PLAA

Summary

PLAA (phospholipase A2 activating protein, HGNC:9043) is a protein-coding gene on chromosome 9p21.2, encoding Phospholipase A-2-activating protein (Q9Y263). Plays a role in protein ubiquitination, sorting and degradation through its association with VCP.

Predicted to enable ubiquitin binding activity. Involved in cellular response to lipopolysaccharide; macroautophagy; and positive regulation of phospholipase A2 activity. Located in cytoplasm; extracellular exosome; and nucleus.

Source: NCBI Gene 9373 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (Strong, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 605 total — 9 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 84
• Druggable target: yes
• MANE Select transcript: NM_001031689

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9043
Approved symbol	PLAA
Name	phospholipase A2 activating protein
Location	9p21.2
Locus type	gene with protein product
Status	Approved
Aliases	PLAP, PLA2P, FLJ11281, FLJ12699, DOA1
Ensembl gene	ENSG00000137055
Ensembl biotype	protein_coding
OMIM	603873
Entrez	9373

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 18 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000397292, ENST00000487173, ENST00000517642, ENST00000520641, ENST00000520884, ENST00000521968, ENST00000523212, ENST00000897950, ENST00000897951, ENST00000897952, ENST00000897953, ENST00000929589, ENST00000929590, ENST00000970087, ENST00000970088, ENST00000970089, ENST00000970090, ENST00000970091, ENST00000970092, ENST00000970093

RefSeq mRNA: 2 — MANE Select: NM_001031689 NM_001031689, NM_001321546

CCDS: CCDS35000

Canonical transcript exons

ENST00000397292 — 14 exons

Exon	Start	End
ENSE00000928010	26907834	26907998
ENSE00000928011	26910338	26910439
ENSE00000928012	26913879	26913947
ENSE00000928014	26919310	26919529
ENSE00000928015	26920227	26920384
ENSE00000928016	26923178	26923347
ENSE00000928017	26925825	26925960
ENSE00000928018	26926393	26926560
ENSE00000928019	26928100	26928220
ENSE00000928020	26928308	26928408
ENSE00001483692	26903372	26906076
ENSE00001609226	26935013	26935206
ENSE00001640499	26946897	26947242
ENSE00003688392	26917097	26917165

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 93.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.6502 / max 252.8718, expressed in 1810 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100317	18.3859	1799
100318	7.6558	1774
100320	0.7483	503
100321	0.3367	146
100319	0.2934	134
100316	0.2301	103

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gastrocnemius	UBERON:0001388	93.08	gold quality
secondary oocyte	CL:0000655	92.70	gold quality
muscle of leg	UBERON:0001383	92.48	gold quality
adrenal tissue	UBERON:0018303	91.18	gold quality
cortical plate	UBERON:0005343	91.17	gold quality
stromal cell of endometrium	CL:0002255	90.66	gold quality
hindlimb stylopod muscle	UBERON:0004252	90.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.24	gold quality
ganglionic eminence	UBERON:0004023	89.83	gold quality
monocyte	CL:0000576	89.79	gold quality
ventricular zone	UBERON:0003053	89.54	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.29	gold quality
mononuclear cell	CL:0000842	89.26	gold quality
leukocyte	CL:0000738	88.97	gold quality
calcaneal tendon	UBERON:0003701	88.77	gold quality
muscle organ	UBERON:0001630	88.73	gold quality
islet of Langerhans	UBERON:0000006	88.53	gold quality
right adrenal gland cortex	UBERON:0035827	88.15	gold quality
left adrenal gland	UBERON:0001234	87.72	gold quality
right adrenal gland	UBERON:0001233	87.68	gold quality
rectum	UBERON:0001052	87.45	gold quality
adrenal gland	UBERON:0002369	87.36	gold quality
popliteal artery	UBERON:0002250	87.10	gold quality
tibial artery	UBERON:0007610	87.10	gold quality
left adrenal gland cortex	UBERON:0035825	87.04	gold quality
oocyte	CL:0000023	86.41	gold quality
heart left ventricle	UBERON:0002084	86.34	gold quality
right atrium auricular region	UBERON:0006631	86.23	gold quality
lower esophagus mucosa	UBERON:0035834	86.23	gold quality
aorta	UBERON:0000947	86.22	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SP1

miRNA regulators (miRDB)

122 targeting PLAA, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-6499-3P	99.90	66.38	1212
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850

Literature-anchored findings (GeneRIF, showing 9)

• Function assignment to conserved residues in mammalian alkaline phosphatases. (PMID:11937510)
• PLAP inhibits sPLA2-triggered release of fatty acids from erythrocyte membranes (PMID:14499668)
• identified one stimulatory element, with Sp1 binding sites, and one inhibitory element, in exon 1 of the plaa gene (PMID:18291623)
• Structural basis for ubiquitin recognition by a novel domain from the human phospholipase A2-activating protein (PMID:19423704)
• This review provides evidence that 1,25-dihydroxy vitamin D3 stimulates PLA2 via PLAA and CaMKII, a process initiated by Pdia3/PLAA interaction, which further triggers CaMKII-dependent PLA2 activation. [review] (PMID:25448737)
• Upon damage, p97 translocates to lysosomes and there cooperates with a distinct set of cofactors including UBXD1, PLAA, and the deubiquitinating enzyme YOD1, which we term ELDR components for Endo-Lysosomal Damage Response. (PMID:27753622)
• This study presented that Phospholipase A2-activating protein is associated with a novel form of leukoencephalopathy. (PMID:28007986)
• In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. (PMID:28413018)
• PLAA suppresses ovarian cancer metastasis via METTL3-mediated m(6)A modification of TRPC3 mRNA. (PMID:35869392)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	plaa	ENSDARG00000042728
mus_musculus	Plaa	ENSMUSG00000028577
rattus_norvegicus	Plaa	ENSRNOG00000007753
drosophila_melanogaster	Plap	FBGN0024314
caenorhabditis_elegans		WBGENE00007333

Protein

Protein identifiers

Phospholipase A-2-activating protein — Q9Y263 (reviewed: Q9Y263)

All UniProt accessions (5): E5RIM3, Q9Y263, H0YAU9, H0YBW4, H0YC16

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in protein ubiquitination, sorting and degradation through its association with VCP. Involved in ubiquitin-mediated membrane proteins trafficking to late endosomes in an ESCRT-dependent manner, and hence plays a role in synaptic vesicle recycling. May play a role in macroautophagy, regulating for instance the clearance of damaged lysosomes. Plays a role in cerebellar Purkinje cell development. Positively regulates cytosolic and calcium-independent phospholipase A2 activities in a tumor necrosis factor alpha (TNF)- or lipopolysaccharide (LPS)-dependent manner, and hence prostaglandin E2 biosynthesis.

Subunit / interactions. Interacts with ubiquitin. Interacts with UBXN6, VCP and YOD1; may form a complex involved in macroautophagy.

Subcellular location. Nucleus. Cytoplasm. Synapse.

Disease relevance. Neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (NDMSBA) [MIM:617527] An autosomal recessive neurodevelopmental disorder characterized by progressive microcephaly, spastic quadriparesis, global developmental delay, profound intellectual disability and severely impaired or absent motor function. More variable features include seizures and optic atrophy. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The PUL domain is composed of 6 armadillo-like repeats and mediates the interaction with VCP C-terminus. The PFU domain mediates interaction with ubiquitin.

Induction. Up-regulated by tumor necrosis factor alpha (TNF) (at protein level).

Similarity. Belongs to the WD repeat PLAP family.

RefSeq proteins (2): NP_001026859, NP_001308475 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001680	WD40_rpt	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR013535	PUL_dom	Domain
IPR015155	PFU	Domain
IPR015943	WD40/YVTN_repeat-like_dom_sf	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR036322	WD40_repeat_dom_sf	Homologous_superfamily
IPR038122	PFU_sf	Homologous_superfamily

Pfam: PF00400, PF08324, PF09070

UniProt features (60 total): helix 21, repeat 13, sequence conflict 11, strand 5, turn 3, modified residue 2, sequence variant 2, domain 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
3EBB	X-RAY DIFFRACTION	1.9
2K89	SOLUTION NMR
2K8A	SOLUTION NMR
2K8B	SOLUTION NMR
2K8C	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y263-F1	84.87	0.58

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 (2): 50, 529

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 416 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, SHEPARD_BMYB_MORPHOLINO_UP, GOBP_PHOSPHOLIPID_METABOLIC_PROCESS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS

GO Biological Process (15): phospholipid metabolic process (GO:0006644), inflammatory response (GO:0006954), signal transduction (GO:0007165), nervous system development (GO:0007399), ubiquitin recycling (GO:0010992), macroautophagy (GO:0016236), positive regulation of prostaglandin biosynthetic process (GO:0031394), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway (GO:0043162), cellular response to lipopolysaccharide (GO:0071222), negative regulation of protein K63-linked ubiquitination (GO:1900045), positive regulation of synaptic vesicle recycling (GO:1903423), positive regulation of dendrite extension (GO:1903861), positive regulation of neuron migration (GO:2001224), lipid metabolic process (GO:0006629)

GO Molecular Function (3): phospholipase A2 activator activity (GO:0016005), ubiquitin binding (GO:0043130), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasmic ubiquitin ligase complex (GO:0000153), nucleus (GO:0005634), cytoplasm (GO:0005737), synapse (GO:0045202), extracellular exosome (GO:0070062)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
ubiquitin-dependent protein catabolic process	2
lipid metabolic process	1
organophosphate metabolic process	1
defense response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
cellular homeostasis	1
autophagosome assembly	1
autophagy	1
prostaglandin biosynthetic process	1
regulation of prostaglandin biosynthetic process	1
positive regulation of unsaturated fatty acid biosynthetic process	1
proteasomal protein catabolic process	1
protein catabolic process in the vacuole	1
multivesicular body sorting pathway	1
response to lipopolysaccharide	1
cellular response to molecule of bacterial origin	1
cellular response to lipid	1
cellular response to oxygen-containing compound	1
protein K63-linked ubiquitination	1
regulation of protein K63-linked ubiquitination	1
negative regulation of protein polyubiquitination	1
synaptic vesicle recycling	1
positive regulation of transport	1
regulation of synaptic vesicle recycling	1
positive regulation of cell growth	1
positive regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
neuron migration	1
positive regulation of cell migration	1
regulation of neuron migration	1
primary metabolic process	1
A2-type glycerophospholipase activity	1
phospholipase activator activity	1
ubiquitin-like protein binding	1

Protein interactions and networks

STRING

1912 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLAA	UBXN6	Q9BZV1	926
PLAA	VCP	P55072	876
PLAA	YOD1	Q5VVQ6	871
PLAA	UFD1	Q92890	823
PLAA	NPLOC4	Q8TAT6	821
PLAA	UBE4A	Q14139	695
PLAA	UBE4B	O95155	685
PLAA	ANKZF1	Q9H8Y5	676
PLAA	UBQLN1	Q9UMX0	632
PLAA	PDIA3	P30101	598
PLAA	NEDD4L	Q96PU5	588
PLAA	ANXA11	P50995	552
PLAA	HDAC6	Q9UBN7	536
PLAA	CSNK2B	P07312	524
PLAA	CDC34	P49427	522

IntAct

121 interactions, top by confidence:

A	B	Type	Score
UBXN6	VCP	psi-mi:“MI:0914”(association)	0.960
ASPSCR1	VCP	psi-mi:“MI:0914”(association)	0.960
FAF2	VCP	psi-mi:“MI:0914”(association)	0.870
PLAA	VCP	psi-mi:“MI:0915”(physical association)	0.830
VCP	PLAA	psi-mi:“MI:0915”(physical association)	0.830
UBXN7	VCP	psi-mi:“MI:0914”(association)	0.820
UBXN1	VCP	psi-mi:“MI:0914”(association)	0.740
CNOT3	CNOT1	psi-mi:“MI:0914”(association)	0.740
VCP	UBXN8	psi-mi:“MI:0914”(association)	0.690
PLAA	UBXN1	psi-mi:“MI:0915”(physical association)	0.670
UBXN1	PLAA	psi-mi:“MI:0915”(physical association)	0.670
FAF1	VCP	psi-mi:“MI:0915”(physical association)	0.640
FAF1	VCP	psi-mi:“MI:0914”(association)	0.640
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
ABCD4	ABCD4	psi-mi:“MI:0914”(association)	0.640
GYPA	TCAF2	psi-mi:“MI:0914”(association)	0.640
PLAA	KPNA4	psi-mi:“MI:0915”(physical association)	0.560
KPNA4	PLAA	psi-mi:“MI:0915”(physical association)	0.560
PLAA	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (143): PLAA (Two-hybrid), PLAA (Two-hybrid), UBXN1 (Two-hybrid), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-MS), PLAA (Affinity Capture-RNA), BASP1 (Co-fractionation), CSE1L (Co-fractionation), FDPS (Co-fractionation), PAK2 (Co-fractionation)

ESM2 similar proteins: A0A3L6DPG1, B0BN85, F8RP11, O35685, O88978, O95757, P27612, P48722, P50503, P54319, Q0IIM3, Q0JL44, Q17QG2, Q2KIK0, Q3T168, Q43468, Q4R4P3, Q5M823, Q5R606, Q5R6Z8, Q5R8R4, Q5RGJ5, Q5XEP2, Q5ZIN1, Q5ZLF0, Q60446, Q61699, Q63525, Q66HA8, Q69YN2, Q6AYK6, Q6N069, Q86X45, Q8CI33, Q8VD33, Q8VZM1, Q8WVJ2, Q92598, Q96EQ0, Q9CQ48

Diamond homologs: A7RHG8, A8QB65, A8XL02, B0W517, B3MJV8, B3N534, B3RQN1, B4GT01, B4HWV6, B4JPT9, B4KKN1, B4LS78, B4MU54, B4P116, B4Q9T6, B5DG67, B7PY76, P25387, P61480, P91343, Q0VC24, Q12788, Q17BB0, Q29KQ0, Q2KJJ5, Q5BJ90, Q5REE6, Q5U2W5, Q6NX08, Q7QJ33, Q8C4J7, Q94BM7, Q9C827, Q9CAA0, Q9GZL7, Q9JJA4, Q9VKQ3, Q9Y263, A6ZPA9, A7ECP3

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 138 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
ERAD pathway	7	10.6×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	4
Uncertain significance	277
Likely benign	268
Benign	13

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
1299891	NM_001031689.3(PLAA):c.861T>A (p.Val287=)	Pathogenic
3307234	NM_001031689.3(PLAA):c.802C>T (p.Arg268Ter)	Pathogenic
427940	NM_001031689.3(PLAA):c.2254C>T (p.Leu752Phe)	Pathogenic
427941	NM_001031689.3(PLAA):c.68G>T (p.Gly23Val)	Pathogenic
427942	NM_001031689.3(PLAA):c.68dup (p.Leu24fs)	Pathogenic
807466	NM_001031689.3(PLAA):c.240_241insTAG (p.Pro81Ter)	Pathogenic
828067	NM_001031689.3(PLAA):c.120C>G (p.Asp40Glu)	Pathogenic
975038	NM_001031689.3(PLAA):c.1049A>T (p.Glu350Val)	Pathogenic
975039	NM_001031689.3(PLAA):c.829T>C (p.Cys277Arg)	Pathogenic
1333605	NM_001031689.3(PLAA):c.850_860del (p.Asp284fs)	Likely pathogenic
1806265	NM_001031689.3(PLAA):c.1570C>T (p.Arg524Ter)	Likely pathogenic
2497674	NM_001031689.3(PLAA):c.1800G>A (p.Trp600Ter)	Likely pathogenic
694395	NM_001031689.3(PLAA):c.2350del (p.Lys783_Val784insTer)	Likely pathogenic

SpliceAI

2157 predictions. Top by Δscore:

Variant	Effect	Δscore
9:26907996:TACCT:T	acceptor_loss	1.0000
9:26907998:CCTAG:C	acceptor_loss	1.0000
9:26910331:AACTT:A	donor_loss	1.0000
9:26910332:ACTT:A	donor_loss	1.0000
9:26910333:CTTAC:C	donor_loss	1.0000
9:26910334:TTAC:T	donor_loss	1.0000
9:26910335:TA:T	donor_loss	1.0000
9:26910438:CC:C	acceptor_gain	1.0000
9:26910439:CC:C	acceptor_gain	1.0000
9:26913874:TGTA:T	donor_loss	1.0000
9:26913875:GTACC:G	donor_loss	1.0000
9:26913876:TAC:T	donor_loss	1.0000
9:26913877:A:AG	donor_loss	1.0000
9:26913878:C:CT	donor_loss	1.0000
9:26913946:ACC:A	acceptor_loss	1.0000
9:26913948:C:CA	acceptor_loss	1.0000
9:26913949:T:C	acceptor_loss	1.0000
9:26919307:TAC:T	donor_loss	1.0000
9:26919308:A:C	donor_loss	1.0000
9:26920225:A:AC	donor_gain	1.0000
9:26920226:C:CC	donor_gain	1.0000
9:26920229:T:A	donor_gain	1.0000
9:26920230:C:A	donor_gain	1.0000
9:26923174:TTA:T	donor_loss	1.0000
9:26923175:TAC:T	donor_loss	1.0000
9:26923176:A:AC	donor_gain	1.0000
9:26923176:AC:A	donor_gain	1.0000
9:26923176:ACC:A	donor_loss	1.0000
9:26923177:C:CA	donor_gain	1.0000
9:26923177:CC:C	donor_gain	1.0000

AlphaMissense

5223 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:26919474:A:G	L418S	1.000
9:26926477:A:G	W217R	1.000
9:26926477:A:T	W217R	1.000
9:26928133:A:G	W178R	1.000
9:26928133:A:T	W178R	1.000
9:26928340:A:G	W138R	1.000
9:26928340:A:T	W138R	1.000
9:26928368:A:C	S128R	1.000
9:26928368:A:T	S128R	1.000
9:26928370:T:G	S128R	1.000
9:26928408:A:T	V115D	1.000
9:26935075:A:T	I94K	1.000
9:26905538:G:C	C787W	0.999
9:26905611:G:T	A763D	0.999
9:26905650:C:T	G750E	0.999
9:26905651:C:G	G750R	0.999
9:26905651:C:T	G750R	0.999
9:26905667:T:A	R744S	0.999
9:26905667:T:G	R744S	0.999
9:26905668:C:G	R744T	0.999
9:26905779:A:G	L707P	0.999
9:26919375:A:T	I451N	0.999
9:26919377:A:C	F450L	0.999
9:26919377:A:T	F450L	0.999
9:26919379:A:G	F450L	0.999
9:26919384:G:T	A448D	0.999
9:26919428:G:C	F433L	0.999
9:26919428:G:T	F433L	0.999
9:26919429:A:G	F433S	0.999
9:26919430:A:G	F433L	0.999

dbSNP variants (sampled 300 via entrez): RS1000135738 (9:26924519 T>C), RS1000156281 (9:26929614 C>A), RS1000216834 (9:26917939 A>G), RS1000305857 (9:26928379 T>A,C), RS1000373458 (9:26922709 C>G), RS1000388395 (9:26911701 T>C), RS1000406791 (9:26948472 T>A,G), RS1000539482 (9:26938325 A>C,G), RS1000623256 (9:26906932 TA>T,TAA,TAAA), RS1000712928 (9:26947346 G>T), RS1000717723 (9:26916889 T>C), RS1000860045 (9:26944406 T>G), RS1000913686 (9:26932263 T>A,C), RS1000915785 (9:26908165 G>A,T), RS1000929193 (9:26913520 T>C)

Disease associations

OMIM: gene MIM:603873 | disease phenotypes: MIM:617527

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies	Strong	Autosomal recessive

Mondo (1): neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies (MONDO:0060502)

Orphanet (1): PLAA-associated neurodevelopmental disorder (Orphanet:521426)

HPO phenotypes

84 total (30 of 84 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000280	Coarse facial features
HP:0000319	Smooth philtrum
HP:0000338	Hypomimic face
HP:0000341	Narrow forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000490	Deeply set eye
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0000768	Pectus carinatum
HP:0000851	Congenital hypothyroidism
HP:0000954	Single transverse palmar crease
HP:0000975	Hyperhidrosis
HP:0001007	Hirsutism
HP:0001162	Postaxial hand polydactyly
HP:0001187	Hyperextensibility of the finger joints
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001276	Hypertonia
HP:0001283	Bulbar palsy

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000607_2	Schizophrenia	2.000000e-06
GCST007673_17	3-month functional outcome in ischaemic stroke (modified Rankin score)	8.000000e-07
GCST009391_1739	Metabolite levels	3.000000e-06
GCST009391_2100	Metabolite levels	6.000000e-06
GCST009391_850	Metabolite levels	9.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009603	stroke outcome severity measurement
EFO:0010376	phosphatidylcholine 34:2 measurement
EFO:0010374	phosphatidylcholine 32:2 measurement
EFO:0010400	triacylglycerol 46:0 measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6114 (SINGLE PROTEIN)

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

ChEMBL bioactivities

21 potent at pChembl≥5 of 27 total, top 21 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.96	IC50	11	nM	CHEMBL1077979
7.44	IC50	36	nM	CHEMBL4068569
6.38	Kd	421.5	nM	CHEMBL5653589
6.38	ED50	421.5	nM	CHEMBL5653589
6.10	IC50	800	nM	CHEMBL608723
6.10	IC50	800	nM	CHEMBL607856
5.92	IC50	1200	nM	CHEMBL597055
5.70	IC50	2000	nM	CHEMBL254255
5.68	IC50	2100	nM	CHEMBL349641
5.66	IC50	2200	nM	CHEMBL598663
5.60	IC50	2500	nM	CHEMBL592869
5.57	IC50	2700	nM	CHEMBL610781
5.52	IC50	3000	nM	CHEMBL610508
5.48	IC50	3300	nM	CHEMBL589756
5.38	IC50	4200	nM	CHEMBL607856
5.31	IC50	4900	nM	CHEMBL597109
5.24	IC50	5800	nM	CHEMBL597027
5.24	IC50	5800	nM	CHEMBL602242
5.18	IC50	6600	nM	CHEMBL597055
5.17	IC50	6700	nM	CHEMBL609899
5.04	IC50	9100	nM	CHEMBL597837

PubChem BioAssay actives

20 with measured affinity, of 46 total; 18 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
(4S,6Z,9S,10S,12E)-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	1469808: Inhibition of TNFalpha-PLAP (unknown origin)	ic50	0.0110	uM
(4S,6E,9S,10S,12E)-7-fluoro-9,10,18-trihydroxy-16-methoxy-4-methyl-3-oxabicyclo[12.4.0]octadeca-1(14),6,12,15,17-pentaene-2,8-dione	1469808: Inhibition of TNFalpha-PLAP (unknown origin)	ic50	0.0360	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149022: Binding affinity to human PLAA incubated for 45 mins by Kinobead based pull down assay	kd	0.4215	uM
1-(3,4-dihydroxyphenyl)-2-(2-ethylimidazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	0.8000	uM
2-(benzimidazol-1-yl)-1-(3,4-dihydroxyphenyl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	0.8000	uM
1-(3,4-dihydroxyphenyl)-2-(2-methylbenzimidazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	1.2000	uM
1-(3,4-dihydroxyphenyl)-2-[1-(4-methoxyphenyl)tetrazol-5-yl]sulfanylethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	2.0000	uM
1-(3,4-dihydroxyphenyl)-2-imidazol-1-ylethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	2.1000	uM
2-[2-(3,4-dihydroxyphenyl)-2-oxoethyl]sulfanyl-4-(methoxymethyl)-6-methylpyridine-3-carbonitrile	459064: Inhibition of PLAP by analogous luminescence assay	ic50	2.2000	uM
1-(3,4-dihydroxyphenyl)-2-(4,6-dimethylpyrimidin-2-yl)sulfanylethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	2.5000	uM
1-(3,4-dihydroxyphenyl)-2-(4-methylpyrazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	2.7000	uM
3-[2-(3,4-dihydroxyphenyl)-2-oxoethyl]-6,7-dimethoxy-3H-2-benzofuran-1-one	459064: Inhibition of PLAP by analogous luminescence assay	ic50	3.0000	uM
1-(3,4-dihydroxyphenyl)-2-(2-methylimidazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	3.3000	uM
2-(4-bromo-2-methylimidazol-1-yl)-1-(3,4-dihydroxyphenyl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	4.9000	uM
1-(3,4-dihydroxyphenyl)-2-(5,6-dimethylbenzimidazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	5.8000	uM
1-(3,4-dihydroxyphenyl)-2-(4-methylimidazol-1-yl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	5.8000	uM
1-(3,4-dihydroxyphenyl)-2-[(4-methyl-5-phenyl-1,2,4-triazol-3-yl)sulfanyl]ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	6.7000	uM
2-(1H-benzimidazol-2-ylamino)-1-(3,4-dihydroxyphenyl)ethanone	459064: Inhibition of PLAP by analogous luminescence assay	ic50	9.1000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
cobaltous chloride	increases expression	2
Tobacco Smoke Pollution	increases expression	2
Cyclosporine	increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
afuresertib	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
salinomycin	decreases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
jinfukang	decreases expression	1
Bortezomib	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Amiodarone	increases expression	1
Catechin	affects cotreatment, decreases expression	1
Dactinomycin	affects cotreatment, increases secretion	1
Doxorubicin	decreases expression	1
Endosulfan	increases expression	1
Estradiol	increases expression	1
Furaldehyde	affects cotreatment, decreases expression, affects localization, increases expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1054562	Binding	Inhibition of PLAP by luminescent assay	Discovery and validation of a series of aryl sulfonamides as selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). — J Med Chem

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2B3	Abcam HeLa PLAA KO	Cancer cell line	Female

Clinical trials (associated diseases)

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