PALS1

Summary

PALS1 (protein associated with LIN7 1, MAGUK p55 family member, HGNC:18669) is a protein-coding gene on chromosome 14q23.3, encoding Protein PALS1 (Q8N3R9). Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells.

This gene encodes a member of the p55-like subfamily of the membrane-associated guanylate kinase (MAGUK) gene superfamily. The encoded protein participates in the polarization of differentiating cells, has been shown to regulate myelinating Schwann cells (PMID: 20237282), and is one of the components of the Crumbs complex in the retina. Mice which express lower levels of the orthologous protein have retinal degeneration and impaired vision (PMID: 22114289). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 64398 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC)
• Clinical variants (ClinVar): 3 total — 1 pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_022474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18669
Approved symbol	PALS1
Name	protein associated with LIN7 1, MAGUK p55 family member
Location	14q23.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ12615
Ensembl gene	ENSG00000072415
Ensembl biotype	protein_coding
OMIM	606958
Entrez	64398

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 15 protein_coding, 4 retained_intron

ENST00000261681, ENST00000554208, ENST00000555925, ENST00000556345, ENST00000557237, ENST00000557783, ENST00000676464, ENST00000676950, ENST00000677222, ENST00000677382, ENST00000677835, ENST00000677972, ENST00000678380, ENST00000909495, ENST00000909496, ENST00000909497, ENST00000954198, ENST00000954199, ENST00000954200

RefSeq mRNA: 2 — MANE Select: NM_022474 NM_001256550, NM_022474

CCDS: CCDS58325, CCDS9779

Canonical transcript exons

ENST00000261681 — 15 exons

Exon	Start	End
ENSE00000444379	67302410	67302571
ENSE00000522816	67320230	67320397
ENSE00000658572	67301389	67301466
ENSE00000658574	67301972	67302118
ENSE00000658576	67312527	67312710
ENSE00000658577	67316832	67316903
ENSE00000658578	67317408	67317479
ENSE00000658580	67321057	67321259
ENSE00000658581	67323702	67323812
ENSE00000807762	67303522	67303599
ENSE00001140603	67292511	67292719
ENSE00001246806	67279018	67279537
ENSE00001246811	67269701	67269783
ENSE00002517375	67241435	67241533
ENSE00003891090	67332780	67336061

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 96.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.3307 / max 237.8671, expressed in 1739 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140207	6.4644	1606
140205	2.4243	1153
140206	1.7389	1055
140208	1.3716	651
140204	0.3491	173
207263	0.3028	126
140212	0.2331	115
140211	0.1917	95
140209	0.1386	31
140210	0.1046	34

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	96.96	gold quality
ventricular zone	UBERON:0003053	93.89	gold quality
germinal epithelium of ovary	UBERON:0001304	93.49	gold quality
esophagus squamous epithelium	UBERON:0006920	93.36	gold quality
pigmented layer of retina	UBERON:0001782	93.20	gold quality
retina	UBERON:0000966	93.18	gold quality
corpus callosum	UBERON:0002336	93.13	gold quality
inferior vagus X ganglion	UBERON:0005363	92.51	gold quality
biceps brachii	UBERON:0001507	92.48	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	91.85	gold quality
jejunum	UBERON:0002115	91.73	gold quality
amniotic fluid	UBERON:0000173	91.48	gold quality
corpus epididymis	UBERON:0004359	91.40	gold quality
superior vestibular nucleus	UBERON:0007227	91.35	gold quality
endothelial cell	CL:0000115	91.15	gold quality
subthalamic nucleus	UBERON:0001906	91.13	gold quality
gingival epithelium	UBERON:0001949	90.10	silver quality
calcaneal tendon	UBERON:0003701	90.02	gold quality
duodenum	UBERON:0002114	89.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	89.59	gold quality
eye	UBERON:0000970	89.57	gold quality
epithelium of esophagus	UBERON:0001976	89.57	gold quality
globus pallidus	UBERON:0001875	89.33	gold quality
parietal pleura	UBERON:0002400	89.28	gold quality
middle temporal gyrus	UBERON:0002771	89.25	gold quality
oral cavity	UBERON:0000167	89.15	gold quality
medial globus pallidus	UBERON:0002477	89.13	gold quality
ventral tegmental area	UBERON:0002691	88.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.89	gold quality
parotid gland	UBERON:0001831	88.77	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-124472	yes	1390.44
E-CURD-119	yes	27.92
E-HCAD-10	yes	22.70
E-ANND-3	yes	7.77
E-GEOD-110499	no	270.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

148 targeting PALS1, 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-4262	100.00	73.26	3931
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192

Literature-anchored findings (GeneRIF, showing 19)

• Pals1 functions as an adapter, linking mammalian homologues of Crumbs and Discs Lost. (PMID:11927608)
• the Crumbs3-Pals1 complex has a role in development of polarity in mammalian epithelial cells (PMID:12771187)
• PDZ domain plasticity has a role in internal recognition in the Par-6-Pals1 complex (PMID:15475968)
• the importance of a conserved Crumbs-MPP5-EPB41L5 polarity complex in mammals for separation of the apical and basolateral domains through specialized cell-cell junctions (PMID:17920587)
• Polarity protein associated with lin seven 1 (Pals1) plays an essential role in radical and longitudinal extension of the myelin sheath in peripheral nerves, likely involving membrane protein trafficking. (PMID:20237282)
• Polycystin-2 activity is controlled by transcriptional coactivator with PDZ binding motif and PALS1-associated tight junction protein (PMID:20833712)
• Data suggest that hijacking of PALS1 by SARS-CoV E plays a determinant role in the disruption of the lung epithelium in SARS patients. (PMID:20861307)
• The cell polarity protein PALS1 is expressed in T lymphocytes and participates to the optimal activation of NF-kappaB following TCR stimulation. (PMID:21479189)
• Crystals of tripartite complex 1 of L27(PATJ)-(L27N,L27C)(Pals1)-L27(MALS) diffracted to 2.05 A resolution (PMID:22102253)
• Small irregularly shaped spots are detected throughout the Pals1-deficient retina of conditional knockdown mice by confocal scanning laser ophthalmoscopy and spectral domain optical coherence tomography. (PMID:22114289)
• the crystal structure of a 4-L27 domain-containing heterotrimer derived from the tripartite complex Patj/Pals1/Mals2 (PMID:22337881)
• The unique in-frame MPP5-FAM71D fusion product is important for proliferation of PC346C cells. (PMID:24488012)
• Removal of this side chain enhances the binding affinity by more than fivefold, suggesting that access of Crb to Pals1 may be regulated by intradomain contacts or by protein-protein interaction. (PMID:25760605)
• Comparing the binding properties of peptides mimicking the Envelope protein of SARS-CoV and SARS-CoV-2 to the PDZ domain of the tight junction-associated PALS1 protein. (PMID:32822073)
• De novo variants in MPP5 cause global developmental delay and behavioral changes. (PMID:33073849)
• Pals1 prevents Rac1-dependent colorectal cancer cell metastasis by inhibiting Arf6. (PMID:33941200)
• Structural basis for SARS-CoV-2 envelope protein recognition of human cell junction protein PALS1. (PMID:34103506)
• Structural basis of coronavirus E protein interactions with human PALS1 PDZ domain. (PMID:34117354)
• Pals1 functions in redundancy with SMAP1 to inhibit Arf6 in order to prevent Rac1-dependent colorectal cancer cell migration and invasion. (PMID:36494580)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pals1b	ENSDARG00000004721
danio_rerio	pals1a	ENSDARG00000006272
mus_musculus	Pals1	ENSMUSG00000021112
rattus_norvegicus	Pals1	ENSRNOG00000008788
drosophila_melanogaster	sdt	FBGN0261873
caenorhabditis_elegans		WBGENE00006467

Paralogs (7): MPP4 (ENSG00000082126), PALS2 (ENSG00000105926), MPP2 (ENSG00000108852), MPP1 (ENSG00000130830), CASK (ENSG00000147044), MPP7 (ENSG00000150054), MPP3 (ENSG00000161647)

Protein

Protein identifiers

Protein PALS1 — Q8N3R9 (reviewed: Q8N3R9)

Alternative names: MAGUK p55 subfamily member 5, Membrane protein, palmitoylated 5, Protein associated with Lin-7 1

All UniProt accessions (3): Q8N3R9, G3V2B0, G3V2H1

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in tight junction biogenesis and in the establishment of cell polarity in epithelial cells. Also involved in adherens junction biogenesis by ensuring correct localization of the exocyst complex protein EXOC4/SEC8 which allows trafficking of adherens junction structural component CDH1 to the cell surface. Plays a role through its interaction with CDH5 in vascular lumen formation and endothelial membrane polarity. Required during embryonic and postnatal retinal development. Required for the maintenance of cerebellar progenitor cells in an undifferentiated proliferative state, preventing premature differentiation, and is required for cerebellar histogenesis, fissure formation, cerebellar layer organization and cortical development. Plays a role in neuronal progenitor cell survival, potentially via promotion of mTOR signaling. Plays a role in the radial and longitudinal extension of the myelin sheath in Schwann cells. May modulate SC6A1/GAT1-mediated GABA uptake by stabilizing the transporter. Plays a role in the T-cell receptor-mediated activation of NF-kappa-B. Required for localization of EZR to the apical membrane of parietal cells and may play a role in the dynamic remodeling of the apical cytoskeleton. Required for the normal polarized localization of the vesicular marker STX4. Required for the correct trafficking of the myelin proteins PMP22 and MAG. Involved in promoting phosphorylation and cytoplasmic retention of transcriptional coactivators YAP1 and WWTR1/TAZ which leads to suppression of TGFB1-dependent transcription of target genes such as CCN2/CTGF, SERPINE1/PAI1, SNAI1/SNAIL1 and SMAD7. (Microbial infection) Acts as an interaction partner for human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope protein E which results in delayed formation of tight junctions and disregulation of cell polarity.

Subunit / interactions. Heterodimer with MPP1. Forms a heterotrimeric complex composed of PALS1, LIN7B and PATJ; the N-terminal L27 domain of PALS1 interacts with the L27 domain of PATJ and the C-terminal L27 domain of PALS1 interacts with the L27 domain of LIN7B. Component of a complex composed of PALS1, CRB1 and MPP4. Component of a complex whose core is composed of ARHGAP17, AMOT, PALS1, PATJ and PARD3/PAR3. Component of a complex composed of PALS1, CRB1 and EPB41L5. Within the complex, interacts (via HOOK domain) with EPB41L5 (via FERM domain), and interacts with CRB1 (via intracellular domain). Component of a complex composed of PALS1, MPP3 and CRB1; PALS1 acts as a bridging protein between MPP3 (via guanylate kinase-like domain) and CRB1. Component of a complex composed of CRB3, PALS1 and PATJ. As part of the Crumbs complex; interacts with WWP1, the interaction is enhanced by AMOTL2 and facilitates WWP1 localization to the plasma membrane. The Crumbs complex promotes monoubiquitination of AMOTL2 by WWP1, which activates the Hippo signaling pathway. Interacts (via PDZ domain) with PATJ (via N-terminus). Interacts with EZR. Interacts (via PDZ domain) with CRB1 (via C-terminal ERLI motif). While the PDZ domain is sufficient for interaction with CRB1, the adjacent SH3 and guanylate kinase-like domains are likely to contribute to a high affinity interaction. Interacts with WWTR1/TAZ (via WW domain). Interacts with MPP7. Interacts (via PDZ domain) with CRB3 (via C-terminus). Interacts with LIN7C. Interacts with MPDZ. Interacts with PARD6B. Interacts with SC6A1. Interacts with CDH5; the interaction promotes PALS1 localization to cell junctions and is required for CDH5-mediated vascular lumen formation and endothelial cell. Interacts with NPHP1 (via coiled coil and SH3 domains). Interacts with NPHP4. Interacts with CRB2. (Microbial infection) Interacts (via PDZ domain) with human coronaviruses SARS-CoV and, probably, SARS-CoV-2 envelope small membrane protein E (via C-terminus); this inhibits the interaction between PALS1 and CRB3.

Subcellular location. Golgi apparatus. Cell membrane. Endomembrane system. Cell junction. Tight junction. Adherens junction. Cell projection. Axon. Perikaryon. Apical cell membrane Endoplasmic reticulum-Golgi intermediate compartment.

Tissue specificity. Expressed at the outer limiting membrane in the retina (at protein level). Expressed in T lymphocytes (at protein level). Expressed in the kidney (at protein level).

Domain organisation. The L27 domain 1 functions in targeting to the tight junctions by binding to and stabilizing PATJ. The PDZ domain binds to the C-terminus of SC6A1.

Similarity. Belongs to the MAGUK family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8N3R9-1	1	yes
Q8N3R9-2	2

RefSeq proteins (2): NP_001243479, NP_071919* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR001478	PDZ	Domain
IPR004172	L27_dom	Domain
IPR008144	Guanylate_kin-like_dom	Domain
IPR008145	GK/Ca_channel_bsu	Domain
IPR014775	L27_C	Domain
IPR015145	L27_N	Domain
IPR020590	Guanylate_kinase_CS	Conserved_site
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR035601	MPP5_SH3	Domain
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036892	L27_dom_sf	Homologous_superfamily
IPR050716	MAGUK	Family

Pfam: PF00595, PF00625, PF02828, PF07653, PF09060

UniProt features (75 total): helix 20, strand 19, sequence conflict 9, turn 6, domain 5, region of interest 5, modified residue 4, compositionally biased region 2, mutagenesis site 2, chain 1, binding site 1, splice variant 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
4UU5	X-RAY DIFFRACTION	1.23
7NTJ	X-RAY DIFFRACTION	1.74
4UU6	X-RAY DIFFRACTION	1.8
7NTK	X-RAY DIFFRACTION	1.9
3UIT	X-RAY DIFFRACTION	2.05
7QCS	X-RAY DIFFRACTION	2.8
4WSI	X-RAY DIFFRACTION	2.95
7M4R	ELECTRON MICROSCOPY	3.65
1Y76	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N3R9-F1	77.25	0.47

Functional residue map

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

Ligand- & substrate-binding residues (1): 486–493

Post-translational modifications (4): 14, 25, 83, 84

Mutagenesis-validated functional residues (2):

Position	Phenotype
318	increases interaction with crb1.
386	reduces binding to drosophila crb and causes incorrect pals1 localization and cell polarity.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-420029	Tight junction interactions
R-HSA-9692912	SARS-CoV-1 targets PDZ proteins in cell-cell junction
R-HSA-9705677	SARS-CoV-2 targets PDZ proteins in cell-cell junction

MSigDB gene sets: 236 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_PLASMA_MEMBRANE_ORGANIZATION, GOBP_GLIAL_CELL_DEVELOPMENT, GOBP_NEUROGENESIS, KEGG_TIGHT_JUNCTION, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_FOREBRAIN_DEVELOPMENT, COUP_01, GOBP_CELLULAR_COMPONENT_ASSEMBLY_INVOLVED_IN_MORPHOGENESIS, GOBP_REGULATION_OF_TRANSMEMBRANE_RECEPTOR_PROTEIN_SERINE_THREONINE_KINASE_SIGNALING_PATHWAY

GO Biological Process (14): morphogenesis of an epithelial sheet (GO:0002011), gene expression (GO:0010467), establishment or maintenance of polarity of embryonic epithelium (GO:0016332), regulation of transforming growth factor beta receptor signaling pathway (GO:0017015), central nervous system neuron development (GO:0021954), cerebral cortex development (GO:0021987), peripheral nervous system myelin maintenance (GO:0032287), myelin assembly (GO:0032288), protein localization to myelin sheath abaxonal region (GO:0035750), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), generation of neurons (GO:0048699), protein localization to plasma membrane (GO:0072659), plasma membrane organization (GO:0007009), intracellular protein localization (GO:0008104)

GO Molecular Function (5): ATP binding (GO:0005524), protein domain specific binding (GO:0019904), identical protein binding (GO:0042802), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (21): cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), adherens junction (GO:0005912), bicellular tight junction (GO:0005923), apical plasma membrane (GO:0016324), axon (GO:0030424), protein-containing complex (GO:0032991), endoplasmic reticulum-Golgi intermediate compartment membrane (GO:0033116), myelin sheath adaxonal region (GO:0035749), perikaryon (GO:0043204), lateral loop (GO:0043219), Schmidt-Lanterman incisure (GO:0043220), apical junction complex (GO:0043296), extracellular exosome (GO:0070062), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), endomembrane system (GO:0012505), membrane (GO:0016020), cell projection (GO:0042995), apical part of cell (GO:0045177), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Cell-cell junction organization	1
SARS-CoV-1-host interactions	1
SARS-CoV-2-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	9
protein binding	2
cytoplasm	2
intracellular membrane-bounded organelle	2
cell-cell junction	2
myelin sheath	2
morphogenesis of an epithelium	1
macromolecule biosynthetic process	1
establishment or maintenance of cell polarity	1
morphogenesis of embryonic epithelium	1
transforming growth factor beta receptor signaling pathway	1
regulation of transmembrane receptor protein serine/threonine kinase signaling pathway	1
regulation of cellular response to transforming growth factor beta stimulus	1
central nervous system neuron differentiation	1
neuron development	1
pallium development	1
anatomical structure development	1
myelination in peripheral nervous system	1
myelin maintenance	1
cellular component assembly involved in morphogenesis	1
myelination	1
intracellular protein localization	1
establishment or maintenance of apical/basal cell polarity	1
neurogenesis	1
protein localization to membrane	1
protein localization to cell periphery	1
endomembrane system organization	1
membrane organization	1
macromolecule localization	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular anatomical structure	1
endomembrane system	1
membrane	1
cell periphery	1
apical junction complex	1
tight junction	1

Protein interactions and networks

STRING

2454 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PALS1	PATJ	Q8NI35	999
PALS1	CRB3	Q9BUF7	999
PALS1	LIN7A	O14910	997
PALS1	CRB1	P82279	997
PALS1	CRB2	Q5IJ48	997
PALS1	AMOT	Q4VCS5	984
PALS1	MPDZ	O75970	978
PALS1	PARD3	Q8TEW0	969
PALS1	ARHGAP17	Q68EM7	899
PALS1	LIN7C	Q9NUP9	874
PALS1	CDC42	P21181	839
PALS1	NPHP1	O15259	817
PALS1	EPB41	P11171	800
PALS1	SCRIB	Q14160	798
PALS1	NPHP4	O75161	793

IntAct

186 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
LIN7A	PALS1	psi-mi:“MI:0915”(physical association)	0.870
PALS1	LIN7A	psi-mi:“MI:0915”(physical association)	0.870
PALS1	LIN7A	psi-mi:“MI:0914”(association)	0.870
PALS1	E	psi-mi:“MI:0407”(direct interaction)	0.850
PALS1	E	psi-mi:“MI:0915”(physical association)	0.850
E	PALS1	psi-mi:“MI:0915”(physical association)	0.850
LIN7A	CASK	psi-mi:“MI:0914”(association)	0.830
PALS1	LIN7C	psi-mi:“MI:0915”(physical association)	0.800
CRB1	PALS1	psi-mi:“MI:0915”(physical association)	0.780
PALS1	CRB1	psi-mi:“MI:0407”(direct interaction)	0.780
CRB1	PALS1	psi-mi:“MI:0403”(colocalization)	0.780
YAP1	MPDZ	psi-mi:“MI:0914”(association)	0.780
PATJ	PALS1	psi-mi:“MI:0915”(physical association)	0.780
CRB1	PALS1	psi-mi:“MI:0914”(association)	0.780
PALS1	LIN7B	psi-mi:“MI:0915”(physical association)	0.740
LRFN4	NCK2	psi-mi:“MI:0914”(association)	0.730

BioGRID (185): MPP5 (Two-hybrid), MPP5 (Affinity Capture-MS), MPP5 (Affinity Capture-MS), AMOTL1 (Affinity Capture-MS), AMOT (Affinity Capture-MS), INADL (Affinity Capture-MS), LIN7A (Affinity Capture-MS), LIN7C (Affinity Capture-MS), MPDZ (Affinity Capture-MS), MPP5 (Affinity Capture-MS), MPP5 (Two-hybrid), MPP5 (Proximity Label-MS), MPP5 (Proximity Label-MS), MPP5 (Affinity Capture-MS), MPP5 (Affinity Capture-MS)

ESM2 similar proteins: A1L1G1, A5A6K6, A7YW45, B4F7E7, E2QY99, F4J0W4, O02485, O14744, O23617, Q14168, Q24325, Q298L5, Q32LU1, Q3SYX0, Q3ZBA8, Q4R4K0, Q4R4Q3, Q4R5M3, Q5PR98, Q5R698, Q5RBN6, Q5RDQ2, Q5ZLR4, Q62433, Q640Z1, Q641F2, Q66IG4, Q66KM2, Q6DFS4, Q6DIS1, Q6DIX1, Q6GQL1, Q6JE36, Q6P0D7, Q7ZVR8, Q7ZWV3, Q7ZY73, Q8BPM2, Q8CIG8, Q8GWT4

Diamond homologs: A0A8C0TYJ0, A0A8P0N4K0, B4F7E7, D3ZAA9, E2QY99, E2QYC9, E7FDW2, F1MAD2, G5ECY0, O14910, O15018, O55164, O75970, O84033, O88382, O88951, O88952, P15454, P31006, P31007, P31016, P46195, P57105, P68907, P70175, P78352, P93757, Q0P5F3, Q0SS73, Q0TPK6, Q12959, Q13425, Q13884, Q14160, Q15700, Q16774, Q24210, Q255A8, Q28C55, Q2KIB6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MPP5	“form complex”	AMOT/MPP5/INADL/LIN7C	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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
Signaling by Hippo	7	40.5×	1e-07
Neurexins and neuroligins	7	14.7×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
hippo signaling	8	50.5×	2e-09

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
983221	NM_022474.4(PALS1):c.1289A>G (p.Glu430Gly)	Pathogenic

SpliceAI

2364 predictions. Top by Δscore:

Variant	Effect	Δscore
14:67269696:TATA:T	acceptor_loss	1.0000
14:67269698:TA:T	acceptor_loss	1.0000
14:67269699:A:AG	acceptor_gain	1.0000
14:67269699:AGA:A	acceptor_loss	1.0000
14:67269700:G:GA	acceptor_gain	1.0000
14:67269700:GA:G	acceptor_gain	1.0000
14:67269780:TAAT:T	donor_gain	1.0000
14:67269784:G:GG	donor_gain	1.0000
14:67292509:A:AG	acceptor_gain	1.0000
14:67292510:G:GG	acceptor_gain	1.0000
14:67292718:AGGT:A	donor_loss	1.0000
14:67292719:GGTA:G	donor_loss	1.0000
14:67292721:T:G	donor_loss	1.0000
14:67301384:CTTA:C	acceptor_loss	1.0000
14:67301386:TAGGT:T	acceptor_loss	1.0000
14:67301387:A:AG	acceptor_gain	1.0000
14:67301387:A:C	acceptor_loss	1.0000
14:67301388:G:GG	acceptor_gain	1.0000
14:67301388:G:GT	acceptor_loss	1.0000
14:67301462:TTCAG:T	donor_loss	1.0000
14:67301463:TCAGG:T	donor_loss	1.0000
14:67301464:CAG:C	donor_loss	1.0000
14:67301465:AGGTA:A	donor_loss	1.0000
14:67301466:GGTAG:G	donor_loss	1.0000
14:67301467:GTAG:G	donor_loss	1.0000
14:67301468:T:G	donor_loss	1.0000
14:67302115:GTTG:G	donor_gain	1.0000
14:67302119:G:C	donor_loss	1.0000
14:67302119:G:GG	donor_gain	1.0000
14:67302120:T:TC	donor_loss	1.0000

AlphaMissense

4504 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:67302410:G:C	G268R	1.000
14:67302411:G:A	G268D	1.000
14:67302420:T:A	V271D	1.000
14:67302423:G:C	R272P	1.000
14:67302441:T:A	V278D	1.000
14:67302453:G:C	R282P	1.000
14:67302492:T:C	L295S	1.000
14:67312540:C:A	A352D	1.000
14:67312545:T:C	F354L	1.000
14:67312547:T:A	F354L	1.000
14:67312547:T:G	F354L	1.000
14:67312566:G:C	D361H	1.000
14:67312567:A:G	D361G	1.000
14:67312567:A:T	D361V	1.000
14:67312578:C:T	P365S	1.000
14:67312579:C:A	P365Q	1.000
14:67312581:T:C	C366R	1.000
14:67312582:G:A	C366Y	1.000
14:67312583:T:G	C366W	1.000
14:67312593:G:C	G370R	1.000
14:67312594:G:A	G370D	1.000
14:67312597:T:C	L371P	1.000
14:67312602:T:C	F373L	1.000
14:67312603:T:C	F373S	1.000
14:67312604:T:A	F373L	1.000
14:67312604:T:G	F373L	1.000
14:67312621:T:A	L379H	1.000
14:67312621:T:C	L379P	1.000
14:67312650:T:A	W389R	1.000
14:67312650:T:C	W389R	1.000

dbSNP variants (sampled 300 via entrez): RS1000001299 (14:67283740 G>A), RS1000022562 (14:67314113 T>C), RS1000046530 (14:67288561 T>C), RS1000091502 (14:67258863 A>G,T), RS1000114470 (14:67263036 C>A,G), RS1000183589 (14:67288327 C>T), RS1000190793 (14:67311361 G>A), RS1000206966 (14:67330942 A>T), RS1000264101 (14:67262749 T>A), RS1000327926 (14:67304196 C>T), RS1000387235 (14:67294964 G>A), RS1000463133 (14:67269989 T>C), RS1000465254 (14:67303759 C>T), RS1000488084 (14:67301541 A>C,T), RS1000497326 (14:67331273 G>A,C)

Disease associations

OMIM: gene MIM:606958 | disease phenotypes: MIM:607834

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant

Mondo (5): intellectual disability (MONDO:0001071), cerebral palsy (MONDO:0006497), arachnoid cyst (MONDO:0008813), anxiety (MONDO:0011918), neurodevelopmental disorder (MONDO:0700092)

Orphanet (2): Arachnoid cyst (Orphanet:2356), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0100021	Cerebral palsy

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D001007	Anxiety	F01.470.132
D016080	Arachnoid Cysts	C04.182.044; C04.588.614.250.387.100; C10.500.142.100; C10.551.240.375.100; C16.131.666.142.100
D002547	Cerebral Palsy	C10.228.140.140.254
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
arsenite	affects binding, decreases reaction	1
coumarin	increases phosphorylation	1
perfluorooctane sulfonic acid	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	decreases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Zoledronic Acid	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Fluvastatin	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Quercetin	decreases expression	1
Rotenone	decreases expression	1
Antirheumatic Agents	increases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1ZV	Abcam HeLa PALS1 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00154830	PHASE4	COMPLETED	Alterations of Functional Activities and Leg Stiffness After Hamstring Lengthening in Cerebral Palsy Children
NCT00432055	PHASE4	COMPLETED	Effects of Botulinum Toxin Type A in Adults With Cerebral Palsy
NCT00549471	PHASE4	TERMINATED	Improvement After Botulinum Toxin Injections to the Arms in Children With Cerebral Palsy
NCT00752934	PHASE4	TERMINATED	Does Oral Baclofen Improve Care and Comfort in Spastic Children in Nursing Homes?
NCT00964639	PHASE4	COMPLETED	Postoperative Pain in Children With Cerebral Palsy After Pelvic and Femoral Osteotomies
NCT01386255	PHASE4	WITHDRAWN	Placebo Controlled Study of Baclofen for GERD in Children With Cerebral Palsy
NCT02546999	PHASE4	COMPLETED	Does Botulinum Toxin A Make Walking Easier in Children With Cerebral Palsy?
NCT02633241	PHASE4	COMPLETED	A Pilot Study of Dexmedetomidine-Propofol in Children Undergoing Magnetic Resonance Imaging
NCT03117322	PHASE4	COMPLETED	Synbiotic, Prebiotics and Probiotics in Children With Cerebral Palsy and Constipation
NCT03648658	PHASE4	UNKNOWN	Paracetamol Study in Patients With Low Muscle Mass
NCT04074265	PHASE4	COMPLETED	Peri-operative Use of a Pain Injection in Pediatric Patients With Cerebral Palsy
NCT04273737	PHASE4	TERMINATED	Amantadine in Treating Cognitive & Motor Impairments in Adolescents and Adults With Cerebral Palsy
NCT04523935	PHASE4	COMPLETED	Excessive Crying in Children With Cerebral Palsy and Communication Deficits
NCT05887765	PHASE4	COMPLETED	Effect of Systematic Dexamethasone on the Duration of Popliteal Nerve Block for Anesthesia After Pediatric Ankle Surgery
NCT06176430	PHASE4	UNKNOWN	Comparison of Twice Weekly Versus Daily Iron Therapy in Treating Anemia in Children With Cerebral Palsy
NCT06189781	PHASE4	RECRUITING	Pain Injection Versus Epidural Anesthesia for Hip Surgery in Pediatric Patients With Cerebral Palsy
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00014989	PHASE3	COMPLETED	Beneficial Effects of Antenatal Magnesium Sulfate (BEAM Trial)
NCT00065949	PHASE3	UNKNOWN	Magnesium Sulfate to Prevent Brain Injury in Premature Infants
NCT00367068	PHASE3	COMPLETED	Dutch National ITB Study in Children With Cerebral Palsy
NCT00491894	PHASE3	COMPLETED	Safety and Efficacy Study of Oral Glycopyrrolate Liquid for the Treatment of Pathologic (Chronic Moderate to Severe) Drooling in Pediatric Patients 3 to 18 Years of Age With Cerebral Palsy or Other Neurologic Conditions
NCT00632528	PHASE3	COMPLETED	MEOPA to Improve Physical Therapy Results After Multilevel Surgery
NCT00822029	PHASE3	TERMINATED	Use of Oral Bisphosphonates in the Treatment of Osteoporosis of Non-walking Children With Cerebral Palsy
NCT00922077	PHASE3	COMPLETED	Individualized Neurodevelopmental Treatment
NCT01249417	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Study
NCT01251380	PHASE3	COMPLETED	Dysport® Pediatric Lower Limb Spasticity Follow-on Study
NCT01437644	PHASE3	COMPLETED	The Post-Operative Pain in Cerebral Palsy (POPPIES) Trial
NCT01492608	PHASE3	COMPLETED	Magnesium Sulphate for Preterm Birth (MASP Study)
NCT01603602	PHASE3	COMPLETED	BOTOX® Treatment in Pediatric Upper Limb Spasticity
NCT01603615	PHASE3	COMPLETED	BOTOX® Open-Label Treatment in Pediatric Upper Limb Spasticity