PNLIP

Summary

PNLIP (pancreatic lipase, HGNC:9155) is a protein-coding gene on chromosome 10q25.3, encoding Pancreatic triacylglycerol lipase (P16233). Plays an important role in fat metabolism.

This gene encodes a member of the lipase family of proteins. The encoded enzyme is secreted by the pancreas and hydrolyzes triglycerides in the small intestine, and is essential for the efficient digestion of dietary fats. Inhibition of the encoded enzyme may prevent high-fat diet-induced obesity in mice and result in weight loss in human patients with obesity. Mutations in this gene cause congenital pancreatic lipase deficiency, a rare disorder characterized by steatorrhea.

Source: NCBI Gene 5406 — RefSeq curated summary.

At a glance

• Gene–disease (curated): pancreatic triacylglycerol lipase deficiency (Strong, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 279 total — 14 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 6
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_000936

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9155
Approved symbol	PNLIP
Name	pancreatic lipase
Location	10q25.3
Locus type	gene with protein product
Status	Approved
Aliases	PL
Ensembl gene	ENSG00000175535
Ensembl biotype	protein_coding
OMIM	246600
Entrez	5406

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000369221, ENST00000470562

RefSeq mRNA: 1 — MANE Select: NM_000936 NM_000936

CCDS: CCDS7594

Canonical transcript exons

ENST00000369221 — 13 exons

Exon	Start	End
ENSE00001097273	116551098	116551232
ENSE00001097275	116560416	116560524
ENSE00001097276	116567735	116567855
ENSE00001097277	116555178	116555297
ENSE00001097279	116559154	116559283
ENSE00001097280	116556000	116556118
ENSE00001097284	116555388	116555507
ENSE00001097286	116561472	116561636
ENSE00001148734	116553727	116553838
ENSE00001449232	116545931	116545958
ENSE00003498439	116548360	116548482
ENSE00003578901	116546093	116546138
ENSE00003671547	116547294	116547448

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 99.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 74.0996 / max 133845.4118, expressed in 19 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
107198	73.9592	19
107200	0.1059	3
107199	0.0268	1
206002	0.0077	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	99.97	gold quality
pancreas	UBERON:0001264	99.60	gold quality
islet of Langerhans	UBERON:0000006	99.52	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	94.75	gold quality
type B pancreatic cell	CL:0000169	93.53	gold quality
epithelial cell of pancreas	CL:0000083	92.69	gold quality
right coronary artery	UBERON:0001625	77.55	gold quality
ectocervix	UBERON:0012249	76.86	gold quality
right lobe of liver	UBERON:0001114	76.38	gold quality
metanephros cortex	UBERON:0010533	74.12	gold quality
descending thoracic aorta	UBERON:0002345	73.46	gold quality
endocervix	UBERON:0000458	73.25	gold quality
right uterine tube	UBERON:0001302	72.76	gold quality
right adrenal gland	UBERON:0001233	72.74	gold quality
left uterine tube	UBERON:0001303	72.70	gold quality
left adrenal gland cortex	UBERON:0035825	71.54	gold quality
lower esophagus mucosa	UBERON:0035834	71.08	gold quality
adult organism	UBERON:0007023	70.98	gold quality
left adrenal gland	UBERON:0001234	70.71	gold quality
fundus of stomach	UBERON:0001160	69.94	gold quality
pancreatic ductal cell	CL:0002079	69.48	silver quality
vermiform appendix	UBERON:0001154	69.34	gold quality
duodenum	UBERON:0002114	69.29	gold quality
body of stomach	UBERON:0001161	69.15	gold quality
right adrenal gland cortex	UBERON:0035827	69.10	gold quality
adrenal cortex	UBERON:0001235	68.89	gold quality
thoracic aorta	UBERON:0001515	66.85	gold quality
left ovary	UBERON:0002119	65.86	gold quality
ascending aorta	UBERON:0001496	65.85	gold quality
apex of heart	UBERON:0002098	65.82	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-5061	yes	13723.39
E-GEOD-81547	yes	31.35
E-ENAD-27	yes	7.64
E-HCAD-31	yes	6.11
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 26)

• Review. The structure and function of the pancreatic lipase C2 domains, based on the recent 3D structures and improved sequence alignments are reviewed. (PMID:12369922)
• analysis of human pancreatic lipase from pancreatic juice (BCR693) and a recombinant form (BCR694) (PMID:12667003)
• examination of tryptophan changes in pancreatic lipase (PMID:14580194)
• a specific method of measuring classical pancreatic lipase in human serum (PMID:15316225)
• analysis of a lid hydrophobicity pattern in pancreatic lipase (PMID:16179352)
• pancreatic lipase-colipase interactions in the presence of bile salt micelles are mediated by Val-407 and Ile-408 of PL (PMID:16431912)
• Electron paramagnetic resonance spectroscopy along with site-directed spin labeling was used to monitor the conformational changes in the human PL lid in solution to assess the effects of partners of the lipase, i.e. colipase and bile salts. (PMID:17269661)
• Introducing a negative charge close to the catalytic histidine induced a shift of the pH optimum toward acidic values but strongly reduced the lipase activity. (PMID:18353248)
• The disulfide bridge between the hinges of the lid kept the secondary structure of the lid intact, whereas the HPL was completely unfolded. (PMID:19113953)
• Trp-107 and Trp-253 contribute to the change in steady state fluorescence that is triggered by mixed micelles of inhibitor and bile salt. (PMID:19346257)
• the amplitude of the lid opening measured in solution or in a frozen solution in the presence of amphiphiles (PMID:20136147)
• Combination of two mutations with a promising one at the entrance of the catalytic cavity (K80E) negatively affected the lipase activity at neutral pH but not that at acidic pH. (PMID:20150178)
• Triacylglycerol lipase and alpha-amylase are highly over-expressed in pancreatic cyst fluids in patients with mucinous pancreatic neoplasms. (PMID:22393262)
• Low PNLIP expression is associated with pancreatic cancer. (PMID:23918603)
• a novel mutation in the PNLIP gene in two brothers with congenital pancreatic lipase deficiency (PMID:24262094)
• All these findings support the use of YLLIP2 in enzyme replacement therapy for the treatment of pancreatic exocrine insufficiency, a pathological situation in which an acidification of intestinal contents occurs. (PMID:24650780)
• In patients with intraductal papillary mucinous neoplasm without a history of pancreatitis, serum pancreatic lipase and amylase outside normal range are associated with risk of malignancy. (PMID:25239347)
• Presence of methionine at position 221 in the PNLIP protein sequence causes protein misfolding and aggregation. (PMID:25862608)
• Serum lipase subtype analysis cannot replace the standard lipase measurement for the diagnosis of acute pancreatitis, but the test demonstrated adequate sensitivity for use in triage or as an add-on test for serum lipase elevation. (PMID:27243230)
• Our data indicate that protease-sensitive PNLIP variants are novel genetic risk factors for the development of CP. (PMID:30789418)
• Pancreatic triglyceride lipase mediates lipotoxic systemic inflammation. (PMID:31917686)
• Missense PNLIP mutations impeding pancreatic lipase secretion cause protein misfolding and endoplasmic reticulum stress. (PMID:34373204)
• In vitro anti-obesity activity by pancreatic lipase inhibition - Simple HPLC approach using EVOO as natural substrate. (PMID:36583522)
• Identification of protease-sensitive but not misfolding PNLIP variants in familial and hereditary pancreatitis. (PMID:37270400)
• Pancreatic lipase and its related proteins: where are we now? (PMID:38081381)
• Exploring the enigmatic association between PNLIP variants and risk of chronic pancreatitis in a large Chinese cohort. (PMID:38485544)

Cross-species orthologs

30 orthologs

Organism	Symbol	Gene ID
danio_rerio	lipib	ENSDARG00000005332
danio_rerio		ENSDARG00000034667
mus_musculus	Pnlip	ENSMUSG00000046008
rattus_norvegicus	Pnlip	ENSRNOG00000017725
drosophila_melanogaster	Yp1	FBGN0004045
drosophila_melanogaster	Yp3	FBGN0004047
drosophila_melanogaster	Yp2	FBGN0005391
drosophila_melanogaster	CG5162	FBGN0030828
drosophila_melanogaster	CG6847	FBGN0030884
drosophila_melanogaster	CG7367	FBGN0031976
drosophila_melanogaster	CG13282	FBGN0032612
drosophila_melanogaster	CG6675	FBGN0032973
drosophila_melanogaster	CG6472	FBGN0034166
drosophila_melanogaster	CG10163	FBGN0035697
drosophila_melanogaster	CG10116	FBGN0036367
drosophila_melanogaster	CG5665	FBGN0036977
drosophila_melanogaster	sxe2	FBGN0038398
drosophila_melanogaster	CG4582	FBGN0039344
drosophila_melanogaster	CG6296	FBGN0039470
drosophila_melanogaster	CG6295	FBGN0039471
drosophila_melanogaster	CG17192	FBGN0039472
drosophila_melanogaster	CG17191	FBGN0039473
drosophila_melanogaster	CG6283	FBGN0039474
drosophila_melanogaster	CG6277	FBGN0039475
drosophila_melanogaster	CG6271	FBGN0039476
drosophila_melanogaster	CG34447	FBGN0085476
drosophila_melanogaster	CG34448	FBGN0085477
drosophila_melanogaster	CG14034	FBGN0250847
drosophila_melanogaster	CG4267	FBGN0264979
drosophila_melanogaster	CG18258	FBGN0265267

Paralogs (9): LIPG (ENSG00000101670), PLA1A (ENSG00000144837), LIPH (ENSG00000163898), LIPC (ENSG00000166035), LPL (ENSG00000175445), PNLIPRP1 (ENSG00000187021), LIPI (ENSG00000188992), PNLIPRP3 (ENSG00000203837), PNLIPRP2 (ENSG00000266200)

Protein

Protein identifiers

Pancreatic triacylglycerol lipase — P16233 (reviewed: P16233)

All UniProt accessions (1): P16233

UniProt curated annotations — full annotation on UniProt →

Function. Plays an important role in fat metabolism. It preferentially splits the esters of long-chain fatty acids at positions 1 and 3, producing mainly 2-monoacylglycerol and free fatty acids, and shows considerably higher activity against insoluble emulsified substrates than against soluble ones.

Subunit / interactions. Forms a 1:1 stoichiometric complex with (pro)colipase/CLPS.

Subcellular location. Secreted.

Disease relevance. Pancreatic lipase deficiency (PNLIPD) [MIM:614338] An autosomal recessive disorder characterized by exocrine pancreatic failure. Clinical findings include oily/greasy stools from infancy or early childhood, absence of discernible pancreatic disease, and significantly decreased pancreatic lipolytic activity. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by bile salts, is reactivated by (pro)colipase/CLPS.

Similarity. Belongs to the AB hydrolase superfamily. Lipase family.

RefSeq proteins (1): NP_000927* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000734	TAG_lipase	Family
IPR001024	PLAT/LH2_dom	Domain
IPR002331	Lipase_panc	Family
IPR013818	Lipase	Domain
IPR016272	Lipase_LIPH	Family
IPR029058	AB_hydrolase_fold	Homologous_superfamily
IPR033906	Lipase_N	Domain
IPR036392	PLAT/LH2_dom_sf	Homologous_superfamily

Pfam: PF00151, PF01477

Enzyme classification (BRENDA):

• EC 3.1.1.3 — triacylglycerol lipase (BRENDA: 184 organisms, 1134 substrates, 958 inhibitors, 148 Km, 57 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
4-NITROPHENYL PALMITATE	0.0002–679.8	30
TRIBUTYRIN	4.7–34.5	14
4-NITROPHENYL BUTYRATE	0.038–7.64	12
OLIVE OIL	0.0016–534	7
TRIOLEIN	0.05–11.5	7
1-MONOLAURIN	6.26–51.7	6
4-NITROPHENYL LAURATE	0.0007–5.05	6
4-NITROPHENYL ACETATE	0.0453–14	4
TRIOLEOYLGLYCEROL	0.33–1.55	4
4-NITROPHENYL CAPRATE	0.0466–0.078	3
4-NITROPHENYL CAPRYLATE	0.27–1.7	3
4-NITROPHENYL OCTANOATE	1.17–2.01	3
TRICAPRYLIN	0.6–6.24	3
1-STEAROYL-2-ARACHIDONOYL-SN-GLYCEROL	0.055–0.063	2
4-METHYLUMBELLIFERYL OLEATE	0.03–0.35	2

Catalyzed reactions (Rhea), 5 shown:

• a triacylglycerol + H2O = a diacylglycerol + a fatty acid + H(+) (RHEA:12044)
• all-trans-retinyl hexadecanoate + H2O = all-trans-retinol + hexadecanoate + H(+) (RHEA:13933)
• 1,2-di-(9Z-octadecenoyl)-glycerol + H2O = (9Z-octadecenoyl)-glycerol + (9Z)-octadecenoate + H(+) (RHEA:38455)
• 1,2,3-tri-(9Z-octadecenoyl)-glycerol + H2O = di-(9Z)-octadecenoylglycerol + (9Z)-octadecenoate + H(+) (RHEA:38575)
• 1,2,3-tributanoylglycerol + H2O = dibutanoylglycerol + butanoate + H(+) (RHEA:40475)

UniProt features (63 total): strand 24, helix 12, turn 9, disulfide bond 6, binding site 4, active site 3, signal peptide 1, chain 1, glycosylation site 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1GPL	X-RAY DIFFRACTION	2.01
1LPB	X-RAY DIFFRACTION	2.46
1LPA	X-RAY DIFFRACTION	3.04
1N8S	X-RAY DIFFRACTION	3.04

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P16233-F1	94.84	0.88

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): 169 (nucleophile); 193 (charge relay system); 280 (charge relay system)

Ligand- & substrate-binding residues (4): 204; 207; 209; 212

Disulfide bonds (6): 20–26, 107–118, 254–278, 302–313, 316–321, 449–465

Glycosylation sites (1): 183

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-192456	Digestion of dietary lipid
R-HSA-975634	Retinoid metabolism and transport
R-HSA-9925561	Developmental Lineage of Pancreatic Acinar Cells
R-HSA-1266738	Developmental Biology
R-HSA-1430728	Metabolism
R-HSA-196854	Metabolism of vitamins and cofactors
R-HSA-2187338	Visual phototransduction
R-HSA-6806667	Metabolism of fat-soluble vitamins
R-HSA-8935690	Digestion
R-HSA-8963743	Digestion and absorption
R-HSA-9709957	Sensory Perception
R-HSA-9734767	Developmental Cell Lineages

MSigDB gene sets: 130 (showing top): GOBP_DIGESTION, GOBP_STEROL_HOMEOSTASIS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_RETINOL_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, ACEVEDO_LIVER_CANCER_WITH_H3K27ME3_UP, LEE_LIVER_CANCER_CIPROFIBRATE_DN, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, MODULE_503, GOBP_LIPID_DIGESTION, GOBP_LIPID_HOMEOSTASIS, GOBP_GLYCEROLIPID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY

GO Biological Process (10): lipid metabolic process (GO:0006629), fatty acid biosynthetic process (GO:0006633), triglyceride catabolic process (GO:0019433), intestinal cholesterol absorption (GO:0030299), high-density lipoprotein particle remodeling (GO:0034375), cholesterol homeostasis (GO:0042632), positive regulation of triglyceride lipase activity (GO:0061365), retinoid metabolic process (GO:0001523), lipid catabolic process (GO:0016042), retinol metabolic process (GO:0042572)

GO Molecular Function (10): lipoprotein lipase activity (GO:0004465), triacylglycerol lipase activity (GO:0004806), glycerophospholipid phospholipase A1 activity (GO:0008970), lipase activity (GO:0016298), metal ion binding (GO:0046872), all-trans-retinyl-palmitate hydrolase, all-trans-retinol forming activity (GO:0047376), protein binding (GO:0005515), hydrolase activity (GO:0016787), retinyl-palmitate esterase activity (GO:0050253), carboxylic ester hydrolase activity (GO:0052689)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Digestion	1
Visual phototransduction	1
Metabolism of fat-soluble vitamins	1
Developmental Cell Lineages of the Exocrine Pancreas	1
Metabolism	1
Sensory Perception	1
Metabolism of vitamins and cofactors	1
Digestion and absorption	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
triacylglycerol lipase activity	2
carboxylic ester hydrolase activity	2
hydrolase activity, acting on ester bonds	2
primary metabolic process	1
fatty acid metabolic process	1
lipid biosynthetic process	1
monocarboxylic acid biosynthetic process	1
triglyceride metabolic process	1
acylglycerol catabolic process	1
lipid digestion	1
intestinal lipid absorption	1
plasma lipoprotein particle remodeling	1
sterol homeostasis	1
positive regulation of lipase activity	1
diterpenoid metabolic process	1
lipid metabolic process	1
catabolic process	1
retinoid metabolic process	1
primary alcohol metabolic process	1
hormone metabolic process	1
olefinic compound metabolic process	1
lipase activity	1
A1-type glycerophospholipase activity	1
cation binding	1
retinyl-palmitate esterase activity	1
binding	1
catalytic activity	1
retinol metabolic process	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1160 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PNLIP	CLPS	P04118	999
PNLIP	LIPF	P07098	982
PNLIP	LIPA	P38571	906
PNLIP	AMY2A	P04746	794
PNLIP	CEL	P19835	778
PNLIP	CTRB1	P17538	763
PNLIP	CTRB2	Q6GPI1	749
PNLIP	AMY1B	P04745	732
PNLIP	AMY2B	P19961	729
PNLIP	SI	P14410	723
PNLIP	MGAM	O43451	723
PNLIP	PLA2G1B	P04054	621
PNLIP	INS	P01308	610
PNLIP	HEPH	Q9BQS7	585
PNLIP	LIPE	Q05469	581
PNLIP	PNPLA2	Q96AD5	581

IntAct

9 interactions, top by confidence:

A	B	Type	Score
ZGPAT	DHX15	psi-mi:“MI:0914”(association)	0.850
CLPS	PNLIP	psi-mi:“MI:0407”(direct interaction)	0.620
PNLIP	LAMC1	psi-mi:“MI:0914”(association)	0.530
ZGPAT	PRPF4	psi-mi:“MI:0914”(association)	0.530
FBXL17	ENC1	psi-mi:“MI:0914”(association)	0.350
PNLIP	YWHAE	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (16): PNLIPRP2 (Affinity Capture-MS), ETNK1 (Affinity Capture-MS), ZNF444 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), PNLIP (Affinity Capture-MS), ZNF787 (Affinity Capture-MS), RSAD1 (Affinity Capture-MS), LAMC1 (Affinity Capture-MS), ZNF444 (Affinity Capture-MS), PNLIPRP2 (Affinity Capture-MS), ETNK1 (Affinity Capture-MS), SUMF1 (Affinity Capture-MS), LAMC1 (Affinity Capture-MS), PNLIP (Affinity Capture-MS), PNLIP (Two-hybrid)

ESM2 similar proteins: A0A0M3KKW3, A2VBC4, A5PK46, A8PUY1, B2D0J5, C0HLL3, D7EZN2, O88354, P00591, P06857, P0CH47, P0CH86, P0CH87, P0DMB4, P0DMB5, P0DPT0, P0DSI2, P16233, P17892, P27657, P29183, P35501, P35502, P49369, P50903, P51528, P53357, P54315, P54316, P54317, P54318, P81139, P86100, P9WEM6, Q02157, Q04456, Q06478, Q17RR3, Q3ZU95, Q5BKQ4

Diamond homologs: A0A0M3KKW3, A2VBC4, A5PK46, C0HLL3, J3RZ81, O46559, O88354, P02843, P06607, P06857, P07867, P0CH47, P0CH86, P0CH87, P0DMB4, P0DMB5, P0DPT0, P0DSI2, P11150, P16233, P27656, P49369, P51528, P53357, P54316, P81139, P83542, P97535, Q06478, Q17RR3, Q32PY2, Q3SZ79, Q3ZU95, Q5BKQ4, Q641F6, Q64425, Q68KK0, Q6NYZ4, Q6P8U6, Q6PA23

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	4
Uncertain significance	132
Likely benign	109
Benign	17

Top pathogenic / likely-pathogenic (18)

Variant ID	HGVS	Classification
2002380	NM_000936.4(PNLIP):c.973_974del (p.Gly325fs)	Pathogenic
2029255	NM_000936.4(PNLIP):c.99G>A (p.Trp33Ter)	Pathogenic
2086911	NM_000936.4(PNLIP):c.817C>T (p.Arg273Ter)	Pathogenic
2703611	NM_000936.4(PNLIP):c.1214C>A (p.Ser405Ter)	Pathogenic
2833869	NM_000936.4(PNLIP):c.399del (p.Ala134fs)	Pathogenic
2898184	NM_000936.4(PNLIP):c.148del (p.Asp50fs)	Pathogenic
3642974	NM_000936.4(PNLIP):c.807G>A (p.Trp269Ter)	Pathogenic
3671560	NM_000936.4(PNLIP):c.23C>G (p.Ser8Ter)	Pathogenic
3690583	NM_000936.4(PNLIP):c.1029T>G (p.Tyr343Ter)	Pathogenic
3701159	NM_000936.4(PNLIP):c.906_907del (p.Ala303fs)	Pathogenic
3725311	NM_000936.4(PNLIP):c.277G>T (p.Gly93Ter)	Pathogenic
427570	NM_000936.4(PNLIP):c.662C>T (p.Thr221Met)	Pathogenic
4710254	NM_000936.4(PNLIP):c.664del (p.Asp222fs)	Pathogenic
522506	NM_000936.4(PNLIP):c.1257G>A (p.Trp419Ter)	Pathogenic
2109236	NM_000936.4(PNLIP):c.571+1G>T	Likely pathogenic
2772101	NM_000936.4(PNLIP):c.460-1G>A	Likely pathogenic
3654926	NM_000936.4(PNLIP):c.1060+1G>A	Likely pathogenic
4753491	NM_000936.4(PNLIP):c.692-2A>G	Likely pathogenic

SpliceAI

1380 predictions. Top by Δscore:

Variant	Effect	Δscore
10:116547449:G:GG	donor_gain	1.0000
10:116548359:GGAA:G	acceptor_gain	1.0000
10:116551079:ATT:A	acceptor_gain	1.0000
10:116551079:ATTGT:A	acceptor_gain	1.0000
10:116551081:T:TA	acceptor_gain	1.0000
10:116551083:T:TA	acceptor_gain	1.0000
10:116551093:A:AG	acceptor_gain	1.0000
10:116551094:C:G	acceptor_gain	1.0000
10:116551096:A:AG	acceptor_gain	1.0000
10:116551097:G:GT	acceptor_gain	1.0000
10:116551097:GA:G	acceptor_gain	1.0000
10:116551097:GAA:G	acceptor_gain	1.0000
10:116551097:GAAT:G	acceptor_gain	1.0000
10:116551097:GAATC:G	acceptor_gain	1.0000
10:116551230:CAG:C	donor_loss	1.0000
10:116551234:T:G	donor_loss	1.0000
10:116553725:A:AG	acceptor_gain	1.0000
10:116553725:AGTC:A	acceptor_gain	1.0000
10:116553725:AGTCG:A	acceptor_gain	1.0000
10:116553726:G:GG	acceptor_gain	1.0000
10:116553726:GTC:G	acceptor_gain	1.0000
10:116553726:GTCG:G	acceptor_gain	1.0000
10:116553726:GTCGG:G	acceptor_gain	1.0000
10:116555295:TGGG:T	donor_loss	1.0000
10:116555296:GG:G	donor_gain	1.0000
10:116555297:GG:G	donor_gain	1.0000
10:116555297:GGTG:G	donor_loss	1.0000
10:116555298:G:C	donor_loss	1.0000
10:116555298:G:GG	donor_gain	1.0000
10:116555299:T:A	donor_loss	1.0000

AlphaMissense

3065 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:116551142:G:C	W123C	0.998
10:116551142:G:T	W123C	0.998
10:116555201:T:C	F199L	0.998
10:116555203:T:A	F199L	0.998
10:116555203:T:G	F199L	0.998
10:116548438:T:C	F94L	0.997
10:116548440:C:A	F94L	0.997
10:116548440:C:G	F94L	0.997
10:116551140:T:A	W123R	0.997
10:116551140:T:C	W123R	0.997
10:116553772:A:C	S169R	0.997
10:116553774:C:A	S169R	0.997
10:116553774:C:G	S169R	0.997
10:116556021:G:A	C278Y	0.997
10:116556028:C:A	H280Q	0.997
10:116556028:C:G	H280Q	0.997
10:116556035:A:C	S283R	0.997
10:116556037:C:A	S283R	0.997
10:116556037:C:G	S283R	0.997
10:116551124:C:A	N117K	0.996
10:116551124:C:G	N117K	0.996
10:116551184:C:A	N137K	0.996
10:116551184:C:G	N137K	0.996
10:116555456:T:A	C254S	0.996
10:116555457:G:C	C254S	0.996
10:116556020:T:A	C278S	0.996
10:116556021:G:C	C278S	0.996
10:116556026:C:G	H280D	0.996
10:116553838:G:T	G191W	0.995
10:116555226:G:C	R207P	0.995

dbSNP variants (sampled 300 via entrez): RS1000103563 (10:116549259 C>T), RS1000494610 (10:116550884 G>A,C), RS1000555658 (10:116545743 C>T), RS1000602256 (10:116545403 G>A), RS1000752235 (10:116552130 C>T), RS1000860051 (10:116563605 T>C,G), RS1000948831 (10:116558231 T>C), RS1001013890 (10:116556639 G>T), RS1001018758 (10:116565297 G>A,T), RS1001110480 (10:116550548 C>T), RS1001177482 (10:116563001 G>T), RS1001234364 (10:116555761 T>C), RS1001277563 (10:116562620 C>A,G,T), RS1001351573 (10:116549925 A>G), RS1001466365 (10:116557189 A>G)

Disease associations

OMIM: gene MIM:246600 | disease phenotypes: MIM:614338

GenCC curated gene-disease

Disease	Classification	Inheritance
pancreatic triacylglycerol lipase deficiency	Strong	Autosomal recessive

Mondo (1): pancreatic triacylglycerol lipase deficiency (MONDO:0013700)

Orphanet (1): Pancreatic triacylglycerol lipase deficiency (Orphanet:309031)

HPO phenotypes

6 total (6 of 6 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0002570	Steatorrhea
HP:0002630	Fat malabsorption
HP:0003146	Hypocholesterolemia
HP:0003623	Neonatal onset
HP:0012236	Elevated sweat chloride

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002324_9	Anger	4.000000e-06
GCST005951_66	Body mass index	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0003015	aggressive behavior
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1812 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 118,845 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL175247	ORLISTAT	4	38,186
CHEMBL50	QUERCETIN	3	74,559
CHEMBL287542	RAFOXANIDE	2	6,100

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Hydrolases & Lipases

Most potent curated ligand interactions (2 total), top 2:

Ligand	Action	Affinity	Parameter
orlistat	Inhibition	8.9	pIC50
cetilistat	Inhibition	8.23	pIC50

ChEMBL bioactivities

45 potent at pChembl≥5 of 74 total, top 45 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.80	IC50	1.57	nM	ORLISTAT
8.22	IC50	6	nM	ORLISTAT
7.48	IC50	33	nM	ORLISTAT
6.72	IC50	190	nM	ORLISTAT
6.31	IC50	490	nM	OLEANONIC ACID
6.11	IC50	780	nM	ORLISTAT
5.96	IC50	1100	nM	CHEMBL4173252
5.90	IC50	1250	nM	CHEMBL4160519
5.89	Ki	1288	nM	CHEMBL5416736
5.87	IC50	1340	nM	MYRICETIN
5.82	IC50	1530	nM	QUERCETIN
5.79	IC50	1630	nM	CHEMBL4641560
5.78	IC50	1650	nM	CHEMBL4164998
5.78	Ki	1670	nM	CHEMBL5410259
5.77	Ki	1700	nM	CHEMBL4641560
5.73	IC50	1870	nM	CHEMBL4167341
5.73	IC50	1860	nM	CHEMBL5410259
5.71	IC50	1945	nM	CHEMBL5416736
5.70	IC50	2010	nM	CHEMBL4165339
5.68	IC50	2100	nM	CHEMBL4847734
5.67	IC50	2130	nM	CHEMBL1631675
5.64	IC50	2310	nM	CHEMBL4163899
5.64	IC50	2280	nM	CHEMBL4168413
5.60	IC50	2520	nM	RAFOXANIDE
5.55	IC50	2800	nM	CHEMBL4128298
5.50	IC50	3200	nM	CHEMBL4102155
5.48	IC50	3280	nM	SANGGENON C
5.39	IC50	4100	nM	CHEMBL4856331
5.37	IC50	4270	nM	CHEMBL5423733
5.35	IC50	4500	nM	CHEMBL4860907
5.23	IC50	5900	nM	CHEMBL4847071
5.22	IC50	5990	nM	CHEMBL5419885
5.21	IC50	6154	nM	CHEMBL5425089
5.21	Ki	6182	nM	CHEMBL5407888
5.20	IC50	6270	nM	CHEMBL5413231
5.17	IC50	6750	nM	CHEMBL5405185
5.16	IC50	6900	nM	CHEMBL4175223
5.13	IC50	7380	nM	CHEMBL4176621
5.11	IC50	7820	nM	CHEMBL4160094
5.05	IC50	9000	nM	CHEMBL4077903
5.04	IC50	9150	nM	CHEMBL4168757
5.04	IC50	9012	nM	CHEMBL5407888
5.03	IC50	9240	nM	CHEMBL5439220
5.00	IC50	9960	nM	CHEMBL5402667
5.00	IC50	1e+04	nM	CHEMBL5399755

PubChem BioAssay actives

45 with measured affinity, of 301 total; 37 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
Orlistat	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	0.0016	uM
(4aS,6aR,6aS,6bR,8aR,12aR,14bS)-2,2,6a,6b,9,9,12a-heptamethyl-10-oxo-3,4,5,6,6a,7,8,8a,11,12,13,14b-dodecahydro-1H-picene-4a-carboxylic acid	1975739: Inhibition of Pancreatic lipase (unknown origin) using 4-MUO as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	0.4900	uM
[1-[(4-fluorophenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	1.1000	uM
[1-[(4-chlorophenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	1.2500	uM
(2Z)-2-benzylidene-4,6-bis(10-hydroxydecoxy)-1-benzofuran-3-one	2004483: Binding affinity to pancreatic lipase (unknown origin) assessed as inhibition constant by Lineweaver-Burk plot analysis	ki	1.2880	uM
3,5,7-trihydroxy-2-(3,4,5-trihydroxyphenyl)chromen-4-one	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	1.3400	uM
Quercetin	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	1.5300	uM
3,5-dichloro-N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	1.6300	uM
[1-[(4-methylsulfanylphenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	1.6500	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-3,5-difluoro-2-hydroxybenzamide	1975736: Negative allosteric modulator activity at human Pancreatic lipase assessed as inhibition of PL-mediated DDAO-ol hydrolysis by measuring inhibition constant using DDAO-ol as fluorescent substrate by Lineweaver-Burk plot analysis	ki	1.6700	uM
[1-[(4-methoxyphenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	1.8700	uM
[1-[(4-nitrophenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	2.0100	uM
[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] 4-hydroxybenzoate	1758169: Inhibition of PTL (unknown origin)	ic50	2.1000	uM
3,5-dibromo-N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	2.1300	uM
[1-[(4-tert-butylphenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	2.2800	uM
[1-[(2-bromo-4-fluorophenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	2.3100	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxy-3,5-diiodobenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	2.5200	uM
N’-[2-[2-[(4-bromophenyl)methyl]-4-oxoquinazolin-3-yl]acetyl]-2-oxochromene-3-carbohydrazide	1952208: Inhibition of pancreatic lipase (unknown origin)	ic50	2.8000	uM
(1R,5S)-3-(dimethoxymethyl)-1-(3-methylbut-2-enyl)-6-oxabicyclo[3.2.0]hept-2-en-7-one	1428459: Inhibition of human pancreatic lipase using 4-methylumbelliferyl oleate as substrate after 30 mins by fluorometric method	ic50	3.2000	uM
(5aR,10aS)-2-[(1S,5S,6R)-6-(2,4-dihydroxybenzoyl)-5-(2,4-dihydroxyphenyl)-3-methylcyclohex-2-en-1-yl]-1,3,8,10a-tetrahydroxy-5a-(3-methylbut-2-enyl)-[1]benzofuro[3,2-b]chromen-11-one	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	3.2800	uM
[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] 4-prop-2-ynoxybenzoate	1758169: Inhibition of PTL (unknown origin)	ic50	4.1000	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-4-fluoro-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	4.2700	uM
[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] 3-methoxybenzoate	1758169: Inhibition of PTL (unknown origin)	ic50	4.5000	uM
[(2S)-1-[(2S,3S)-3-hexyl-4-oxooxetan-2-yl]tridecan-2-yl] 4-methoxybenzoate	1758169: Inhibition of PTL (unknown origin)	ic50	5.9000	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxy-4-(propylamino)benzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	5.9900	uM
(2Z)-2-benzylidene-6-(10-hydroxydecoxy)-1-benzofuran-3-one	2004480: Inhibition of pancreatic lipase (unknown origin) by spectrophotometeric analysis	ic50	6.1540	uM
(2Z)-2-benzylidene-6-(6-hydroxyhexoxy)-1-benzofuran-3-one	2004483: Binding affinity to pancreatic lipase (unknown origin) assessed as inhibition constant by Lineweaver-Burk plot analysis	ki	6.1820	uM
4-amino-N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	6.2700	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	6.7500	uM
[1-[(2-bromo-5-methoxyphenyl)methyl]triazol-4-yl]methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	6.9000	uM
prop-2-ynyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	7.3800	uM
(1-phenacyltriazol-4-yl)methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	7.8200	uM
(1R,5S)-3-(hydroxymethyl)-1-[(E)-4-hydroxy-3-methylbut-2-enyl]-6-oxabicyclo[3.2.0]hept-2-en-7-one	1428459: Inhibition of human pancreatic lipase using 4-methylumbelliferyl oleate as substrate after 30 mins by fluorometric method	ic50	9.0000	uM
(1-benzyltriazol-4-yl)methyl (E)-5-[(4aS,8aS)-5,5,8a-trimethyl-2-methylidene-3,4,4a,6,7,8-hexahydro-1H-naphthalen-1-yl]-3-formylpent-3-enoate	1356358: Inhibition of human pancreatic lipase using emulsified olive oil as substrate pretreated with substrate for 5 mins followed by enzyme addition and measured after 30 mins	ic50	9.1500	uM
2-hydroxy-N-[4-(4-propan-2-yloxyphenoxy)phenyl]benzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	9.2400	uM
N-(3-chloro-4-phenoxyphenyl)-2-hydroxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	9.9600	uM
N-[3-chloro-4-(4-chlorophenoxy)phenyl]-2-hydroxy-4-methoxybenzamide	1975735: Negative allosteric modulator activity at human Pancreatic lipase using DDAO-ol as fluorescent substrate preincubated for 3 mins followed by substrate addition measured after 20 mins by microplate reader assay	ic50	10.0000	uM

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Orlistat	decreases secretion, decreases activity, affects folding, affects cotreatment, decreases reaction (+2 more)	4
4-hydroxybenzyl alcohol	decreases activity	1
1,2-didecanoylglycerol	increases metabolic processing	1
sciadopitysin	decreases activity	1
CGP 52608	increases reaction, affects binding	1
OMDM 169	decreases activity	1
Olive Oil	decreases reaction, increases hydrolysis, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Calcitriol	increases expression, affects cotreatment	1
Doxorubicin	decreases expression	1
Fatty Acids, Nonesterified	decreases abundance, decreases secretion	1
Dihydrotestosterone	increases expression	1
Taurodeoxycholic Acid	affects folding	1
Testosterone	affects cotreatment, increases expression	1
Triglycerides	affects hydrolysis	1
Valproic Acid	increases methylation	1

ChEMBL screening assays

65 unique, capped per target: 65 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1016783	Binding	Inhibition of pancreatic lipase assessed as effect on oleic acid release from triolein at 1 mg/mL relative to control	New biologically active triterpenoid saponins from Scabiosa tschiliensis. — J Nat Prod

Cellosaurus cell lines

2 cell lines: 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_GS83	GM13278	Transformed cell line	Female
CVCL_GS84	GM13322	Transformed cell line	Male

Clinical trials (associated diseases)

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