ALPP

Summary

ALPP (alkaline phosphatase, placental, HGNC:439) is a protein-coding gene on chromosome 2q37.1, encoding Alkaline phosphatase, placental type (P05187). Alkaline phosphatase that can hydrolyze various phosphate compounds.

The protein encoded by this gene is an alkaline phosphatase, a metalloenzyme that catalyzes the hydrolysis of phosphoric acid monoesters. It belongs to a multigene family composed of four alkaline phosphatase isoenzymes. The enzyme functions as a homodimer and has a catalytic site containing one magnesium and two zinc ions, which are required for its enzymatic function. One of the main sources of this enzyme is the liver, and thus, it’s one of several indicators of liver injury in different clinical conditions. In pregnant women, this protein is primarily expressed in placental and endometrial tissue, however, strong ectopic expression has been detected in ovarian adenocarcinoma, serous cystadenocarcinoma, and other ovarian cancer cells.

Source: NCBI Gene 250 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 143 total
• Druggable target: yes
• MANE Select transcript: NM_001632

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:439
Approved symbol	ALPP
Name	alkaline phosphatase, placental
Location	2q37.1
Locus type	gene with protein product
Status	Approved
Aliases	PALP, PLAP
Ensembl gene	ENSG00000163283
Ensembl biotype	protein_coding
OMIM	171800
Entrez	250

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 retained_intron, 1 protein_coding

ENST00000392027, ENST00000474529, ENST00000485563

RefSeq mRNA: 1 — MANE Select: NM_001632 NM_001632

CCDS: CCDS2490

Canonical transcript exons

ENST00000392027 — 11 exons

Exon	Start	End
ENSE00001510464	232381497	232382889
ENSE00001510465	232378751	232378878
ENSE00002431321	232380420	232380492
ENSE00002443102	232381251	232381367
ENSE00002457466	232380623	232380757
ENSE00002461374	232379513	232379687
ENSE00002479677	232380840	232381031
ENSE00002484303	232379764	232379936
ENSE00002523810	232380186	232380320
ENSE00003471894	232378971	232379087
ENSE00003571638	232379200	232379315

Expression profiles

Bgee: expression breadth broad, 59 present calls, max score 83.01.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 8.7320 / max 1488.4704, expressed in 82 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25951	7.8785	77
25950	0.5147	42
25961	0.1265	18
25962	0.0363	12
25949	0.0321	13
25963	0.0266	10
25960	0.0248	12
25958	0.0240	14
25952	0.0239	12
25957	0.0203	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	83.01	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.71	gold quality
right uterine tube	UBERON:0001302	73.46	gold quality
upper lobe of left lung	UBERON:0008952	73.07	gold quality
upper lobe of lung	UBERON:0008948	71.28	gold quality
olfactory bulb	UBERON:0002264	71.21	gold quality
type B pancreatic cell	CL:0000169	71.01	gold quality
right lung	UBERON:0002167	70.03	gold quality
oocyte	CL:0000023	69.36	gold quality
buccal mucosa cell	CL:0002336	67.91	gold quality
tongue squamous epithelium	UBERON:0006919	64.51	gold quality
lung	UBERON:0002048	62.18	gold quality
lower lobe of lung	UBERON:0008949	60.52	silver quality
endocervix	UBERON:0000458	59.17	gold quality
tendon of biceps brachii	UBERON:0008188	58.23	gold quality
gluteal muscle	UBERON:0002000	57.43	gold quality
triceps brachii	UBERON:0001509	57.30	gold quality
fallopian tube	UBERON:0003889	56.42	gold quality
cervix epithelium	UBERON:0004801	56.13	gold quality
vastus lateralis	UBERON:0001379	55.99	gold quality
quadriceps femoris	UBERON:0001377	55.81	gold quality
uterine cervix	UBERON:0000002	55.06	gold quality
ectocervix	UBERON:0012249	54.69	gold quality
lateral globus pallidus	UBERON:0002476	54.17	gold quality
oviduct epithelium	UBERON:0004804	54.03	gold quality
lateral nuclear group of thalamus	UBERON:0002736	53.58	gold quality
medial globus pallidus	UBERON:0002477	52.52	gold quality
hair follicle	UBERON:0002073	52.43	gold quality
epithelial cell of pancreas	CL:0000083	52.09	gold quality
thymus	UBERON:0002370	51.92	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.13

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, SMAD2

miRNA regulators (miRDB)

30 targeting ALPP, 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-4795-3P	100.00	74.62	4024
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-1304-5P	98.90	68.58	1054
HSA-MIR-2355-5P	98.83	65.51	1589
HSA-MIR-6840-3P	98.68	65.95	1923
HSA-MIR-6868-3P	98.63	69.64	2259
HSA-MIR-4722-5P	98.46	66.34	1611
HSA-MIR-4664-5P	98.17	65.07	1020
HSA-MIR-4736	97.96	65.89	1287
HSA-MIR-4675	97.69	64.82	774
HSA-MIR-4741	97.69	64.14	883
HSA-MIR-342-5P	97.25	64.10	817
HSA-MIR-939-5P	97.10	65.80	1579
HSA-MIR-4433A-5P	96.79	65.01	599
HSA-MIR-1343-5P	96.48	66.06	1506
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-6821-3P	95.21	66.79	578
HSA-MIR-5588-3P	94.96	65.59	500

Literature-anchored findings (GeneRIF, showing 40)

• The PLAP D allele contains two amino acid substitutions: P209R (692C>G) and E429G (1352 A>G). (PMID:11857742)
• Proximity of the protein moiety of a GPI-anchored protein to the membrane surface: a FRET study. (PMID:12081485)
• the structural differences in human AP isoforms are demonstrated through models (PMID:12372831)
• the beta-N-acetylglucosaminyl phosphate diester residue is attached to the glycosylphosphatidylinositol anchor of human placental alkaline phosphatase and is a target of the channel-forming toxin aerolysin (PMID:12851398)
• receptor for Aeromonas sobria hemolysin. (PMID:15715171)
• analysis of human placental alkaline phosphatase in complex with functional ligands (PMID:15946677)
• The effect of parity on placental weight and birth weight is examined through a series of birth records from an Indian population in Calcutta. (PMID:16431676)
• crystal structure of strontium-substituted human placental alkaline phosphatase shows that strontium substitutes the calcium ion with concomitant modification of the metal coordination (PMID:16815919)
• The role of the N-terminus and its microenvironment in determining the enzyme stability and catalysis using human placental (PLAP) and tissue-nonspecific AP (TNAP) as paradigms, is analyzed. (PMID:16893177)
• activity of GPI-anchored enzymes may be modulated by membrane microenvironment features (PMID:18416535)
• Serum bilirubin, alkaline phosphatase, and aspartate aminotransferase are an efficient set of biochemistries to identify UDCA-treated patients with primary biliary cirrhosis at risk of death or liver transplantation (LT). (PMID:18752324)
• Elevations of alkaline phosphatase is associated with therapy related pediatric cancer. (PMID:18802949)
• Data show that serum alkaline phosphatase, Gleason score, and intensity of bone metastasis are important and statistically significant prognostic factors, and affects time to progression and life time. (PMID:19450995)
• SALL4 is a more sensitive marker than PLAP, AFP, or glypican-3 for extragonadal yolk sac tumors. (PMID:19574883)
• Low magnitudes of tensile strain enhance expression of alkaline phosphatase in human osteoblasts. (PMID:19595020)
• High serum alkaline phosphatase is associated with chronic kidney disease. (PMID:20299338)
• Serum total calcium (r -0.1362, p<0.001), serum inorganic phosphate (r -0.45, p<0.001) and serum alkaline phosphatase (r -0.5587, p<0.001) have shown inverse relationship with age. (PMID:20655896)
• differential expression of Pl(1) and Pl(2) probably results from linkage disequilibrium with the sequence variation rs2014683G>A in the ALPP gene promoter that was shown to have allele-specific binding patterns to placental nuclear proteins. (PMID:20663553)
• structure of placental alkaline phosphatase with pNPP contained only p-nitrophenol in three distinct sites, while the structure with 5’-AMP contained the p-nitrophenyl group in two of the sites instead of 5’-AMP (PMID:20693656)
• at a certain time point during adrenocortical development, some fetal zone cells survive owing to defective apoptosis and develop into childhood ACT, maintaining some characteristics of the embryonal period, such as PLAP expression (PMID:21516013)
• The proximity of undifferentiated gonadal tissue with the tumors as well as the immunostaining patterns (PLAP+, OCT3/4+, and CD117/KIT+) suggests that germ cells found in them are a risk factor for gonadal tumors. (PMID:21692598)
• PLAP exerts a positive effect on DNA replication and acts as a proliferative factor in trophoblastic cells. (PMID:21868091)
• Calculation of the electrostatic potentials within the active site of human placental alkaline phosphatase also suggests that the local positive electrostatic environment may account for its capability to distinguish various substrates (PMID:21910833)
• the catalytic mechanism of human placental alkaline phosphatase (PMID:21939286)
• High serum alkaline phosphatase cooperating with MMP-9 is associated with metastasis in patients with primary osteosarcoma. (PMID:22333159)
• Data indicate that p180 is required for the efficient targeting of placental alkaline phosphatase (ALPP) mRNA to the endoplasmic reticulum (ER). (PMID:24019514)
• The objective of the following study was to record the specificity and sensitivity of alpha5(IV) loss, smoothelin expression and PLAP expression as markers of gastrointestinal smooth muscle neoplasms (PMID:24043717)
• Anti-PLAP antibodies may serve as a modular building blocks for the development of targeted therapeutic products, armed with cytotoxic drugs, radionuclides or cytokines as payloads. (PMID:24247025)
• A candidate gene, ALPP, encoding the placental alkaline phosphatase, was identified as being potentially involved in recurrent spontaneous abortion. (PMID:24296104)
• term placental explants, but not their conditioned medium, can de-phosphorylate IGFBP-1 through the action of placental alkaline phosphatase (PMID:24856042)
• Quantum-mechanical computational methods were employed to study the catalytic mechanism of human placental AP (PLAP). An active-site model was used, constructed on the basis of the X-ray crystal structure of the enzyme. (PMID:25409280)
• SALL4 also outperformed PLAP on a small sample of cytology blocks. Although SALL4 is not entirely specific, it is a highly sensitive marker with strong diffuse nuclear reactivity in the majority of MGCTs in the posttreatment setting, at significantly higher levels than PLAP (PMID:25906119)
• Concentrations of PLAP were elevated in gingival crevicular fluid of patients with pre-eclampsia. (PMID:26988336)
• This meta-analysis suggests that high serum ALP level is obviously associated with lower OS rate in patients with osteosarcoma, and it is an effective biomarker of prognosis. (PMID:29970708)
• High ALP expression is associated with gastric cancer. (PMID:30417313)
• PLAP -CAR T cells mediate high specific cytotoxicity against colon cancer cells. (PMID:32472757)
• Osteogenic cocktail induces calcifications in human breast cancer cell line via placental alkaline phosphatase expression. (PMID:32728117)
• Diagnostic Capability of Cerebrospinal Fluid-Placental Alkaline Phosphatase Value in Intracranial Germ Cell Tumor. (PMID:32906115)
• Extremely high levels of alkaline phosphatase and pregnancy outcome: case series and review of the literature. (PMID:32918806)
• Placental Alkaline Phosphatase Promotes Zika Virus Replication by Stabilizing Viral Proteins through BIP. (PMID:32934082)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	alpi.2	ENSDARG00000053774
mus_musculus	Alppl2	ENSMUSG00000026246
mus_musculus	Akp3	ENSMUSG00000036500
mus_musculus	Alpi	ENSMUSG00000079440
rattus_norvegicus	Alpi	ENSRNOG00000030020
rattus_norvegicus	Alpp	ENSRNOG00000033672
rattus_norvegicus	Alpg	ENSRNOG00000042889
rattus_norvegicus	Akp3	ENSRNOG00000058652
drosophila_melanogaster	Alp4	FBGN0016123
drosophila_melanogaster	Alp11	FBGN0030661
drosophila_melanogaster	Alp12	FBGN0032779
drosophila_melanogaster	Alp6	FBGN0033423
drosophila_melanogaster	Alp7	FBGN0034710
drosophila_melanogaster	Alp8	FBGN0034712
drosophila_melanogaster	Alp10	FBGN0035619
drosophila_melanogaster	Alp9	FBGN0035620
drosophila_melanogaster	Alp13	FBGN0037786
drosophila_melanogaster	Alp5	FBGN0038845
drosophila_melanogaster	phu	FBGN0043791
drosophila_melanogaster	Alp1	FBGN0283479
drosophila_melanogaster	Alp2	FBGN0283480

Paralogs (3): ALPL (ENSG00000162551), ALPG (ENSG00000163286), ALPI (ENSG00000163295)

Protein

Protein identifiers

Alkaline phosphatase, placental type — P05187 (reviewed: P05187)

Alternative names: Alkaline phosphatase Regan isozyme, Placental alkaline phosphatase 1

All UniProt accessions (1): P05187

UniProt curated annotations — full annotation on UniProt →

Function. Alkaline phosphatase that can hydrolyze various phosphate compounds.

Subunit / interactions. Homodimer.

Subcellular location. Cell membrane.

Tissue specificity. Detected in placenta (at protein level).

Cofactor. Binds 1 Mg(2+) ion. Binds 2 Zn(2+) ions.

Polymorphism. Placental ALP is highly polymorphic, there are at least three common alleles.

Miscellaneous. In most mammals there are four different isozymes: placental (ALPP), germ cell (ALPG), intestinal (ALPI) and tissue non-specific (liver/bone/kidney) (ALPL/TNAP).

Similarity. Belongs to the alkaline phosphatase family.

RefSeq proteins (1): NP_001623* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001952	Alkaline_phosphatase	Family
IPR017850	Alkaline_phosphatase_core_sf	Homologous_superfamily
IPR018299	Alkaline_phosphatase_AS	Active_site

Pfam: PF00245

Enzyme classification (BRENDA):

• EC 3.1.3.1 — alkaline phosphatase (BRENDA: 134 organisms, 346 substrates, 667 inhibitors, 331 Km, 180 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
4-NITROPHENYL PHOSPHATE	—	218
P-NITROPHENYL PHOSPHATE	0.0094–5.02	37
PHENYL PHOSPHATE	6.1–101.2	13
3-(4-METHOXYSPIRO [1,2-DIOXETANE-3,2’-(5’-CHLORO	0.037–0.1159	7
BETA-GLYCEROPHOSPHATE	0.3–3.35	7
ATP	0.1–5.7	5
DIPHOSPHATE	0.12–4	5
2-CHLORO-5-(4-METHOXYSPIRO (1,2-DIOXETANE-3,2’-(	0.01–0.177	3
2-NAPHTHYL PHOSPHATE	0.026–0.078	2
ADP	2.26–4.4	2
GLUCOSE 1-PHOSPHATE	2.22–4.8	2
PHOSPHO-DL-THR	0.39–0.9	2
PHOSPHO-DL-TYR	0.4–0.72	2
PHOSPHO-L-SER	0.38–0.68	2
PYRIDOXAL PHOSPHATE	0.2–0.37	2

Catalyzed reactions (Rhea), 1 shown:

• a phosphate monoester + H2O = an alcohol + phosphate (RHEA:15017)

UniProt features (82 total): helix 23, strand 16, binding site 14, sequence conflict 9, sequence variant 5, turn 3, glycosylation site 2, disulfide bond 2, signal peptide 1, chain 1, propeptide 1, lipid moiety-binding region 1, transmembrane region 1, region of interest 1, compositionally biased region 1, active site 1

Structure

Experimental structures (PDB)

8 structures.

PDB	Method	Resolution (Å)
1ZED	X-RAY DIFFRACTION	1.57
3MK1	X-RAY DIFFRACTION	1.57
2GLQ	X-RAY DIFFRACTION	1.6
1EW2	X-RAY DIFFRACTION	1.82
3MK2	X-RAY DIFFRACTION	1.89
1ZEB	X-RAY DIFFRACTION	1.9
1ZEF	X-RAY DIFFRACTION	1.9
3MK0	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05187-F1	93.73	0.90

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 (1): 114 (phosphoserine intermediate)

Ligand- & substrate-binding residues (14): 177; 238; 291; 292; 307; 333; 338; 342; 379; 380; 454; 64 …

Post-translational modifications (1): 506

Disulfide bonds (2): 143–205, 489–496

Glycosylation sites (2): 144, 271

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6811438	Intra-Golgi traffic

MSigDB gene sets: 44 (showing top): GOCC_CELL_SURFACE, REACTOME_MEMBRANE_TRAFFICKING, GOZGIT_ESR1_TARGETS_UP, GNF2_KISS1, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GNF2_CDKN1C, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP, SHEN_SMARCA2_TARGETS_DN, GOCC_SIDE_OF_MEMBRANE, GOMF_MAGNESIUM_ION_BINDING, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, GNF2_TIMP2, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_UP, LU_EZH2_TARGETS_DN

GO Biological Process (0):

GO Molecular Function (7): magnesium ion binding (GO:0000287), alkaline phosphatase activity (GO:0004035), zinc ion binding (GO:0008270), protein binding (GO:0005515), hydrolase activity (GO:0016787), phosphatase activity (GO:0016791), metal ion binding (GO:0046872)

GO Cellular Component (4): plasma membrane (GO:0005886), cell surface (GO:0009986), side of membrane (GO:0098552), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
membrane	2
metal ion binding	1
phosphatase activity	1
transition metal ion binding	1
binding	1
catalytic activity	1
phosphoric ester hydrolase activity	1
cation binding	1
cell periphery	1
leaflet of membrane bilayer	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALPP	PAX3	P23760	774
ALPP	AFP	P02771	697
ALPP	CHRND	Q07001	692
ALPP	INHA	P05111	688
ALPP	AVIL	O75366	672
ALPP	GGT6	Q6P531	665
ALPP	GOT1L1	Q8NHS2	658
ALPP	GGT7	Q9UJ14	651
ALPP	GGT2P	P36268	607
ALPP	COL4A3	Q01955	601
ALPP	GGT5	P36269	588
ALPP	TNFRSF8	P28908	581
ALPP	CSH1	P01243	580
ALPP	GOT1	P17174	577
ALPP	CSH1	P01243	574

IntAct

147 interactions, top by confidence:

A	B	Type	Score
ALPP	KRTAP5-9	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
	ALPP	psi-mi:“MI:0915”(physical association)	0.560
ALPP	KRTAP4-12	psi-mi:“MI:0915”(physical association)	0.560
ALPP		psi-mi:“MI:0915”(physical association)	0.560
ALPP	LCE3B	psi-mi:“MI:0915”(physical association)	0.560
ALPP	GEMIN4	psi-mi:“MI:0915”(physical association)	0.560
ALPP	KRTAP10-8	psi-mi:“MI:0915”(physical association)	0.560
ALPP	TGM1	psi-mi:“MI:0915”(physical association)	0.560
ALPP	OTX1	psi-mi:“MI:0915”(physical association)	0.560
ALPP	LCE1D	psi-mi:“MI:0915”(physical association)	0.560
ALPP	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
CYSRT1	ALPP	psi-mi:“MI:0915”(physical association)	0.560
ALPP	LCE1E	psi-mi:“MI:0915”(physical association)	0.560
ALPP	POU4F2	psi-mi:“MI:0915”(physical association)	0.560
ALPP	CRCT1	psi-mi:“MI:0915”(physical association)	0.560
ALPP	ADAMTSL4	psi-mi:“MI:0915”(physical association)	0.560
ALPP	LCE2C	psi-mi:“MI:0915”(physical association)	0.560
ALPP	NR4A3	psi-mi:“MI:0915”(physical association)	0.560
ALPP	CXCL5	psi-mi:“MI:0915”(physical association)	0.560
ALPP	IGFBP6	psi-mi:“MI:0915”(physical association)	0.560
ALPP	LCE3D	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (138): COL2A1 (Co-purification), KRTAP5-9 (Two-hybrid), KRTAP4-12 (Two-hybrid), KRTAP10-3 (Two-hybrid), ALPP (Two-hybrid), BTRC (Affinity Capture-Western), ALPP (Affinity Capture-MS), ALPP (Affinity Capture-MS), ALPP (Affinity Capture-MS), ALPP (Affinity Capture-MS), ALPP (Affinity Capture-MS), ALPP (Affinity Capture-MS), ALPP (Two-hybrid), ALPP (Two-hybrid), ALPP (Two-hybrid)

ESM2 similar proteins: A5D6U8, A6NGU5, B5MD39, B8NM71, D4B387, O00754, O09159, O35409, P05187, P06865, P07314, P07686, P0DPU3, P0DPU6, P15693, P17439, P19111, P19440, P20060, P20735, P24822, P29416, P36268, P49614, P51740, P51854, P70627, Q0V8R6, Q14390, Q29451, Q29548, Q4R6M8, Q501L1, Q5RC84, Q5RFI5, Q5XIG6, Q60928, Q60HE9, Q641X3, Q680I5

Diamond homologs: O60109, P00634, P05186, P05187, P08289, P09242, P09487, P09923, P10696, P11491, P15693, P19111, P21948, P24822, P24823, P29523, P51740, P83456, Q24238, Q29486, Q92058, P19405, P19147, P35483, Q02QC9, P09401, P19406

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 62 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Formation of the cornified envelope	12	23.4×	5e-12
Keratinization	16	19.8×	5e-15

GO biological processes:

GO term	Partners	Fold	FDR
keratinization	10	47.8×	2e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	114
Likely benign	11
Benign	9

Top pathogenic / likely-pathogenic (0)

SpliceAI

841 predictions. Top by Δscore:

Variant	Effect	Δscore
2:232378874:CCCAG:C	donor_loss	1.0000
2:232378876:CAGG:C	donor_loss	1.0000
2:232378877:AGGT:A	donor_loss	1.0000
2:232378878:GGT:G	donor_loss	1.0000
2:232378879:GTA:G	donor_loss	1.0000
2:232378964:T:A	acceptor_gain	1.0000
2:232378965:G:A	acceptor_gain	1.0000
2:232378966:GCCAG:G	acceptor_loss	1.0000
2:232378967:CCAGT:C	acceptor_loss	1.0000
2:232378968:CA:C	acceptor_loss	1.0000
2:232378969:A:AC	acceptor_loss	1.0000
2:232378969:A:AG	acceptor_gain	1.0000
2:232378969:AGTT:A	acceptor_gain	1.0000
2:232378970:G:GC	acceptor_gain	1.0000
2:232378970:GT:G	acceptor_gain	1.0000
2:232378970:GTT:G	acceptor_gain	1.0000
2:232378970:GTTG:G	acceptor_gain	1.0000
2:232378970:GTTGA:G	acceptor_gain	1.0000
2:232379084:GATG:G	donor_gain	1.0000
2:232379085:ATG:A	donor_gain	1.0000
2:232379086:TG:T	donor_gain	1.0000
2:232379087:GG:G	donor_gain	1.0000
2:232379088:G:GA	donor_loss	1.0000
2:232379088:G:GG	donor_gain	1.0000
2:232379089:T:A	donor_loss	1.0000
2:232379092:G:GG	donor_gain	1.0000
2:232379198:A:AG	acceptor_gain	1.0000
2:232379198:AG:A	acceptor_gain	1.0000
2:232379198:AGG:A	acceptor_gain	1.0000
2:232379199:G:A	acceptor_gain	1.0000

AlphaMissense

3459 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:232379087:G:T	G65W	0.992
2:232379581:G:C	K126N	0.992
2:232379581:G:T	K126N	0.992
2:232380852:A:T	D338V	0.992
2:232379543:A:C	S114R	0.991
2:232379545:T:A	S114R	0.991
2:232379545:T:G	S114R	0.991
2:232379085:A:T	D64V	0.990
2:232380853:C:A	D338E	0.990
2:232380853:C:G	D338E	0.990
2:232379898:G:C	D207H	0.989
2:232380975:A:T	D379V	0.989
2:232381559:G:C	D458H	0.989
2:232379200:G:T	G65V	0.987
2:232380852:A:C	D338A	0.987
2:232380739:T:C	F328L	0.986
2:232380741:C:A	F328L	0.986
2:232380741:C:G	F328L	0.986
2:232380978:A:C	H380P	0.986
2:232380846:G:C	R336P	0.985
2:232379085:A:C	D64A	0.983
2:232379086:T:A	D64E	0.983
2:232379086:T:G	D64E	0.983
2:232379573:G:T	G124W	0.983
2:232380746:T:A	L330H	0.983
2:232380972:C:A	A378D	0.983
2:232380976:C:A	D379E	0.983
2:232380976:C:G	D379E	0.983
2:232380979:C:A	H380Q	0.983
2:232380979:C:G	H380Q	0.983

dbSNP variants (sampled 300 via entrez): RS1001934270 (2:232377335 T>C), RS1002981097 (2:232382807 G>A), RS1003298312 (2:232382631 A>G), RS1003445019 (2:232383077 G>T), RS1006447095 (2:232377839 G>A), RS1006496474 (2:232377392 A>T), RS1007529941 (2:232379402 G>A,T), RS1008556166 (2:232382257 C>A), RS1009587266 (2:232381941 C>A,T), RS1009891048 (2:232377817 GC>G), RS1010297964 (2:232377047 C>T), RS1010405487 (2:232382597 G>A,C), RS1010415258 (2:232382790 T>A,C,G), RS1010880850 (2:232377553 G>A), RS1012578476 (2:232378472 T>G)

Disease associations

OMIM: gene MIM:171800 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST000431_1	Height	3.000000e-09
GCST006585_2901	Blood protein levels	2.000000e-35
GCST010002_411	Refractive error	1.000000e-123

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4458 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.50	IC50	32	nM	CHEMBL5173145
5.60	IC50	2500	nM	CHEMBL597055

PubChem BioAssay actives

2 with measured affinity, of 103 total; 2 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
(2R)-3-[3-(3,5-dichloro-4-methoxyphenyl)phenyl]-2-[[5-(5-methylfuran-2-yl)-1H-pyrazole-3-carbonyl]amino]propanoic acid	1895874: Inhibition of human PLAP using biotinylated CDP as substrate incubated for 30 mins by chemiluminescent assay	ic50	0.0320	uM
1-(3,4-dihydroxyphenyl)-2-(2-methylbenzimidazol-1-yl)ethanone	1895872: Inhibition of PLAP (unknown origin)	ic50	2.5000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases expression, affects cotreatment, decreases expression	4
sulforaphane	decreases expression, increases expression	2
chloropicrin	increases expression	2
Decitabine	affects methylation, decreases expression, decreases reaction	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Tretinoin	decreases expression	2
Genistein	increases expression	2
Nanotubes, Carbon	increases expression	2
alternariol	increases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, decreases expression	1
bisphenol A	increases expression	1
glycidyl methacrylate	decreases expression	1
nitrophenylphosphate	increases chemical synthesis	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	decreases expression	1
tobacco tar	decreases expression, decreases reaction	1
strontium chloride	affects binding	1
ICI 118551	decreases reaction, increases expression	1
potassium chromate(VI)	increases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
coumarin	decreases phosphorylation	1
norfluoxetine	increases expression, decreases reaction	1
acetophenone	increases chemical synthesis	1
3-(hydroxymethyl)phenytoin	increases chemical synthesis	1
nefazodone	affects cotreatment, decreases expression	1
icariin	increases secretion	1
perfluorooctane sulfonic acid	decreases expression	1
27-hydroxycholesterol	decreases activity	1
perfluoro-n-nonanoic acid	decreases expression	1

ChEMBL screening assays

20 unique, capped per target: 12 binding, 8 admet

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1014657	Binding	Inhibition of PLAP	Design and synthesis of pyrazole derivatives as potent and selective inhibitors of tissue-nonspecific alkaline phosphatase (TNAP). — Bioorg Med Chem Lett
CHEMBL3624979	ADMET	Stability assessed as human placental ALP-mediated drug degradation by measuring compound remaining level in pH 7.5 tris buffer at 10 uM incubated for 0.25 hrs by LC/MS/MS method	Discovery of ((4-(5-(Cyclopropylcarbamoyl)-2-methylphenylamino)-5-methylpyrrolo[1,2-f][1,2,4]triazine-6-carbonyl)(propyl)carbamoyloxy)methyl-2-(4-(phosphonooxy)phenyl)acetate (BMS-751324), a Clinical Prodrug of p38α MAP Kinase Inhibitor. — J Med Chem

Cellosaurus cell lines

160 cell lines: 90 transformed cell line, 66 cancer cell line, 2 spontaneously immortalized cell line, 2 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0C87	MOCHA	Cancer cell line	Male
CVCL_5333	MFB-F11	Spontaneously immortalized cell line	Sex unspecified
CVCL_5I73	A549-Dual	Cancer cell line	Male
CVCL_5I74	HCT116-Dual	Cancer cell line	Male
CVCL_5I75	J774-Dual	Cancer cell line	Female
CVCL_5I78	HEK-Blue KD-TLR5	Transformed cell line	Female
CVCL_5J54	THP1-Dual KO-MyD	Cancer cell line	Male
CVCL_8936	Psi2 DAP	Transformed cell line	Male
CVCL_9Y72	A5-DAP	Transformed cell line	Male
CVCL_A7YK	HEK-Blue hACE2	Transformed cell line	Female

Clinical trials (associated diseases)

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