PALS1

protein-coding

protein associated with LIN7 1, MAGUK p55 family member, the group of Crumbs complex|PDZ domain containing|Membrane associated guanylate kinases

Gene summary

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. [provided by RefSeq, Feb 2012]

Previous symbols:

MPP5

MANE transcript

NM_022474.4

Inheritance

ClinVar variants

P:2U:87B:13

Top phenotype

neurodevelopmental disorder

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr14:67,240,713-67,336,061

External References & Databases

Ensembl (ENSG00000072415)

Transcript & Mutation Effects

hg38 • Region Span ~95.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neurodevelopmental disorderSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PALS1 variants in ClinVar

11 Conditions Cataloged

not specifiedTotal: 79

not providedTotal: 9

PALS1-related disorderTotal: 5

Neurodevelopmental disorderTotal: 2

Cerebral palsyTotal: 1

Arachnoid cystTotal: 1

Abnormal facial shapeTotal: 1

AnxietyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_022474.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			1 clinvar		1 clinvar	2
missense	1 clinvar		77 clinvar	11 clinvar	1 clinvar	90
nonsense			1 clinvar			1
start loss						0
frameshift		1 clinvar	1 clinvar			2
splice donor/acceptor (+/-2bp)			7 clinvar			7
Total	1	1	87	11	2	102

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_022474.4	RefSeq	NP_071919.2	13	MANE Select
ENST00000261681.9	Ensembl	ENSP00000261681.4	13	MANE Select
NM_001256550.2	RefSeq	NP_001243479.1	13	Standard
ENST00000555925.5	Ensembl	ENSP00000451488.1	13	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
mpp5a	Danio rerio	Structure: cardiac muscle cell Quality: structure abnormal

Gene / Model

Organism

Observed Phenotype

mpp5a

Danio rerio

Structure: cardiac muscle cell

Quality: structure

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Tight junction - Homo sapiens (human)
Hippo signaling pathway - Homo sapiens (human)
Human papillomavirus infection - Homo sapiens (human)
EMT transition in Colorectal Cancer
Tight junction interactions

Biological Process

morphogenesis of an epithelial sheet
peripheral nervous system myelin maintenance
myelin assembly
protein localization to myelin sheath abaxonal region
bicellular tight junction assembly

Molecular Function

protein binding
protein domain specific binding

Cellular Component

cytoplasm
plasma membrane
cell-cell adherens junction
bicellular tight junction
endomembrane system

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261681
Coding exons: 13
Length: 94711
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 22
Defined: 125747
p: 0.0000875

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.41	296	372	0.795	0.0000200	4481
Missense (PolyPhen)		98	141.33	0.69343		1707
Synonymous	-0.969	137	123	1.11	0.00000647	1213
Loss of Function	4.10	8	33.7	0.238	0.00000173	423

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.00013	0.00013	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May play a role in tight junctions biogenesis and in the establishment of cell polarity in epithelial cells. May modulate SC6A1/GAT1-mediated GABA uptake by stabilizing the transporter. 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 (By similarity). {ECO:0000250}.;

Recessive Scores

pRec: 0.137

Intolerance Scores

LoFtool: 0.451
RVIS EVS: 0.47
RVIS percentile EVS: 78.74

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.876

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium