PLD1

Summary

PLD1 (phospholipase D1, HGNC:9067) is a protein-coding gene on chromosome 3q26.31, encoding Phospholipase D1 (Q13393). Function as phospholipase selective for phosphatidylcholine.

This gene encodes a phosphatidylcholine-specific phospholipase which catalyzes the hydrolysis of phosphatidylcholine in order to yield phosphatidic acid and choline. The enzyme may play a role in signal transduction and subcellular trafficking. Alternative splicing results in multiple transcript variants with both catalytic and regulatory properties.

Source: NCBI Gene 5337 — RefSeq curated summary.

At a glance

• Gene–disease (curated): PLD1-related congenital heart disease (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 16
• Clinical variants (ClinVar): 402 total — 15 pathogenic, 13 likely-pathogenic (top 8% of genes corpus-wide)
• GTEx eGene: eQTL in 38 tissues, sQTL in 27 (q < 0.05)
• Phenotypes (HPO): 29
• ChEMBL bioactivity: 2 clinical-phase molecules tested; no curated mechanism-of-action drug
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.82 (unconstrained)
• MANE Select transcript: NM_002662

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9067
Approved symbol	PLD1
Name	phospholipase D1
Location	3q26.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000075651
Ensembl biotype	protein_coding
OMIM	602382
Entrez	5337

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 16 protein_coding, 6 protein_coding_CDS_not_defined, 4 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000351298

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 1, TSL 4: 6, TSL 5: 2

ENST00000351298, ENST00000356327, ENST00000418087, ENST00000440204, ENST00000446289, ENST00000460926, ENST00000463281, ENST00000465816, ENST00000467432, ENST00000471075, ENST00000475273, ENST00000481505, ENST00000489995, ENST00000497307, ENST00000498278, ENST00000861047, ENST00000861048, ENST00000861049, ENST00000861050, ENST00000861051, ENST00000861052, ENST00000861053, ENST00000959554, ENST00000959555, ENST00000959556, ENST00001106674, ENST00001106675, ENST00001139722

RefSeq mRNA: 2 — MANE Select: NM_002662 NM_001130081, NM_002662

CCDS: CCDS3216, CCDS46957

Canonical transcript exons

ENST00000351298 — 27 exons

Exon	Start	End
ENSE00000446890	171688676	171688876
ENSE00000780377	171686685	171686798
ENSE00000780378	171687371	171687584
ENSE00000826235	171708755	171708838
ENSE00000826236	171709560	171709709
ENSE00001015327	171713893	171714045
ENSE00001791884	171600404	171603302
ENSE00001820986	171810399	171810483
ENSE00003460297	171677566	171677694
ENSE00003477151	171734865	171734970
ENSE00003495840	171620386	171620520
ENSE00003522841	171726018	171726076
ENSE00003553247	171676715	171676833
ENSE00003565148	171733444	171733509
ENSE00003573341	171692332	171692442
ENSE00003575848	171659213	171659301
ENSE00003597684	171735492	171735637
ENSE00003614968	171737532	171737659
ENSE00003619170	171605299	171605416
ENSE00003634040	171724696	171724788
ENSE00003641757	171644910	171645023
ENSE00003643036	171612279	171612432
ENSE00003646525	171662060	171662170
ENSE00003667546	171674500	171674613
ENSE00003678637	171642840	171642889
ENSE00003682124	171699745	171699826
ENSE00003687155	171737892	171738082

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 98.22.

FANTOM5 (CAGE): breadth broad, TPM avg 2.5241 / max 128.4012, expressed in 753 samples.

Highest expression (Bgee): gall bladder, adrenal tissue, adrenal gland cortex, esophagus mucosa, adrenal gland.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PLD1 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 38 tissues and its splicing (sQTL) in 27 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 65 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	sqtl	1.8e-46	-1.09	3:171789367:C:A
Spleen	eqtl	1.5e-39	-0.93	3:171689589:T:C
Skin Not Sun Exposed Suprapubic	sqtl	6.2e-39	-1.11	3:171789367:C:A
Artery Aorta	eqtl	9.4e-39	-0.53	3:171720487:G:A
Artery Tibial	eqtl	8.5e-34	-0.40	3:171725817:C:G
Adipose Subcutaneous	eqtl	1.2e-30	-0.53	3:171791187:T:C
Esophagus Mucosa	sqtl	1.9e-22	-0.71	3:171789367:C:A
Cells Cultured fibroblasts	eqtl	3.0e-22	-0.28	3:171812145:T:G
Lung	eqtl	3.6e-21	-0.46	3:171788908:C:T
Artery Tibial	sqtl	1.2e-20	+0.75	3:171708248:T:C
Thyroid	eqtl	6.1e-20	-0.36	3:171788908:C:T
Adipose Subcutaneous	sqtl	4.8e-15	-0.69	3:171800888:A:G
Nerve Tibial	sqtl	9.6e-14	+0.63	3:171595825:A:G
Breast Mammary Tissue	eqtl	7.7e-13	-0.31	3:171788585:G:A
Esophagus Mucosa	eqtl	2.1e-11	-0.48	3:171602222:A:T
Colon Transverse	sqtl	7.6e-11	-0.78	3:171789367:C:A
Esophagus Muscularis	eqtl	6.2e-10	-0.27	3:171774040:G:A
Testis	eqtl	7.4e-10	+0.39	3:171605515:T:C
Skin Sun Exposed Lower leg	eqtl	8.0e-10	-0.17	3:171810493:GGA:G
Adipose Visceral Omentum	sqtl	1.8e-09	-0.53	3:171708248:T:C

FANTOM5 promoters

showing 10 of 12 alternative TSS:

Promoter ID	TPM avg	Samples expressed
45608	13.6451	1667
45600	1.8445	493
45610	0.3678	111
203027	0.2145	93
45609	0.2090	88
45611	0.1155	50
45607	0.1048	38
45601	0.0806	34
45606	0.0726	22
45596	0.0338	12

Top tissues by expression

showing 100 of 291 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
gall bladder	UBERON:0002110	98.22	gold quality
adrenal tissue	UBERON:0018303	94.98	gold quality
right adrenal gland cortex	UBERON:0035827	93.06	gold quality
esophagus mucosa	UBERON:0002469	92.52	gold quality
right adrenal gland	UBERON:0001233	92.36	gold quality
lower esophagus mucosa	UBERON:0035834	92.02	gold quality
duodenum	UBERON:0002114	91.95	gold quality
tongue squamous epithelium	UBERON:0006919	91.73	gold quality
left adrenal gland	UBERON:0001234	91.54	gold quality
corpus callosum	UBERON:0002336	91.33	gold quality
left adrenal gland cortex	UBERON:0035825	91.21	gold quality
adrenal gland	UBERON:0002369	91.17	gold quality
adrenal cortex	UBERON:0001235	91.09	gold quality
skin of abdomen	UBERON:0001416	90.77	gold quality
skin of leg	UBERON:0001511	90.64	gold quality
jejunal mucosa	UBERON:0000399	90.17	gold quality
left ovary	UBERON:0002119	90.09	gold quality
gingiva	UBERON:0001828	89.80	gold quality
gingival epithelium	UBERON:0001949	89.75	gold quality
zone of skin	UBERON:0000014	89.14	gold quality
epithelium of esophagus	UBERON:0001976	89.06	gold quality
secondary oocyte	CL:0000655	88.95	gold quality
colonic epithelium	UBERON:0000397	88.84	gold quality
esophagus squamous epithelium	UBERON:0006920	88.84	gold quality
mouth mucosa	UBERON:0003729	88.71	gold quality
squamous epithelium	UBERON:0006914	88.59	gold quality
rectum	UBERON:0001052	88.55	gold quality
minor salivary gland	UBERON:0001830	88.54	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	88.47	gold quality
skin of hip	UBERON:0001554	88.41	gold quality
mucosa of transverse colon	UBERON:0004991	87.91	gold quality
islet of Langerhans	UBERON:0000006	87.88	gold quality
upper leg skin	UBERON:0004262	87.68	gold quality
pancreas	UBERON:0001264	87.47	gold quality
epithelial cell of pancreas	CL:0000083	87.37	silver quality
calcaneal tendon	UBERON:0003701	87.36	gold quality
body of pancreas	UBERON:0001150	87.35	gold quality
vagina	UBERON:0000996	87.24	gold quality
right ovary	UBERON:0002118	87.24	gold quality
cervix epithelium	UBERON:0004801	86.91	gold quality
ovary	UBERON:0000992	86.90	gold quality
heart left ventricle	UBERON:0002084	86.88	gold quality
spinal cord	UBERON:0002240	86.76	gold quality
cardiac ventricle	UBERON:0002082	86.66	gold quality
buccal mucosa cell	CL:0002336	86.62	gold quality
palpebral conjunctiva	UBERON:0001812	86.57	gold quality
stromal cell of endometrium	CL:0002255	86.54	gold quality
tonsil	UBERON:0002372	86.43	gold quality
descending thoracic aorta	UBERON:0002345	86.42	gold quality
right atrium auricular region	UBERON:0006631	86.42	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.38	gold quality
ileal mucosa	UBERON:0000331	86.31	gold quality
saliva-secreting gland	UBERON:0001044	86.30	gold quality
small intestine	UBERON:0002108	86.29	gold quality
ectocervix	UBERON:0012249	86.24	gold quality
cardiac atrium	UBERON:0002081	86.23	gold quality
esophagus	UBERON:0001043	86.21	gold quality
heart	UBERON:0000948	86.09	gold quality
pancreatic ductal cell	CL:0002079	86.08	silver quality
popliteal artery	UBERON:0002250	85.66	gold quality
tibial artery	UBERON:0007610	85.65	gold quality
left ventricle myocardium	UBERON:0006566	85.57	silver quality
oral cavity	UBERON:0000167	85.56	gold quality
small intestine Peyer’s patch	UBERON:0003454	85.52	gold quality
right lobe of liver	UBERON:0001114	85.44	gold quality
uterine cervix	UBERON:0000002	85.32	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	85.22	gold quality
cervix squamous epithelium	UBERON:0006922	84.93	silver quality
liver	UBERON:0002107	84.80	gold quality
trabecular bone tissue	UBERON:0002483	84.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	84.64	gold quality
aorta	UBERON:0000947	84.46	gold quality
cardiac muscle of right atrium	UBERON:0003379	84.45	silver quality
apex of heart	UBERON:0002098	84.42	gold quality
bone marrow cell	CL:0002092	84.38	gold quality
myocardium	UBERON:0002349	84.03	silver quality
amniotic fluid	UBERON:0000173	83.39	gold quality
colonic mucosa	UBERON:0000317	83.19	gold quality
bone marrow	UBERON:0002371	83.15	gold quality
mammalian vulva	UBERON:0000997	83.05	gold quality
thoracic aorta	UBERON:0001515	82.97	gold quality
oocyte	CL:0000023	82.81	gold quality
transverse colon	UBERON:0001157	82.74	gold quality
ascending aorta	UBERON:0001496	82.69	gold quality
intestine	UBERON:0000160	82.26	gold quality
mucosa of sigmoid colon	UBERON:0004993	82.19	gold quality
inferior vagus X ganglion	UBERON:0005363	82.00	gold quality
sural nerve	UBERON:0015488	81.85	gold quality
upper arm skin	UBERON:0004263	81.64	gold quality
epithelium of nasopharynx	UBERON:0001951	81.52	gold quality
omental fat pad	UBERON:0010414	81.35	gold quality
peritoneum	UBERON:0002358	81.31	gold quality
left coronary artery	UBERON:0001626	81.04	gold quality
subthalamic nucleus	UBERON:0001906	81.04	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.77	gold quality
lymph node	UBERON:0000029	80.65	gold quality
large intestine	UBERON:0000059	80.58	gold quality
coronary artery	UBERON:0001621	80.50	gold quality
colon	UBERON:0001155	80.47	gold quality
substantia nigra	UBERON:0002038	80.38	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-9067	yes	13.62
E-ANND-3	yes	8.57
E-MTAB-10596	no	185.27

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 79 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Gallbladder	tissue	81.4	high
Duodenum	tissue	44.0	high
Small intestine	tissue	41.3	high
Corpus callosum	tissue	33.9
Spinal cord	tissue	32.6
Liver	tissue	31.4	high
Esophagus	tissue	30.9
Superior colliculi	tissue	27.4
Skin 1	tissue	26.7	high
Ovary	tissue	25.5	not detected
Adrenal gland	tissue	24.8	high
Heart muscle	tissue	22.8	low
Nucleus accumbens	tissue	22.8
Substantia nigra	tissue	22.2
Medulla oblongata	tissue	21.6
Pancreas	tissue	20.0	medium
Locus coeruleus	tissue	18.7
Periaqueductal gray	tissue	18.0
Midbrain	tissue	17.9
Hippocampus	tissue	17.9	not detected
Hypothalamus	tissue	15.5
Pons	tissue	15.1
Putamen	tissue	14.6
Spleen	tissue	14.6	medium
Thalamus	tissue	14.3
Choroid plexus	tissue	13.7
Rectum	tissue	13.5	high
Colon	tissue	13.5	medium
Septum	tissue	12.7
Ventral forebrain	tissue	12.4
Salivary gland	tissue	11.7	medium
Vagina	tissue	11.3	medium
Kidney	tissue	11.2	medium
Postcentral gyrus	tissue	10.5
Tonsil	tissue	10.1
Placenta	tissue	10.0	low
Hippocampal formation	tissue	9.7
Amygdala	tissue	9.0
Lymph node	tissue	8.5	medium
Basal ganglia	tissue	8.1	not detected
Stomach 1	tissue	7.6	medium
Adipose tissue	tissue	7.3	low
Entorhinal cortex	tissue	7.0
Breast	tissue	6.9	low
Olfactory bulb	tissue	6.7
Cerebral cortex	tissue	6.6	low
Motor cortex	tissue	6.6
Retrosplenial cortex	tissue	6.6
Insular cortex	tissue	6.4
Tongue	tissue	6.3
Appendix	tissue	6.2	medium
Fallopian tube	tissue	6.0	high
Bone marrow	tissue	5.9	medium
Somatosensory cortex	tissue	5.8
Temporal cortex	tissue	5.8
Endometrium 1	tissue	5.7	medium
Caudate putamen	tissue	5.7
Seminal vesicle	tissue	5.6	low
Retrosplenial and cingulate cortex	tissue	5.6
Prefrontal cortex	tissue	5.5

Brain sub-regions (HPA Brain Atlas): detected in 292; highest nTPM — Nucleus gracilis (122.2), Cerebellar white matter (114.9), Globus pallidus, externus (113.3), Medial olivary nucleus (112.3), Nucleus ambiguus (111.5).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF2, CEBPA, CEBPB, CTNNB1, EWSR1, FLI1, NFATC2, NFKB, PGR, RXRA, SP1, TCF4, TCF7L2, VDR, ZHX2

miRNA regulators (miRDB)

Targeting PLD1 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 109 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-101-3P	99.94	75.03	2230

Functional genomics

gnomAD constraint: pLI 1.65e-06, LOEUF 0.822, missense Z 0.597 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000351298 — one region, missense o/e 0.98.

Literature-anchored findings (GeneRIF, showing 40)

• alpha-Synuclein interacts with phospholipase D isozymes and inhibits pervanadate-induced phospholipase D activation in human embryonic kidney-293 cells (PMID:11821392)
• regulation of polymorphonuclear leukocyte degranulation and oxidant production (PMID:11830497)
• Detecting protein-phospholipid interactions. Epidermal growth factor-induced activation of phospholipase D1b in situ (PMID:11950840)
• binding of the Rho family member Cdc42 to PLD1 and the subsequent stimulation of its enzymatic activity are distinct events (PMID:12011045)
• PLD1 is threonine-phosphorylated in human-airway epithelial cells by a PKCdelta and src dependent mechanism (PMID:12014986)
• activation of phospholipases D1 and D2 by S1P regulates the phosphorylation of extracellular-signal-regulated kinase and IL-8 secretion in Beas-2B cells (PMID:12149127)
• activity regulated by actin in a polymerization-dependent, isoform-specific manner (PMID:12388543)
• activated by ADP-ribosylated RhoA (PMID:12593858)
• elevated PLD activity generates survival signals allowing cells to overcome default apoptosis programs (PMID:12615079)
• PLD isozymes stimulate cell growth by repressing expression of p21 gene (PMID:12782287)
• Phospholipase D confers rapamycin resistance in human breast cancer cells. Elevated PLD activity in MCF-7 cells also caused rapamycin resistance for S6 kinase phosphorylation and serum-induced Myc expression. (PMID:12813467)
• protein kinase C alpha associates with phospholipase D1 and enhances basal phospholipase D activity in a protein phosphorylation-independent manner in melanoma cells, which contributes to the cell’s high invasive potential. (PMID:12839565)
• results indicate that PKCdelta inhibits TPA-induced PLD1 activation mediated by PKCalpha through the association with PLD1 (PMID:14596936)
• isoenzyme PLD1 is stimulated by phorbol ester and requires ADP-ribosylation factor, protein kinase C and Rho proteins for full activity (PMID:14646617)
• phospholipase D causes translocation of protein kinase C (PKC)betaII but not PKCbetaI to a juxtanuclear subset of recycling endosomes (PMID:15067001)
• phospholipase D isozymes mediate EGCG-induced COX-2 expression through PKC and p38 in immortalized astroglial line and normal astrocyte cells (PMID:15210717)
• PLD1 activity by regulating phosphatidic acid formation controls the early signals initiated by FcepsilonRI aggregation that lead to mast cell degranulation.PH (PMID:15339843)
• importance of phospholipase D in the oncogenic ability of Ras (PMID:15668389)
• phospholipase D suppresses protein phosphatase 2A and is involved in the mTOR survival pathway in the transformation of human cells (PMID:16109716)
• PLD1 is activated by exclusion from lipid rafts and that this activation conveys antiproliferative signals in lymphoid cells (PMID:16339545)
• These results suggest that intact phosphorylation sites within the MARCKS ED are required for PLD activation and influence both membrane-cytoskeletal organization and cell viability. (PMID:16341931)
• overexpression of PLD1 decreases, and down-presenilin 1, through its loop region, binds to phospholipase D1 (PLD1), thereby recruiting it to the Golgi/trans-Golgi network (PMID:16449386)
• adhesion stimulates PLD activity, and that PLD1 regulates the initial stages of phagocyte adhesion (PMID:16517737)
• endogenous PLD1 is a critical factor in the organization of the actin-based cytoskeleton, with regard to cell adhesion and migration (PMID:16608858)
• PLD functions as a GTPase activating protein (GAP) through its phox homology domain (PX), which directly activates the GTPase domain of dynamin and increased epidermal growth factor receptor (EGFR) endocytosis at physiological EGF concentrations. (PMID:16622417)
• demonstration of the involvement of PLD1 and PLD2 and its enzymatic activity toward chemokines in the key physiologic process of leukocyte migration (PMID:16873675)
• PLD1 may play a crucial role in collagen type I production through mTOR signaling in human dermal fibroblast. (PMID:16919239)
• We show that human PLD1b (hPLD1b) is an actin-binding protein and the N-terminus is predominantly involved in this interaction. (PMID:16978840)
• PLD1 regulates 8-Br-cAMP-induced decidualization through PLA2G1B, and PLD1 upregulation is essential for decidualization of endometrial stromal cells. (PMID:17065600)
• TNFalpha/CHX-induced cell death was significantly lowered in cells overexpressing PLD1 (PMID:17069807)
• isoform selective Arf/PLD interaction and not Arf/PtdIns4P5K will be the critical trigger in the formation of distinct, optimal triples of Arf/PLDs/PtdIns4P5Ks (PMID:17071135)
• Our results indicate a possible role for novel PKC isoforms in the regulation of P2X(7)-mediated PLD activity. (PMID:17130901)
• VDR and retinoid X receptor alpha (RXRalpha) binds to the VDRE and increases PLD1 gene expression in HaCaT cells. (PMID:17433303)
• Plays a major role in promoting HIV-1 long terminal repeat transactivation and virus replication. (PMID:17627030)
• These results demonstrate for the first time that PLD1 and PLD2 isozymes enhance cobalt chlorde-induced COX-2 expression through differential signaling pathways in astroglioma cells. (PMID:17640750)
• PLD control over expression of the Mac-1 activation epitope is critical for neutrophil migration to fMLP but not C5a. (PMID:17724165)
• PLD1 and phospho-mTOR are coexpressed in a subset of phospho-Akt-negative breast carcinomas. (PMID:17726467)
• phospho-cofilin by its stimulatory effect on PLD1 may control a large variety of cellular functions. (PMID:17853892)
• These findings indicate the involvement of phospholipase D activation in hBD-2 up-regulation in gingival epithelial cells. (PMID:17986621)
• These results suggest that elevated expression and activity of PLD attenuate phorbol myristate acetate-induced Egr-1 expression via PI3K pathway. (PMID:18067864)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pld1a	ENSDARG00000056228
danio_rerio	pld1b	ENSDARG00000057125
mus_musculus	Pld1	ENSMUSG00000027695
rattus_norvegicus	Pld1	ENSRNOG00000028156
drosophila_melanogaster	Pld	FBGN0286511
caenorhabditis_elegans		WBGENE00004040

Paralogs (1): PLD2 (ENSG00000129219)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109585) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 13 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased metastatic potential	1
increased mean platelet volume	1
decreased tumor growth/size	1
decreased susceptibility to injury	1
abnormal platelet physiology	1
decreased angiogenesis	1
decreased cerebral infarct size	1
decreased susceptibility to ischemic brain injury	1
abnormal platelet activation	1
abnormal autophagy	1
decreased platelet aggregation	1
decreased susceptibility to induced morbidity/mortality	1
abnormal tumor vascularization	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Brassica oleracea var. capitata	O82549	94.7%	Diamond
Arabidopsis thaliana	Q38882	94.7%	Diamond
Bos taurus	Q0V8L6	92.3%	Diamond
Cricetulus griseus	O08684	90.7%	Diamond
Oryza sativa Japonica Group	Q43007	90.1%	Diamond
Vigna unguiculata	O04865	85.5%	Diamond
Ricinus communis	Q41142	85.5%	Diamond
Cynara cardunculus	Q70EW5	78.1%	Diamond
Saccharomyces cerevisiae S288C	P36126	40.1%	Diamond
Dictyostelium discoideum	Q54UK0	39.9%	Diamond
Phytophthora infestans	Q5BMR2	39.3%	Diamond
Schizosaccharomyces pombe 972h-	Q09706	37.9%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
TMEM212	protein-coding	389177
FNDC3B	protein-coding	64778
TMEM212-AS1	ncRNA	100874219
TNIK	protein-coding	23043

Protein

Protein identifiers

Phospholipase D1 — Q13393 (reviewed: Q13393)

Alternative names: Choline phosphatase 1, Phosphatidylcholine-hydrolyzing phospholipase D1

All UniProt accessions (4): C9IY79, F8WBV7, H7C0L3, Q13393

UniProt curated annotations — full annotation on UniProt →

Function. Function as phospholipase selective for phosphatidylcholine. Implicated as a critical step in numerous cellular pathways, including signal transduction, membrane trafficking, and the regulation of mitosis. May be involved in the regulation of perinuclear intravesicular membrane traffic.

Subunit / interactions. Interacts with PIP5K1B.

Subcellular location. Cytoplasm. Perinuclear region. Endoplasmic reticulum membrane. Golgi apparatus membrane. Late endosome membrane.

Tissue specificity. Expressed abundantly in the pancreas and heart and at high levels in brain, placenta, spleen, uterus and small intestine.

Disease relevance. Cardiac valvular dysplasia 1 (CVDP1) [MIM:212093] An autosomal recessive form of congenital heart defects, characterized by valvular malformations involving the pulmonic, tricuspid and mitral valves. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Stimulated by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate, activated by the phosphokinase C-alpha, by the ADP-ribosylation factor-1 (ARF-1), and to a lesser extent by GTP-binding proteins: RHO A, RAC-1 and CDC42. Inhibited by oleate.

Similarity. Belongs to the phospholipase D family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q13393-1	PLD1A	yes
Q13393-2	PLD1B
Q13393-3	PLD1C
Q13393-4	PLD1D

RefSeq proteins (2): NP_001123553, NP_002653* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001683	PX_dom	Domain
IPR001736	PLipase_D/transphosphatidylase	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR015679	PLipase_D_fam	Family
IPR016555	PLipase_D_euk	Family
IPR025202	PLD-like_dom	Domain
IPR036871	PX_dom_sf	Homologous_superfamily

Pfam: PF00169, PF00614, PF00787, PF13091

Enzyme classification (BRENDA)

• EC 3.1.4.4 — phospholipase D (BRENDA: 94 organisms, 465 substrates, 320 inhibitors, 67 Km, 27 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PHOSPHATIDYLCHOLINE	0.0015–2.5	18
N-PALMITOYL-PHOSPHATIDYLETHANOLAMINE	0.0029–0.045	16
DIOLEOYL-PHOSPHATIDYLCHOLINE	0.0015–3	4
LYSOPHOSPHATIDYLCHOLINE	1–3	4
EGG PHOSPHATIDYLCHOLINE	30.2–33.17	2
L-ALPHA-PHOSPHATIDYLCHOLINE	2.71–3.44	2
PHOSPHATIDYL-P-NITROPHENOL	0.075–1.16	2
PHOSPHATIDYLETHANOLAMINE	0.91–4	2
1,2-DIBUTYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.16	1
1-PALMITOYL-2-OLEOYL-SN-GLYCERO-3-PHOSPHOCHOLINE	0.271	1
BIS(P-NITROPHENYL)PHOSPHATE	0.6	1
DIBUTYROYLPHOSPHATIDYLCHOLINE	0.2	1
DIHEPTANOYLPHOSPHATIDYLCHOLINE	0.23	1
DIHEXANOYLPHOSPHATIDYLCHOLINE	2.64	1
DIPALMITOYLPHOSPHATIDYLCHOLINE	0.78	1

Catalyzed reactions (Rhea)

• a 1,2-diacyl-sn-glycero-3-phosphocholine + H2O = a 1,2-diacyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:14445)
• ethanol + a 1,2-diacyl-sn-glycero-3-phosphocholine = 1,2-diacyl-sn-glycero-3-phosphoethanol + choline (RHEA:44868)
• 1,2-dihexadecanoyl-sn-glycero-3-phosphocholine + H2O = 1,2-dihexadecanoyl-sn-glycero-3-phosphate + choline + H(+) (RHEA:44872)

UniProt features (74 total): helix 26, strand 21, splice variant 5, sequence variant 5, turn 5, domain 4, modified residue 3, lipid moiety-binding region 2, chain 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
6U8Z	Crystal Structure of Catalytic Domain of Human Phospholipase D1	X-RAY DIFFRACTION	1.8
6OHR	Structure of compound 5 bound human Phospholipase D1 catalytic domain	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13393-F1	81.92	0.64

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Metabolic proteins, Predicted intracellular proteins, Plasma proteins, RAS pathway related proteins, Disease related genes, Potential drug targets, Human disease related genes, Congenital malformations, Congenital malformations of the circulatory system

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): plasma membrane; golgi apparatus; vesicles

Antibody reliability (HPA): IH enhanced · IF approved

Functional residue map

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

Post-translational modifications (5)

Type	Positions
S-palmitoyl cysteine	241, 240
Phosphoserine	499, 561, 629

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 19; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

19 pathways:

ID	Pathway	Evidence
R-HSA-9013148	CDC42 GTPase cycle	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-9013149	RAC1 GTPase cycle	curated
R-HSA-8980692	RHOA GTPase cycle	curated
R-HSA-9013408	RHOG GTPase cycle	curated
R-HSA-2029485	Role of phospholipids in phagocytosis	curated
R-HSA-1483166	Synthesis of PA	curated
R-HSA-2029480	Fcgamma receptor (FCGR) dependent phagocytosis	—
R-HSA-1483206	Glycerophospholipid biosynthesis	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-1430728	Metabolism	—
R-HSA-556833	Metabolism of lipids	—
R-HSA-1483257	Phospholipid metabolism	—
R-HSA-9012999	RHO GTPase cycle	—
R-HSA-162582	Signal Transduction	—
R-HSA-194315	Signaling by Rho GTPases	—
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3	—
R-HSA-1483148	Synthesis of PG	electronic

MSigDB gene sets: 379 (showing top): GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, REACTOME_INNATE_IMMUNE_SYSTEM, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, ENK_UV_RESPONSE_KERATINOCYTE_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, chr3q26, GOBP_ORGANOPHOSPHATE_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_PHOSPHOLIPID_BIOSYNTHETIC_PROCESS, GOBP_TRANSLATION

GO Biological Process (12): phosphatidic acid biosynthetic process (GO:0006654), chemotaxis (GO:0006935), small GTPase-mediated signal transduction (GO:0007264), Ras protein signal transduction (GO:0007265), phospholipid catabolic process (GO:0009395), cellular response to nutrient (GO:0031670), positive regulation of translation (GO:0045727), regulation of vesicle-mediated transport (GO:0060627), regulation of synaptic vesicle cycle (GO:0098693), lipid metabolic process (GO:0006629), lipid catabolic process (GO:0016042), intracellular signal transduction (GO:0035556)

GO Molecular Function (5): D-type glycerophospholipase activity (GO:0004630), phosphatidylinositol binding (GO:0035091), catalytic activity (GO:0003824), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (19): Golgi membrane (GO:0000139), lysosome (GO:0005764), lysosomal membrane (GO:0005765), endosome (GO:0005768), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020), apical plasma membrane (GO:0016324), endocytic vesicle (GO:0030139), cytoplasmic vesicle (GO:0031410), late endosome membrane (GO:0031902), specific granule membrane (GO:0035579), perinuclear region of cytoplasm (GO:0048471), tertiary granule membrane (GO:0070821), cholinergic synapse (GO:0098981), cytoplasm (GO:0005737), endomembrane system (GO:0012505), organelle subcompartment (GO:0031984)

Reactome top-level categories

11 top-level categories:

Category	Pathways
RHO GTPase cycle	4
Glycerophospholipid biosynthesis	2
Innate Immune System	2
Fcgamma receptor (FCGR) dependent phagocytosis	1
Phospholipid metabolism	1
Metabolism of lipids	1
Immune System	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Metabolism	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

60 GO namespaces:

Category	Terms
cellular anatomical structure	5
cytoplasm	3
intracellular anatomical structure	2
endomembrane system	2
cytoplasmic vesicle	2
secretory granule membrane	2
phosphatidic acid metabolic process	1
glycerophospholipid biosynthetic process	1
response to chemical	1
taxis	1
intracellular signaling cassette	1
small GTPase-mediated signal transduction	1
phospholipid metabolic process	1
lipid catabolic process	1
organophosphate catabolic process	1
response to nutrient	1
cellular response to nutrient levels	1
cellular response to chemical stimulus	1
translation	1
regulation of translation	1
positive regulation of gene expression	1
positive regulation of protein metabolic process	1
vesicle-mediated transport	1
regulation of cellular process	1
regulation of transport	1
regulation of vesicle-mediated transport	1
synaptic vesicle cycle	1
primary metabolic process	1
lipid metabolic process	1
catabolic process	1
signal transduction	1
glycerophospholipase activity	1
phosphoric diester hydrolase activity	1
anion binding	1
molecular_function	1
binding	1
catalytic activity	1
Golgi apparatus	1
bounding membrane of organelle	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
intracellular vesicle	1
late endosome	1
endosome membrane	1
specific granule	1
tertiary granule	1
synapse	1
vacuole	1
plasma membrane	1
membrane-bounded organelle	1
intracellular organelle	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 12 of 36 annotations. The rest are phylogenetic / computational / electronic (IEA).

12 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to nutrient	BP	direct assay
positive regulation of translation	BP	mutant phenotype
regulation of synaptic vesicle cycle	BP	direct assay
Golgi apparatus	CC	direct assay
apical plasma membrane	CC	direct assay
cholinergic synapse	CC	direct assay
endocytic vesicle	CC	direct assay
endosome	CC	direct assay
lysosomal membrane	CC	high-throughput assay
lysosome	CC	direct assay
membrane	CC	high-throughput assay
D-type glycerophospholipase activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 1,390 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLD1	GPLD1	P80108	839
PLD1	APH1A	Q96BI3	551
PLD1	PSENEN	Q9NZ42	547
PLD1	NCSTN	Q92542	527
PLD1	SMPD2	O60906	502
PLD1	PSEN1	P49768	502
PLD1	KLC4	Q9NSK0	494
PLD1	RALA	P11233	485
PLD1	ARF1	P10947	478
PLD1	APP	P05067	468
PLD1	PRKCA	P17252	447
PLD1	PIK3C3	Q8NEB9	443
PLD1	KLC2	Q9H0B6	434
PLD1	ARF6	P26438	432
PLD1	KLC3	Q6P597	429

IntAct

Human interaction partners of PLD1 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

19 partners by confidence:

Partner	Interaction type	MIscore	Records
CFL1	direct interaction	0.570	4
APP	physical association	0.560	3
ASCL4	physical association	0.560	3
ESRP1	physical association	0.560	3
FANCG	physical association	0.560	3
INCA1	physical association	0.560	3
LIAT1	physical association	0.560	3
SPIRE1	physical association	0.560	3
SYNC	physical association	0.560	3
TCF3	physical association	0.560	3
TP53BP1	physical association	0.560	3
PKN3	physical association	0.540	3
RHEB	physical association	0.400	2
LMO7	physical association	0.400	1
RPS6KA3	physical association	0.400	1
S100A10	physical association	0.400	1
PLCG1	direct interaction	0.360	1
STXBP1	direct interaction	0.360	1
DNAJB5	association	0.350	1

BioGRID (202 interactions; top human partners by supporting records): RHOA (Protein-peptide; 7 records), ARL11 (Proximity Label-MS; 4 records), PEA15 (Two-hybrid; 4 records), AMPH (Phenotypic Suppression; 3 records), ARF1 (Co-fractionation; 3 records), ARF6 (Proximity Label-MS; 3 records), ARL14 (Proximity Label-MS; 3 records), C1orf186 (Affinity Capture-MS; 3 records), CDC42 (Reconstituted Complex; 3 records), EGLN1 (Affinity Capture-Western; 3 records), KCTD17 (Affinity Capture-MS; 3 records), MIER2 (Affinity Capture-MS; 3 records), RHEB (Affinity Capture-Western; 3 records), SNCA (Affinity Capture-Western; 3 records), SPACA1 (Affinity Capture-MS; 3 records)

SIGNOR signaling

showing 6 of 8 signaling interactions:

A	Effect	B	Mechanism
PRKAA2	up-regulates	PLD1	phosphorylation
RHEB	up-regulates	PLD1	binding
AMPK	up-regulates	PLD1	phosphorylation
PLD1	up-regulates	“phosphatidic acid”	“chemical modification”
PRKCA	up-regulates	PLD1	phosphorylation
RHOA	up-regulates	PLD1	binding

Protein complexes (CORUM) (3)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

3 complexes by size:

Complex	Subunits	Members
★ EGLN1-HIF1A-PLD1-VHL complex	4	EGLN1, HIF1A, PLD1, VHL
★ EGLN1-HIF1A-PLD1 complex	3	EGLN1, HIF1A, PLD1
PKC-alpha-PLD1-PLC-gamma-2 signaling complex, lacritin stimulated	3	PLD1, PRKCA, PLCG2

Disease & clinical

Genetic variants

Variant evidence for PLD1: 402 ClinVar records (28 pathogenic / likely pathogenic); 16 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	13
Uncertain significance	196
Likely benign	68
Benign	66

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 28 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
3251798	NM_002662.5(PLD1):c.2034del (p.Trp678fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1211263	NM_002662.5(PLD1):c.2681A>C (p.Tyr894Ser)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1071285	NM_002662.5(PLD1):c.880A>T (p.Lys294Ter)	Pathogenic	criteria provided, single submitter	1
1313339	NM_002662.5(PLD1):c.607-2A>C	Pathogenic	criteria provided, single submitter	1
2042304	NM_002662.5(PLD1):c.1276_1279del (p.Ala426fs)	Pathogenic	criteria provided, single submitter	1
2903572	NM_002662.5(PLD1):c.2178del (p.Ala727fs)	Pathogenic	criteria provided, single submitter	1
3239271	NM_002662.5(PLD1):c.472C>T (p.Arg158Ter)	Pathogenic	criteria provided, single submitter	1
4056489	NM_002662.5(PLD1):c.892C>T (p.Arg298Ter)	Pathogenic	criteria provided, single submitter	1
4748179	NM_002662.5(PLD1):c.1745del (p.Ser582fs)	Pathogenic	criteria provided, single submitter	1
4775586	NM_002662.5(PLD1):c.2914G>T (p.Glu972Ter)	Pathogenic	criteria provided, single submitter	1
4798150	NM_002662.5(PLD1):c.904_905del (p.Leu302fs)	Pathogenic	criteria provided, single submitter	1
4812895	NM_002662.5(PLD1):c.665+1G>A	Pathogenic	criteria provided, single submitter	1
4849884	NM_002662.5(PLD1):c.434+1G>T	Pathogenic	criteria provided, single submitter	1
426090	NM_002662.5(PLD1):c.1484_1485del (p.Thr495fs)	Likely pathogenic	criteria provided, single submitter	2
992859	NM_002662.5(PLD1):c.2083C>T (p.Arg695Cys)	Likely pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore PLD1’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 34 predictions of 3,192):

Position(s)	Effect	Δscore	Sites
3:171612277–171612278	donor_loss	1.0000	5
3:171612433–171612434	acceptor_loss	1.0000	4
3:171642838–171642839	donor_loss	1.0000	5
3:171642898	acceptor_gain	1.0000
3:171659211–171659212	donor_loss	1.0000	5
3:171659302–171659303	acceptor_loss	1.0000	6
3:171659304	acceptor_gain	1.0000
3:171659311	acceptor_gain	1.0000
3:171662058–171662059	donor_loss	1.0000	5
3:171662180	acceptor_gain	1.0000

AlphaMissense

2,900 missense substitutions predicted likely pathogenic (of 7,149 scored), across 678 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M676	9	0.935	0.997
H464	8	0.997	0.999
D648	8	0.997	0.999
D481	8	0.996	0.999
D488	8	0.995	0.999
D496	8	0.995	0.998
D680	8	0.995	0.999
H463	8	0.994	0.999
D924	8	0.994	0.998
H896	8	0.988	0.996
D656	8	0.987	0.997
D916	8	0.984	0.997
F827	8	0.978	0.998
D666	8	0.977	0.995
D279	8	0.973	0.996
H679	8	0.973	0.996
D904	8	0.973	0.996
N702	8	0.970	0.999
N913	8	0.969	1.000
N994	8	0.969	0.997

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000166
Liver Hepatocellular Carcinoma (validation)	unfavorable	0.000239

Disease associations

OMIM: gene MIM:602382 | disease phenotypes: MIM:212093

GenCC curated gene-disease

2 curated gene-disease records:

Disease	Classification	Inheritance	Records
cardiac valvular defect, developmental	Definitive	Autosomal recessive	4
PLD1-related congenital heart disease	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity

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

1 validity classifications:

Disease	Classification	Inheritance
PLD1-related congenital heart disease	Definitive	AR

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (6 panels, 4 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

6 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Paediatric disorders	green
Paediatric disorders - additional genes	green
Paediatric or syndromic cardiomyopathy	amber
Unexplained death in infancy and sudden unexplained death in childhood	amber

Mondo (2): cardiac valvular defect, developmental (MONDO:0008913), PLD1-related congenital heart disease (MONDO:1010144)

HPO phenotypes

29 phenotypes (HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000072	Hydroureter
HP:0000126	Hydronephrosis
HP:0000961	Cyanosis
HP:0000969	Edema
HP:0001629	Ventricular septal defect
HP:0001631	Atrial septal defect
HP:0001634	Mitral valve prolapse
HP:0001642	Pulmonic stenosis
HP:0001653	Mitral regurgitation
HP:0001655	Patent foramen ovale
HP:0001704	Tricuspid valve prolapse
HP:0001718	Mitral stenosis
HP:0001789	Hydrops fetalis
HP:0003577	Congenital onset
HP:0004762	Hypoplasia of right ventricle
HP:0004935	Pulmonary artery atresia
HP:0005180	Tricuspid regurgitation
HP:0008722	Urethral diverticulum
HP:0010446	Tricuspid stenosis
HP:0011555	Double inlet left ventricle
HP:0011591	Left aortic arch with cervical origin of the right subclavian artery
HP:0011623	Muscular ventricular septal defect
HP:0011662	Tricuspid atresia
HP:0031295	Left atrial enlargement
HP:0031632	Aberrant right subclavian artery
HP:0034348	Subpulmonary stenosis
HP:0034350	Valvular pulmonary stenosis

GWAS associations

16 associations:

Study	Trait	p-value
GCST90002404_485	Red cell distribution width	2e-43
GCST004621_192	Red cell distribution width	7e-43
GCST90002404_486	Red cell distribution width	1e-42
GCST90002404_487	Red cell distribution width	8e-39
GCST90002404_488	Red cell distribution width	2e-37
GCST004621_196	Red cell distribution width	5e-34
GCST006804_38	Red cell distribution width	2e-26
GCST90002404_489	Red cell distribution width	1e-17
GCST004621_194	Red cell distribution width	2e-15
GCST006804_29	Red cell distribution width	9e-15
GCST006804_27	Red cell distribution width	5e-13
GCST004621_193	Red cell distribution width	3e-11
GCST90002381_19	Eosinophil count	7e-10
GCST004621_195	Red cell distribution width	2e-9
GCST90002406_258	Reticulocyte fraction of red cells	7e-9
GCST007012_1	Cerebrospinal fluid AB1-42 levels	5e-7

EFO canonical traits (from GWAS)

3 canonical traits:

EFO ID	Trait name
EFO:0009188	Red cell distribution width
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004842	eosinophil count

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C565882	Cardiac Valvular Defect, Developmental *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2536 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 79,240 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

2 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL81	RALOXIFENE	4	78,815
CHEMBL245621	HALOPEMIDE	2	425

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Phosphatidylcholine-specific phospholipase D

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

Ligand	Action	Affinity	Parameter
FIPI	Inhibition	8.02	pIC50
compound 69 [PMID: 19136975]	Inhibition	7.34	pIC50

Binding affinities (BindingDB)

701 measured of 760 human assays (797 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
cid_44573642	IC50	1 nM
CHEMBL4453586	IC50	1 nM
N-[(2S)-1-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-1H-indole-2-carboxamide	IC50	1 nM
5-fluoranyl-N-[(2S)-1-[4-(2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-1H-indole-2-carboxamide	IC50	1 nM
CID25105701	IC50	1.7 nM
(S)-N-(1-(4-(6-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-naphthamide	IC50	2 nM
CHEMBL2304616	IC50	2 nM
cid_53470042	IC50	2 nM
N-[(2R)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)-1-piperidinyl]propan-2-yl]-1H-indole-2-carboxamide;2,2,2-trifluoroacetic acid	IC50	2 nM
VU0361535-1	IC50	2 nM
N-[(2S)-1-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-2-phenoxyacetamide;2,2,2-trifluoroacetic acid	IC50	2 nM
cid_53470207	IC50	2 nM
(S)-N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-3,4-difluorobenzamide	IC50	3 nM
cid_44573690	IC50	3 nM
VU0404360-1	IC50	3 nM
N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)-1-piperidinyl]propan-2-yl]-3,4-difluorobenzamide;2,2,2-trifluoroacetic acid	IC50	3 nM
N-[(2S)-1-[4-(6-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]naphthalene-2-carboxamide;2,2,2-trifluoroacetic acid	IC50	3 nM
(S)-N-(1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-3,4-difluorobenzamide	IC50	3.5 nM
(S)-N-(1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-4-chlorobenzamide	IC50	4 nM
cid_44573687	IC50	4 nM
cid_21428895	IC50	4 nM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-chlorobenzamide;2,2,2-trifluoroacetic acid	IC50	4 nM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-fluorobenzamide;2,2,2-trifluoroacetic acid	IC50	4 nM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-3,4-difluorobenzamide;2,2,2-trifluoroacetic acid	IC50	4 nM
VU0359566-1	IC50	4 nM
(2-{4-[(1Z)-1,2-diphenylbut-1-en-1-yl]phenoxy}ethyl)dimethylamine	KI	5 nM
4-chloro-N-[2-[4-(5-iodo-2-oxo-3H-benzimidazol-1-yl)-1-piperidinyl]ethyl]benzamide;2,2,2-trifluoroacetic acid	IC50	5 nM
N-[(2S)-1-[1-[3,4-bis(fluoranyl)phenyl]-4-oxidanylidene-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]-5-fluoranyl-1H-indole-2-carboxamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	5 nM
3,4-bis(fluoranyl)-N-[(2S)-1-[4-(6-fluoranyl-2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	5 nM
(S)-N-(1-(4-(5-bromo-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-naphthamide	IC50	5.5 nM
2-(4-hydroxyphenyl)-3-({4-[2-(piperidin-1-yl)ethoxy]phenyl}carbonyl)-1-benzothiophen-6-ol	IC50	5.7 nM
4-chloranyl-N-[(2S)-1-[4-(5-chloranyl-2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	6 nM
(S)-4-chloro-N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)benzamide	IC50	6.4 nM
Halopemide	IC50	7 nM
N-[(2S)-3-methyl-1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)butan-2-yl]-1H-indole-2-carboxamide;2,2,2-trifluoroacetic acid	IC50	7 nM
N-[(2S)-1-[4-(5-bromanyl-2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-methyl-benzamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	7 nM
4-chloranyl-N-[(2S)-1-[4-(5-fluoranyl-2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	7 nM
VU0249424-1	IC50	7 nM
(S)-4-chloro-N-(1-(4-(5-fluoro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)benzamide	IC50	7.4 nM
racemic trans-N-((S)-1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-2-phenylcyclopropanecarboxamide	IC50	8 nM
N-[(2S)-1-[4-(6-fluoranyl-2-oxidanylidene-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-methyl-benzamide;2,2,2-tris(fluoranyl)ethanoic acid	IC50	8 nM
N’-[(2S)-1-[5-(2-bromo-5-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl]propan-2-yl]oxamide	IC50	9 nM	US-20240101572: DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF
N-[2-[4-(5-iodo-2-oxo-3H-benzimidazol-1-yl)-1-piperidinyl]ethyl]-2-phenyl-1-cyclopropanecarboxamide;2,2,2-trifluoroacetic acid	IC50	9 nM
cid_21429000	IC50	10 nM
(S)-N-(1-(4-(5-chloro-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)piperidin-1-yl)propan-2-yl)-4-fluorobenzamide	IC50	10 nM
(S)-N-(1-(1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl)propan-2-yl)-2-naphthamide	IC50	10 nM
N’-[(2S)-1-[5-(2-bromo-4-fluorophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl]propan-2-yl]-N-methyloxamide	IC50	10 nM	US-20240101572: DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF
N-[(2S)-1-[5-[2-bromo-4-(2-hydroxy-2-methylpropoxy)phenyl]-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl]propan-2-yl]-3-chloro-1,2-oxazole-5-carboxamide	IC50	10 nM	US-20240101572: DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF
N-cyclopropyl-N’-[(2S)-1-[5-(4-fluoro-2-iodophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl]propan-2-yl]oxamide	IC50	10 nM	US-20240101572: DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF
N-[(2S)-1-[5-(2-bromo-4-cyanophenyl)-2-oxo-1-oxa-3,4-diazaspiro[5.5]undec-4-en-9-yl]propan-2-yl]-5-methyl-1H-pyrazole-3-carboxamide	IC50	10 nM	US-20240101572: DIHYDROOXADIAZINONE COMPOUND AND PHARMACEUTICAL USE THEREOF

ChEMBL bioactivities

232 potent at pChembl≥5 of 239 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.00	IC50	1	nM	CHEMBL4453586
9.00	IC50	1	nM	CHEMBL398567
8.70	IC50	2	nM	CHEMBL2304616
8.70	IC50	2	nM	CHEMBL493521
8.52	IC50	3	nM	CHEMBL492561
8.52	IC50	3	nM	CHEMBL492558
8.46	IC50	3.5	nM	CHEMBL492559
8.43	IC50	3.7	nM	CHEMBL3947795
8.43	IC50	3.7	nM	CHEMBL524182
8.40	IC50	4	nM	CHEMBL493010
8.40	IC50	4	nM	CHEMBL521990
8.40	IC50	4	nM	CHEMBL492972
8.40	IC50	4	nM	CHEMBL523011
8.26	IC50	5.5	nM	CHEMBL492704
8.22	IC50	6	nM	CHEMBL2325485
8.22	IC50	6	nM	CHEMBL3357311
8.22	IC50	6	nM	CHEMBL4446255
8.20	IC50	6.3	nM	CHEMBL1213097
8.19	IC50	6.4	nM	CHEMBL494145
8.15	IC50	7	nM	CHEMBL492971
8.13	IC50	7.4	nM	CHEMBL522488
8.10	IC50	8	nM	CHEMBL246032
8.10	IC50	8	nM	CHEMBL521677
8.05	IC50	8.9	nM	CHEMBL1213066
8.02	IC50	9.5	nM	CHEMBL398567
8.00	IC50	10	nM	CHEMBL494183
8.00	IC50	10	nM	CHEMBL492589
8.00	IC50	10	nM	CHEMBL1254495
7.96	IC50	11	nM	CHEMBL492588
7.96	IC50	11	nM	CHEMBL492572
7.92	IC50	12	nM	CHEMBL492369
7.92	IC50	12	nM	CHEMBL493736
7.85	IC50	14	nM	CHEMBL398568
7.82	IC50	15	nM	CHEMBL3947795
7.80	IC50	16	nM	CHEMBL4448918
7.80	IC50	16	nM	CHEMBL4514153
7.77	IC50	17	nM	CHEMBL3357312
7.77	IC50	17	nM	CHEMBL1213067
7.75	IC50	18	nM	CHEMBL3357310
7.75	IC50	18	nM	CHEMBL523162
7.72	IC50	19	nM	CHEMBL1213069
7.70	IC50	20	nM	CHEMBL2325482
7.70	IC50	20	nM	CHEMBL1213068
7.68	IC50	21	nM	CHEMBL3357315
7.68	IC50	21	nM	CHEMBL3357311
7.68	IC50	21	nM	CHEMBL492797
7.68	IC50	21	nM	HALOPEMIDE
7.68	IC50	21	nM	CHEMBL4475943
7.66	IC50	22	nM	CHEMBL5085284
7.66	IC50	22	nM	CHEMBL1213141

PubChem BioAssay actives

355 with measured affinity, of 431 total; 50 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
5-fluoro-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-1H-indole-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0010	uM
N-[(2S)-1-[(4S)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]propan-2-yl]-1H-indole-2-carboxamide	1532924: Inhibition of PLD1 in human Calu1 cells	ic50	0.0010	uM
4-methyl-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	1799396: d.311 Enzymatic Inhibition Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ic50	0.0017	uM
N-[(2S)-1-[4-(6-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]naphthalene-2-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0020	uM
(2S)-N-[2-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-2-phenylcyclopropane-1-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0020	uM
N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-3,4-difluorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0030	uM
N-[2-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-4-chlorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0030	uM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-3,4-difluorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0035	uM
trans-(1R,2R)-N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-2-phenylcyclopropane-1-carboxamide	1532920: Inhibition of PLD1 (unknown origin)	ic50	0.0037	uM
N-[2-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-4-fluorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0040	uM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-chlorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0040	uM
N-[2-[4-(5-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]naphthalene-2-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0040	uM
3,4-difluoro-N-[2-[4-(6-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0040	uM
1-(4-methoxyphenyl)-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine	1800492: PLD In Vitro Kinetic Assay from Article 10.1111/cbdd.12319: “1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D.”	ic50	0.0050	uM
N-[(2S)-1-[4-(5-bromo-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]naphthalene-2-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0055	uM
N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl]-1H-indole-2-carboxamide	1174992: Inhibition of PLD2 (unknown origin) expressed in HEK293-gfp cells by cell-based assay	ic50	0.0060	uM
4-bromo-N-[(2S)-1-[1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]benzamide	1532920: Inhibition of PLD1 (unknown origin)	ic50	0.0060	uM
4-bromo-N-[(2S)-1-[1-(3-methylphenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]benzamide	729468: Inhibition of PLD1 in human Calu-1 cells assessed as deuterated 1-butanol incorporation pretreated for 5 mins prior to substrate addition measured after 30 mins by mass spectrometry	ic50	0.0060	uM
4-chloro-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0063	uM
4-chloro-N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0064	uM
4-chloro-N-[2-[4-(6-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0070	uM
4-chloro-N-[(2S)-1-[4-(5-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0074	uM
N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]quinoline-3-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0080	uM
trans-(1R,2R)-N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-2-phenylcyclopropane-1-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0080	uM
4,5-dibromo-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]furan-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0089	uM
N-[2-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-4-methylbenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0100	uM
N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-4-fluorobenzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0100	uM
N-[(2S)-1-[1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]naphthalene-2-carboxamide	515548: Inhibition of PLD1 in human calu1 cells	ic50	0.0100	uM
N-[(2S)-1-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]naphthalene-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0110	uM
4-fluoro-N-[(2S)-1-[4-(5-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0110	uM
N-[2-[4-(5-chloro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-4-fluorobenzamide	1799396: d.311 Enzymatic Inhibition Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ic50	0.0110	uM
trans-(1R,2R)-N-[(2S)-1-[4-(6-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]propan-2-yl]-2-phenylcyclopropane-1-carboxamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0120	uM
4-fluoro-N-[2-[4-(5-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0120	uM
N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]-1-benzothiophene-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0140	uM
N-[(2S)-1-[(4R)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]propan-2-yl]-1H-indole-2-carboxamide	1532924: Inhibition of PLD1 in human Calu1 cells	ic50	0.0160	uM
N-[(2S)-1-[(4S)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]propan-2-yl]-3-phenylprop-2-ynamide	1532924: Inhibition of PLD1 in human Calu1 cells	ic50	0.0160	uM
3,4-difluoro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl]benzamide	1174992: Inhibition of PLD2 (unknown origin) expressed in HEK293-gfp cells by cell-based assay	ic50	0.0170	uM
3,4-difluoro-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0170	uM
5-fluoro-N-[2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propyl]-1H-indole-2-carboxamide	1174992: Inhibition of PLD2 (unknown origin) expressed in HEK293-gfp cells by cell-based assay	ic50	0.0180	uM
4-chloro-N-[2-[4-(5-fluoro-2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	418766: Inhibition of human PLD1 in Calu1 cells	ic50	0.0180	uM
3,4-dichloro-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0190	uM
9-oxo-N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]fluorene-4-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0200	uM
4-fluoro-N-[(2S)-1-[1-(3-fluorophenyl)-4-oxo-1,3,8-triazaspiro[4.5]decan-8-yl]propan-2-yl]benzamide	729468: Inhibition of PLD1 in human Calu-1 cells assessed as deuterated 1-butanol incorporation pretreated for 5 mins prior to substrate addition measured after 30 mins by mass spectrometry	ic50	0.0200	uM
1-methyl-3-naphthalen-1-ylpyrazolo[3,4-d]pyrimidin-4-amine	1800492: PLD In Vitro Kinetic Assay from Article 10.1111/cbdd.12319: “1,3-disubstituted-4-aminopyrazolo [3, 4-d] pyrimidines, a new class of potent inhibitors for phospholipase D.”	ic50	0.0200	uM
3,4-difluoro-N-[2-[3-fluoro-4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]benzamide	1174991: Inhibition of PLD1 (unknown origin) expressed in human Calu1 cells by cell-based assay	ic50	0.0210	uM
N-[2-[(4S)-4-(4-fluorophenyl)-1-oxo-2,8-diazaspiro[4.5]decan-8-yl]ethyl]-1H-indole-2-carboxamide	1532924: Inhibition of PLD1 in human Calu1 cells	ic50	0.0210	uM
N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]naphthalene-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0210	uM
4-fluoro-N-[(2S)-1-[(5R)-5-(3-fluorophenyl)-2-oxo-1-oxa-3,9-diazaspiro[5.5]undecan-9-yl]propan-2-yl]benzamide	1827970: Inhibition of PLD1 (unknown origin) expressed in human HEK cells by immunoprecipitation assay	ic50	0.0220	uM
N-[2-[4-(2-oxo-3H-benzimidazol-1-yl)piperidin-1-yl]ethyl]furan-2-carboxamide	1799397: Calu-1 Cell-Based Assay from Article 10.1038/nchembio.140: “Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness.”	ec50	0.0220	uM
N-[(2S)-1-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decan-8-yl)propan-2-yl]naphthalene-2-carboxamide	349537: Inhibition of PLD1 in human Calu1 cells	ic50	0.0250	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	8
sodium arsenite	decreases expression, affects cotreatment, increases abundance	4
Benzo(a)pyrene	increases expression, affects methylation, decreases expression	4
bisphenol A	decreases expression, increases expression, increases methylation	3
Smoke	decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	3
Tretinoin	increases expression	3
trichostatin A	increases expression	2
epigallocatechin gallate	increases expression, increases reaction, affects cotreatment, decreases expression	2
perfluoro-n-nonanoic acid	decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression, decreases activity, increases activity, increases localization	2
Air Pollutants	decreases expression, increases abundance	2
Arsenic	decreases expression, increases abundance, affects methylation, affects cotreatment	2
Hydrogen Peroxide	decreases expression, affects expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Quercetin	decreases expression	2
Tobacco Smoke Pollution	decreases expression, decreases reaction, increases expression, increases phosphorylation, affects reaction (+1 more)	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
sotorasib	affects cotreatment, increases expression	1
2-methyl-4-isothiazolin-3-one	decreases expression	1
sulforaphane	decreases expression	1
cobaltous chloride	affects reaction, decreases reaction, increases expression, increases reaction, increases activity (+1 more)	1
ethylene dichloride	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
oxophenylarsine	increases phosphorylation, decreases reaction, increases expression	1
hydroquinone	decreases expression	1
muconaldehyde	decreases expression	1

ChEMBL screening assays

33 unique, capped per target: 29 binding, 4 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1220060	Binding	Inhibition of PLD1 mediated cancer cell migration in human MDA-231 cells at 200 nM by transwell invasion assay	Design of isoform-selective phospholipase D inhibitors that modulate cancer cell invasiveness. — *Nat Chem Biol*
CHEMBL1794331	Functional	PUBCHEM_BIOASSAY: Cellular PLD1 concentration response. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID588854]	PubChem BioAssay data set

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YG	Abcam A-549 PLD1 KO	Cancer cell line	Male
CVCL_D2CM	Abcam HCT 116 PLD1 KO	Cancer cell line	Male
CVCL_F5I3	EDITGENE PLD1 Knockout HAP1 Cell Line	Cancer cell line	Male
CVCL_TE42	HAP1 PLD1 (-) 1	Cancer cell line	Male
CVCL_TE43	HAP1 PLD1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for PLD1 across ~30M SureChEMBL compounds — explore on Sugi Predict.