3200	nM	CHEMBL5428186
5.37	IC50	4300	nM	CHEMBL4861272
5.06	IC50	8800	nM	CHEMBL4856971

PubChem BioAssay actives

22 with measured affinity, of 90 total; 15 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
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149904: Binding affinity to human PARL incubated for 45 mins by Kinobead based pull down assay	kd	0.0045	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-N-[(2S)-3,4-dioxo-4-(4-phenylbutylamino)butan-2-yl]-4-methylpentanamide	1964731: Inhibition of recombinant C-terminal hexahistidine tagged mature human PARL using Ac-RRRAVFLA-4mc as substrate preincubated for 1 hr followed by substrate addition by fluorescence based plate reader assay	ic50	0.0280	uM
(2S)-2-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-(diaminomethylideneamino)-N-[(2S)-1-[[(2S)-3,4-dioxo-4-(4-phenylbutylamino)butan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]pentanamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0350	uM
(2S)-1-acetyl-N-[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-3,4-dioxo-4-(4-phenylbutylamino)butan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0420	uM
(2S)-1-acetyl-N-[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-3,4-dioxo-4-[[(2S)-1-phenyl-3-phenylmethoxypropan-2-yl]amino]butan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]pyrrolidine-2-carboxamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0470	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamidopropanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-N-[(2S)-3,4-dioxo-4-[[(2S)-1-phenyl-3-phenylmethoxypropan-2-yl]amino]butan-2-yl]-4-methylpentanamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0500	uM
(2S)-N-[(2S)-3,4-dioxo-4-(4-phenylbutylamino)butan-2-yl]-4-methyl-2-[[(2S)-2-(3-methylbutanoylamino)-3-phenylpropanoyl]amino]pentanamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0520	uM
(2S)-2-[[(2S)-2-acetamido-3-methylbutanoyl]amino]-5-(diaminomethylideneamino)-N-[(2S)-1-[[(2S)-3,4-dioxo-4-[[(2S)-1-phenyl-3-phenylmethoxypropan-2-yl]amino]butan-2-yl]amino]-3-(1H-imidazol-5-yl)-1-oxopropan-2-yl]pentanamide	2116570: Inhibition of recombinant human PARL using KSp106 as substrate	ic50	0.0590	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]propanoyl]amino]-3-methylbutanoyl]amino]-3-phenylpropanoyl]amino]-N-[(2S)-3,4-dioxo-4-(4-phenylbutylamino)butan-2-yl]-4-methylpentanamide	1964731: Inhibition of recombinant C-terminal hexahistidine tagged mature human PARL using Ac-RRRAVFLA-4mc as substrate preincubated for 1 hr followed by substrate addition by fluorescence based plate reader assay	ic50	0.0800	uM
1-(4-phenylphenyl)sulfonylpyrrolidine-2,5-dione	1768548: Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	ic50	0.7000	uM
1-(4-nitrophenyl)sulfonylpyrrolidine-2,5-dione	1768548: Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	ic50	0.9000	uM
(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-phenylpropanoyl]amino]-6-amino-N-[(2S,3S)-1-[[(2S)-3,4-dioxo-1-phenyl-4-(4-phenylbutylamino)butan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]hexanamide	1964731: Inhibition of recombinant C-terminal hexahistidine tagged mature human PARL using Ac-RRRAVFLA-4mc as substrate preincubated for 1 hr followed by substrate addition by fluorescence based plate reader assay	ic50	1.0420	uM
(2,5-dioxopyrrolidin-1-yl) 4-phenylbenzenesulfonate	1768548: Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	ic50	1.9000	uM
1-(benzenesulfonyl)pyrrolidine-2,5-dione	1768548: Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	ic50	4.3000	uM
(1,1,3-trioxo-1,2-benzothiazol-2-yl)methyl 2-chlorobenzoate	1768548: Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	ic50	8.8000	uM

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
perfluorooctanoic acid	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Sarin	decreases expression	1
Urethane	decreases expression	1
Vitamin E	increases expression	1
Aflatoxin B1	increases methylation	1
Copper Sulfate	decreases expression	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4827762	Binding	Inhibition of human PARL transfected in HEK293T cell membrane assessed as inhibition of FP-Rh labeling treated with compound for 30 mins prior to FP-Rh addition by competitive ABPP based analysis	Development of succinimide-based inhibitors for the mitochondrial rhomboid protease PARL. — Bioorg Med Chem Lett

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3DE	Abcam HEK293T PARL KO	Transformed cell line	Female
CVCL_D9MA	Ubigene HEK293 PARL KO	Transformed cell line	Female
CVCL_E2G5	HAP1 PARL (-) 1	Cancer cell line	Male
CVCL_E2G6	HAP1 PARL (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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