PLD4

Summary

PLD4 (phospholipase D family member 4, HGNC:23792) is a protein-coding gene on chromosome 14q32.33, encoding 5’-3’ exonuclease PLD4 (Q96BZ4). 5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments.

Predicted to enable single-stranded DNA 5’-3’ DNA exonuclease activity. Predicted to be involved in hematopoietic progenitor cell differentiation; phagocytosis; and regulation of cytokine production involved in inflammatory response. Predicted to act upstream of or within establishment of localization in cell. Predicted to be located in early endosome and endoplasmic reticulum membrane. Predicted to be active in several cellular components, including endoplasmic reticulum; phagocytic vesicle; and trans-Golgi network membrane.

Source: NCBI Gene 122618 — RefSeq curated summary.

At a glance

• Gene–disease (curated): systemic lupus erythematosus 18 (Moderate, ClinGen)
• GWAS associations: 8
• Clinical variants (ClinVar): 123 total — 7 pathogenic
• Phenotypes (HPO): 62
• Druggable target: yes
• MANE Select transcript: NM_138790

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23792
Approved symbol	PLD4
Name	phospholipase D family member 4
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000166428
Ensembl biotype	protein_coding
OMIM	618488
Entrez	122618

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 retained_intron

ENST00000392593, ENST00000472702, ENST00000472901, ENST00000540372, ENST00000553861, ENST00000557573, ENST00000649344, ENST00000862746, ENST00000862747

RefSeq mRNA: 2 — MANE Select: NM_138790 NM_001308174, NM_138790

CCDS: CCDS76725, CCDS9995

Canonical transcript exons

ENST00000392593 — 11 exons

Exon	Start	End
ENSE00001102868	104932765	104933236
ENSE00001102872	104930742	104930942
ENSE00001102879	104932259	104932355
ENSE00001102890	104929978	104930105
ENSE00001302777	104929307	104929427
ENSE00001320127	104928749	104928932
ENSE00003545108	104927141	104927230
ENSE00003577989	104932012	104932177
ENSE00003610404	104931748	104931887
ENSE00003648027	104927673	104927866
ENSE00003903694	104924879	104924990

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 90.00.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1154 / max 962.9836, expressed in 299 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
141855	3.7620	291
141853	0.2565	36
141854	0.0968	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	90.00	gold quality
leukocyte	CL:0000738	86.00	gold quality
monocyte	CL:0000576	85.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.04	gold quality
spinal cord	UBERON:0002240	83.19	gold quality
bone marrow cell	CL:0002092	82.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.95	gold quality
pancreatic ductal cell	CL:0002079	80.74	silver quality
spleen	UBERON:0002106	77.71	gold quality
substantia nigra	UBERON:0002038	76.06	gold quality
vermiform appendix	UBERON:0001154	75.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	75.51	gold quality
hypothalamus	UBERON:0001898	75.19	gold quality
cerebellar hemisphere	UBERON:0002245	75.02	gold quality
cerebellar cortex	UBERON:0002129	74.80	gold quality
lymph node	UBERON:0000029	74.57	gold quality
midbrain	UBERON:0001891	74.38	gold quality
bone marrow	UBERON:0002371	74.26	gold quality
amygdala	UBERON:0001876	74.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.02	gold quality
cerebellum	UBERON:0002037	72.61	gold quality
inferior vagus X ganglion	UBERON:0005363	72.36	silver quality
caudate nucleus	UBERON:0001873	71.40	gold quality
blood	UBERON:0000178	71.36	gold quality
prefrontal cortex	UBERON:0000451	71.36	gold quality
ileal mucosa	UBERON:0000331	71.34	gold quality
putamen	UBERON:0001874	71.28	gold quality
nucleus accumbens	UBERON:0001882	70.96	gold quality
anterior cingulate cortex	UBERON:0009835	70.79	gold quality
right frontal lobe	UBERON:0002810	70.48	gold quality

Single-cell (SCXA)

Detected in 23 experiment(s), a significant marker in 23.

Experiment	Marker?	Max mean expression
E-MTAB-8498	yes	1810.63
E-CURD-120	yes	1559.58
E-MTAB-9067	yes	1297.31
E-HCAD-15	yes	1233.71
E-GEOD-149689	yes	1222.79
E-CURD-55	yes	1121.01
E-MTAB-8530	yes	1014.78
E-MTAB-10042	yes	987.13
E-CURD-77	yes	952.45
E-CURD-112	yes	870.62
E-CURD-122	yes	807.58
E-MTAB-8410	yes	783.19
E-HCAD-6	yes	549.01
E-HCAD-4	yes	541.61
E-HCAD-10	yes	44.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

3 targeting PLD4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4308	97.56	67.13	1385

Literature-anchored findings (GeneRIF, showing 4)

• We determined that PLD4 is a novel susceptibility gene for sysetmic sclerosis in Japanese, thus confirming the involvement of PLD4 in autoimmunity. (PMID:23124809)
• PLD4 expression in colon cancer tissues (PMID:27840999)
• PLD4 is a genetic determinant to systemic lupus erythematosus. (PMID:30679154)
• Phospholipase D4 as a signature of toll-like receptor 7 or 9 signaling is expressed on blastic T-bet + B cells in systemic lupus erythematosus. (PMID:37840148)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000113386
mus_musculus	Pld4	ENSMUSG00000052160
rattus_norvegicus	Pld4	ENSRNOG00000028566
drosophila_melanogaster	Pld3	FBGN0032923
drosophila_melanogaster	CG43345	FBGN0263050
caenorhabditis_elegans		WBGENE00013080
caenorhabditis_elegans		WBGENE00017124
caenorhabditis_elegans		WBGENE00017316
caenorhabditis_elegans		WBGENE00020256

Paralogs (2): PLD3 (ENSG00000105223), PLD5 (ENSG00000180287)

Protein

Protein identifiers

5’-3’ exonuclease PLD4 — Q96BZ4 (reviewed: Q96BZ4)

Alternative names: (S,S)-bis(monoacylglycero)phosphate synthase PLD4, Phospholipase D family member 4, Phospholipase D4

All UniProt accessions (5): A0A3B3IT68, Q96BZ4, F5H2B5, G3V3J8, G3V472

UniProt curated annotations — full annotation on UniProt →

Function. 5’->3’ exonuclease that hydrolyzes the phosphodiester bond of single-stranded DNA (ssDNA) and RNA molecules to form nucleoside 3’-monophosphates and 5’-end 5’-hydroxy deoxyribonucleotide/ribonucleotide fragments. Partially redundant with PLD3, can cleave all four nucleotides displaying higher efficiency for ssDNA and RNA fragments initiated with uridine and guanosine residues and lower efficiency for cytidine-initiated substrates. As a result, it does not always degrade polynucleotides to the single nucleotide level, it can stall at specific sites sparing certain fragments from exonucleolytic degradation. Processes self and pathogenic ssDNA and RNA molecules that reach the endolysosomal compartment via phagocytosis or autophagy and may serve as ‘danger’ signals for recognition by innate immune receptors such as toll-like receptors (TLRs). Degrades mitochondrial CpG-rich ssDNA fragments to prevent TLR9 activation and autoinflammatory response, but it can cleave viral RNA to generate ligands for TLR7 activation and initiate antiviral immune responses. In plasmacytoid dendritic cells, it cooperates with endonuclease RNASET2 to release 2’,3’-cyclic guanosine monophosphate (2’,3’-cGMP), a potent stimulatory ligand for TLR7. Produces 2’,3’-cGMPs and cytidine-rich RNA fragments that occupy TLR7 ligand-binding pockets and trigger a signaling-competent state. Can exert polynucleotide phosphatase activity toward 5’-phosphorylated ssDNA substrates although at a slow rate. Transphosphatidylase that catalyzes the exchange with R to S stereo-inversion of the glycerol moiety between (S,R)-lysophosphatidylglycerol (LPG) and monoacylglycerol (MAG) substrates to yield (S,S)-bis(monoacylglycero)phosphate (BMP). Can synthesize a variety of (S,S)-BMPs representing the main phospholipid constituent of lysosomal intralumenal vesicle (ILV) membranes that bind acid hydrolases for lipid degradation. Regulates the homeostasis and interorganellar communication of the endolysosomal system with an overall impact on cellular removal of dysfunctional organelles via autophagy as well as proper protein and lipid turnover. May play a role in myotube formation in response to ER stress.

Subunit / interactions. Homodimer.

Subcellular location. Endoplasmic reticulum membrane. Golgi apparatus. trans-Golgi network membrane. Nucleus. Early endosome. Cytoplasmic vesicle. Phagosome. Lysosome.

Tissue specificity. Expressed in plasmacytoid dendritic cells and monocytes (at protein level).

Post-translational modifications. Highly N-glycosylated.

Activity regulation. The exonuclease activity toward ssDNA substrate is Ca(2+) and Mg(2+)-independent, but it is inhibited by Fe(2+), Cu(2+) and to a lesser extent Zn(2+) ions.

Domain organisation. The catalytic domain contains two conserved PLD phosphodiesterase HxK(x4)D(E) motifs that accomodate the phosphate group of the nucleic acid substrates, with one nucleophile histidine residue forming a phosphohistidine intermediate and the other histidine protonating the leaving 5’-OH ssDNA/RNA fragment, resulting in the cleavage of the phosphodiester bond. The homodimer has two independent catalytic domains arranged at the dimer interface.

Similarity. Belongs to the phospholipase D family.

RefSeq proteins (2): NP_001295103, NP_620145* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001736	PLipase_D/transphosphatidylase	Domain
IPR032803	PLDc_3	Domain
IPR050874	Diverse_PLD-related	Family

Pfam: PF13918

Catalyzed reactions (Rhea), 6 shown:

• a ribonucleoside 3’-phosphate-2’-3’-cyclophospho-GMP + H2O = a ribonucleoside 3’-phosphate + 2’,3’-cyclophospho-GMP + H(+) (RHEA:81319)
• a 5’-end 5’-dephospho-ribonucleotidyl-ribonucleotide-RNA + H2O = a ribonucleoside 3’-phosphate + a 5’-end dephospho-ribonucleoside-RNA + H(+) (RHEA:81375)
• a 5’-end 5’-dephospho-2’-deoxyribonucleotidyl-2’-deoxyribonucleotide in single-stranded DNA + H2O = a 5’-end dephospho-2’-deoxyribonucleoside in single-stranded DNA + a 2’-deoxyribonucleoside 3’-phosphate + H(+) (RHEA:81379)
• a 5’-end 5’-phospho-2’-deoxyribonucleotide in single-stranded DNA + H2O = a 5’-end 5’-dephospho-2’-deoxyribonucleotide in single-stranded DNA + phosphate (RHEA:82335)
• an (R,S)-glycero-3-phospho-(3’-acyl-1’-glycerol) + a 1-acyl-sn-glycerol = a 3-acyl-sn-glycero-1-phospho-(3’-acyl-1’-sn-glycerol) + glycerol (RHEA:82563)
• 3-lyso-sn-glycero-1-phospho-(3’-(9Z-octadecenoyl)-1’-sn-glycerol) + 1-(9Z-octadecenoyl)-sn-glycerol = 3-(9Z-octadecenoyl)-sn-glycero-1-phospho-(3’-(9Z-octadecenoyl)-1’-sn-glycerol) + glycerol (RHEA:82567)

UniProt features (79 total): strand 22, mutagenesis site 17, helix 13, glycosylation site 8, turn 6, active site 4, sequence variant 3, disulfide bond 2, domain 2, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8V08	X-RAY DIFFRACTION	3
9VBK	ELECTRON MICROSCOPY	3.06
9VBJ	ELECTRON MICROSCOPY	3.31

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BZ4-F1	86.12	0.76

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 (4): 214 (proton donor); 216; 221; 428 (nucleophile)

Disulfide bonds (2): 94–250, 379–502

Glycosylation sites (8): 249, 281, 403, 417, 427, 444, 150, 171

Mutagenesis-validated functional residues (17):

Position	Phenotype
183	loss of exonuclease activity toward ssdna substrate.
212	loss of exonuclease activity toward ssdna substrate; when associated with a-348.
214	loss of exonuclease and phosphatase activities toward ssdna; when associated with a-414. loss of (s,s)-bmp synthase acti
216	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
221	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes. loss of protein stabi
235	tends to form aggregates. loss of exonuclease activity toward ssdna substrate.
252	no effect on exonuclease activity toward ssdna substrate.
255	no effect on exonuclease activity toward ssdna substrate.
283	tends to form aggregates. decreases exonuclease activity toward ssdna substrate.
326	no effect on exonuclease activity toward ssdna substrate.
348	loss of exonuclease activity toward ssdna; when associated with a-212.
368	increases exonuclease activity toward ssdna substrate.
426	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes.
428	loss of exonuclease and phosphatase activities; when associated with a-414. loss of (s,s)-bmp synthase activity. no effe
435	loss of (s,s)-bmp synthase activity. no effect on protein expression or localization to lysosomes. loss of protein stabi
435	no effect on (s,s)-bmp synthase activity, protein expression or localization to lysosomes.
497	no effect on exonuclease activity toward ssdna substrate.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-1483148	Synthesis of PG
R-HSA-1855204	Synthesis of IP3 and IP4 in the cytosol
R-HSA-2029485	Role of phospholipids in phagocytosis

MSigDB gene sets: 194 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, SHEPARD_BMYB_MORPHOLINO_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOMF_NUCLEASE_ACTIVITY, GOBP_VESICLE_MEDIATED_TRANSPORT, GOLDRATH_ANTIGEN_RESPONSE, GOCC_TRANS_GOLGI_NETWORK, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, RAMALHO_STEMNESS_DN, GOBP_PRODUCTION_OF_MOLECULAR_MEDIATOR_INVOLVED_IN_INFLAMMATORY_RESPONSE, GOBP_CYTOKINE_PRODUCTION, MARTIN_NFKB_TARGETS_UP, MARTIN_VIRAL_GPCR_SIGNALING_UP

GO Biological Process (10): hematopoietic progenitor cell differentiation (GO:0002244), lipid metabolic process (GO:0006629), phagocytosis (GO:0006909), inflammatory response (GO:0006954), innate immune response (GO:0045087), establishment of localization in cell (GO:0051649), regulation of cytokine production involved in inflammatory response (GO:1900015), immune system process (GO:0002376), DNA metabolic process (GO:0006259), lipid catabolic process (GO:0016042)

GO Molecular Function (5): single-stranded DNA 5’-3’ DNA exonuclease activity (GO:0045145), catalytic activity (GO:0003824), nuclease activity (GO:0004518), exonuclease activity (GO:0004527), hydrolase activity (GO:0016787)

GO Cellular Component (13): nucleus (GO:0005634), lysosome (GO:0005764), early endosome (GO:0005769), endoplasmic reticulum membrane (GO:0005789), endomembrane system (GO:0012505), trans-Golgi network membrane (GO:0032588), phagocytic vesicle (GO:0045335), Golgi membrane (GO:0000139), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), Golgi apparatus (GO:0005794), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Glycerophospholipid biosynthesis	1
Inositol phosphate metabolism	1
Fcgamma receptor (FCGR) dependent phagocytosis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
endomembrane system	3
cytoplasm	3
organelle membrane	2
cellular anatomical structure	2
hemopoiesis	1
cell differentiation	1
primary metabolic process	1
endocytosis	1
defense response	1
immune response	1
defense response to symbiont	1
establishment of localization	1
cellular localization	1
regulation of cytokine production	1
cytokine production involved in inflammatory response	1
biological_process	1
nucleic acid metabolic process	1
lipid metabolic process	1
catabolic process	1
single-stranded DNA exodeoxyribonuclease activity	1
5’-3’ DNA exonuclease activity	1
molecular_function	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
hydrolase activity, acting on ester bonds	1
catalytic activity	1
lytic vacuole	1
endosome	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
vacuole	1
plasma membrane	1
trans-Golgi network	1
endocytic vesicle	1
Golgi apparatus	1
bounding membrane of organelle	1
cytoplasmic vesicle	1
intracellular vesicle	1

Protein interactions and networks

STRING

964 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLD4	PLD6	Q8N2A8	710
PLD4	PLD2	O14939	584
PLD4	ANKMY2	Q8IV38	499
PLD4	B3GNT2	Q9NY97	431
PLD4	TEX22	C9J3V5	404
PLD4	MOCS1	Q9NZB8	402
PLD4	TUBD1	Q9UJT1	390
PLD4	PDIA3	P30101	389
PLD4	PDE2A	O00408	381
PLD4	PXK	Q7Z7A4	370
PLD4	ARAP1	Q96P48	351
PLD4	UNC5C	O95185	348
PLD4	ADAM10	O14672	341
PLD4	PLA2G15	Q8NCC3	328
PLD4	ARID5B	Q14865	326

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (88): PLD4 (Affinity Capture-MS), PLD3 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-Western), PLD4 (Affinity Capture-MS), HSPA5 (Affinity Capture-MS), UGGT1 (Affinity Capture-MS), NUP210 (Affinity Capture-MS), EMC1 (Affinity Capture-MS), TMTC3 (Affinity Capture-MS), SERPINH1 (Affinity Capture-MS)

ESM2 similar proteins: A1L1C2, A3KNW0, A6H603, A6NFQ2, A6QLU7, A9ULG4, B1H1N7, E1BE10, E2RD63, O35405, O55230, O60294, O60906, O75771, O95479, P21709, P51839, P56201, Q0V8L6, Q149M9, Q1JPJ9, Q28DT3, Q2KJJ8, Q2TBP8, Q4R583, Q5FVH2, Q5R4Y7, Q5XIA3, Q60750, Q643R3, Q6NVG1, Q6QHF9, Q80XS7, Q865R1, Q8BG07, Q8BYR1, Q8C0L6, Q8CFX1, Q8IV08, Q8N0W3

Diamond homologs: A0A7H0DN15, O17405, O35405, P18377, P20537, Q2KJJ8, Q3UNN8, Q4R583, Q54K50, Q54SA1, Q5FVH2, Q5R4Y7, Q640B3, Q6PB03, Q8BG07, Q8IV08, Q8N7P1, Q96BZ4, P36316, P26579, P63800, P63801, P63802, Q5HEB2, Q5HMD3, Q6G7M2, Q6GEY7, Q8CNK3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	0
Uncertain significance	96
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
4277317	P181L	Pathogenic
4277318	A323V	Pathogenic
4277319	D189E	Pathogenic
4277320	G457D	Pathogenic
4277321	PLD4, ARG201GLN	Pathogenic
4277322	PLD4, 1-BP DEL, 1088G	Pathogenic
4277323	PLD4, TYR248CYS	Pathogenic

SpliceAI

2450 predictions. Top by Δscore:

Variant	Effect	Δscore
14:104928447:GGC:G	donor_gain	1.0000
14:104928856:A:T	donor_gain	1.0000
14:104928929:GCTG:G	donor_gain	1.0000
14:104928978:GCAA:G	donor_gain	1.0000
14:104928982:G:GG	donor_gain	1.0000
14:104929426:AGGT:A	donor_loss	1.0000
14:104929428:GTG:G	donor_loss	1.0000
14:104930943:G:GG	donor_gain	1.0000
14:104931849:G:GT	donor_gain	1.0000
14:104931885:GAG:G	donor_gain	1.0000
14:104931888:G:C	donor_loss	1.0000
14:104931888:G:GG	donor_gain	1.0000
14:104931889:T:G	donor_loss	1.0000
14:104932004:A:AG	acceptor_gain	1.0000
14:104932008:CAAG:C	acceptor_loss	1.0000
14:104932009:AAG:A	acceptor_gain	1.0000
14:104932010:A:AG	acceptor_loss	1.0000
14:104932011:G:GA	acceptor_loss	1.0000
14:104932257:A:G	acceptor_gain	1.0000
14:104927867:G:GG	donor_gain	0.9900
14:104928448:GC:G	donor_gain	0.9900
14:104928747:A:AG	acceptor_gain	0.9900
14:104928748:G:GA	acceptor_gain	0.9900
14:104928748:GGCTT:G	acceptor_gain	0.9900
14:104928855:G:GT	donor_gain	0.9900
14:104928987:G:GT	donor_gain	0.9900
14:104929301:TTGCA:T	acceptor_loss	0.9900
14:104929302:TGCA:T	acceptor_loss	0.9900
14:104929303:GCA:G	acceptor_loss	0.9900
14:104929304:CAGG:C	acceptor_loss	0.9900

AlphaMissense

3258 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:104930073:A:C	S229R	0.992
14:104930075:T:A	S229R	0.992
14:104930075:T:G	S229R	0.992
14:104932776:T:A	W445R	0.990
14:104932776:T:C	W445R	0.990
14:104930035:A:T	K216I	0.989
14:104930040:T:A	W218R	0.984
14:104930040:T:C	W218R	0.984
14:104930090:G:C	W234C	0.983
14:104930090:G:T	W234C	0.983
14:104932077:T:C	L375P	0.983
14:104932898:G:C	W485C	0.983
14:104932898:G:T	W485C	0.983
14:104930088:T:A	W234R	0.981
14:104930088:T:C	W234R	0.981
14:104932884:T:C	F481L	0.980
14:104932886:T:A	F481L	0.980
14:104932886:T:G	F481L	0.980
14:104930794:T:C	L257P	0.979
14:104930070:G:C	G228R	0.977
14:104928828:T:A	W122R	0.976
14:104928828:T:C	W122R	0.976
14:104928882:T:A	W140R	0.976
14:104928882:T:C	W140R	0.976
14:104931853:T:G	Y342D	0.976
14:104930805:T:C	F261L	0.975
14:104930807:C:A	F261L	0.975
14:104930807:C:G	F261L	0.975
14:104932775:C:A	N444K	0.975
14:104932775:C:G	N444K	0.975

dbSNP variants (sampled 300 via entrez): RS1000008445 (14:104928966 G>A,C,T), RS1000075004 (14:104930334 T>G), RS1000142192 (14:104924808 G>C,T), RS1000524825 (14:104929091 C>T), RS1000546330 (14:104933489 C>G,T), RS1000581842 (14:104929107 G>A), RS1000747370 (14:104923419 G>A), RS1000805872 (14:104923402 C>A,T), RS1001191196 (14:104923709 C>T), RS1001499665 (14:104933623 C>A,G,T), RS1001528800 (14:104933430 A>C), RS1001740209 (14:104927317 C>T), RS1001952658 (14:104932659 C>A,T), RS1002084689 (14:104927609 C>T), RS1002333438 (14:104934972 C>T)

Disease associations

OMIM: gene MIM:618488 | disease phenotypes: MIM:613237, MIM:614455, MIM:621369

GenCC curated gene-disease

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
systemic lupus erythematosus 18	Moderate	AR

Mondo (4): breast ductal adenocarcinoma (MONDO:0005590), focal segmental glomerulosclerosis 5 (MONDO:0013191), Charcot-Marie-Tooth disease dominant intermediate E (MONDO:0013758), systemic lupus erythematosus 18 (MONDO:1060185)

Orphanet (2): Hereditary steroid-resistant nephrotic syndrome (Orphanet:656), Autosomal dominant intermediate Charcot-Marie-Tooth disease type E (Orphanet:93114)

HPO phenotypes

62 total (30 of 62 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000093	Proteinuria
HP:0000123	Nephritis
HP:0000217	Xerostomia
HP:0000388	Otitis media
HP:0000790	Hematuria
HP:0000822	Hypertension
HP:0000988	Skin rash
HP:0000989	Pruritus
HP:0000992	Cutaneous photosensitivity
HP:0001025	Urticaria
HP:0001041	Facial erythema
HP:0001369	Arthritis
HP:0001581	Recurrent skin infections
HP:0001596	Alopecia
HP:0001698	Pericardial effusion
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001882	Decreased total leukocyte count
HP:0001890	Autoimmune hemolytic anemia
HP:0001903	Anemia
HP:0001955	Unexplained fevers
HP:0002027	Abdominal pain
HP:0002110	Bronchiectasis
HP:0002202	Pleural effusion
HP:0002205	Recurrent respiratory infections
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002725	Systemic lupus erythematosus
HP:0002783	Recurrent lower respiratory tract infections

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001454_8	Rheumatoid arthritis	2.000000e-14
GCST002318_173	Rheumatoid arthritis	3.000000e-07
GCST002318_88	Rheumatoid arthritis	5.000000e-08
GCST006959_183	Rheumatoid arthritis	7.000000e-06
GCST006959_95	Rheumatoid arthritis	4.000000e-06
GCST007002_7	Cerebrospinal fluid t-tau levels in normal cognition	7.000000e-09
GCST007007_3	Cerebrospinal fluid t-tau levels	7.000000e-06
GCST011389_2	Rheumatoid arthritis	2.000000e-16

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004760	t-tau measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
C567687	Focal Segmental Glomerulosclerosis 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879501 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha phellandrene	increases expression	1
potassium perchlorate	decreases expression	1
terbufos	decreases methylation	1
sulforaphane	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
(+)-JQ1 compound	decreases expression	1
Microplastics	increases abundance, decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Diazinon	decreases methylation	1
Fonofos	decreases methylation	1
Iron	decreases expression	1
Parathion	decreases methylation	1
Polyethylene Terephthalates	decreases expression, increases abundance	1
Tretinoin	increases expression	1
Valproic Acid	increases methylation	1
Vitamin D	affects expression	1
Sodium Selenite	increases expression	1

ChEMBL screening assays

10 unique, capped per target: 10 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4827773	Binding	Substrate activity at PLD4 (unknown origin) assessed as Km by Michaelis-Menten kinetic model based fluorescence assay	Modulators of immunoregulatory exonucleases PLD3 and PLD4 identified by high-throughput screen. — Bioorg Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT00637364	PHASE1/PHASE2	SUSPENDED	High Intensity Focused Ultrasound Tumor Treatment for Pancreatic Cancer Pain
NCT02779855	PHASE1/PHASE2	COMPLETED	Talimogene Laherparepvec in Combination With Neoadjuvant Chemotherapy in Triple Negative Breast Cancer
NCT01753908	EARLY_PHASE1	COMPLETED	Broccoli Sprout Extract in Treating Patients With Breast Cancer
NCT01796041	EARLY_PHASE1	COMPLETED	Intraoperative Imaging of Breast Cancer With Indocyanine Green
NCT01208974	Not specified	ACTIVE_NOT_RECRUITING	Nipple-Areola Complex (NAC) Irradiation After Nipple-Sparing Mastectomy and Reconstruction
NCT01875198	Not specified	TERMINATED	Oncologic Impact of Splenectomy-omitting Radical Pancreatectomy in Well-selected Left-sided Pancreatic Cancer
NCT03543397	Not specified	UNKNOWN	MRI in Ductal Carcinoma in Situ (DCIS)
NCT03834532	Not specified	COMPLETED	Living Well After Breast Surgery