PCDHA4

protein-coding

protocadherin alpha 4, the group of Clustered protocadherins

Gene summary

This gene is a member of the protocadherin alpha gene cluster, one of three related gene clusters tandemly linked on chromosome five that demonstrate an unusual genomic organization similar to that of B-cell and T-cell receptor gene clusters. The alpha gene cluster is composed of 15 cadherin superfamily genes related to the mouse CNR genes and consists of 13 highly similar and 2 more distantly related coding sequences. The tandem array of 15 N-terminal exons, or variable exons, are followed by downstream C-terminal exons, or constant exons, which are shared by all genes in the cluster. The large, uninterrupted N-terminal exons each encode six cadherin ectodomains while the C-terminal exons encode the cytoplasmic domain. These neural cadherin-like cell adhesion proteins are integral plasma membrane proteins that most likely play a critical role in the establishment and function of specific cell-cell connections in the brain. Alternative splicing has been observed and additional variants have been suggested but their full-length nature has yet to be determined. [provided by RefSeq, Jul 2008]

MANE transcript

NM_018907.4

Inheritance

—

ClinVar variants

U:125B:14

Top phenotype

PCDHA9-related disorder

gnomAD constraint

pLI —, LoF o/e 1.17

Max pathogenic AF

—

Genomic locus

chr5:140,807,037-141,012,347

External References & Databases

Ensembl (ENSG00000204967)

Transcript & Mutation Effects

hg38 • Region Span ~205.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PCDHA4 variants in ClinVar

9 Conditions Cataloged

not specifiedTotal: 1786

not providedTotal: 83

PCDHA9-related disorderTotal: 35

EBV-positive nodal T- and NK-cell lymphomaTotal: 3

PCDHA13-related disorderTotal: 2

Prostate cancerTotal: 1

PCDHA12-related conditionTotal: 1

ThrombocytosisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018907.4. 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				9 clinvar	1 clinvar	10
missense			125 clinvar	4 clinvar		129
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	125	13	1	139

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018907.4	RefSeq	NP_061730.1	4	MANE Select
ENST00000530339.2	Ensembl	ENSP00000435300.1	4	MANE Select
NM_031500.3	RefSeq	NP_113688.1	1	Standard
ENST00000512229.6	Ensembl	ENSP00000423470.2	5	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

cell adhesion
homophilic cell adhesion via plasma membrane adhesion molecules
nervous system development

Molecular Function

calcium ion binding
protein binding
identical protein binding

Cellular Component

integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000530339
Coding exons: 4
Length: 205271
Individuals with no LoFs: 125517
Homozygous LoFs: 11
Heterozygous LoFs: 220
Defined: 125748
p: 0.000919

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.774	630	578	1.09	0.0000412	6057
Missense (PolyPhen)		212	195.36	1.0851		2325
Synonymous	-0.398	288	280	1.03	0.0000243	2075
Loss of Function	-0.829	32	27.3	1.17	0.00000138	331

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00031	0.00031	rare
Latino/Admixed American	0.0011	0.00093	notable
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0061	0.0060	notable
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00050	0.00046	rare
South Asian	0.00090	0.00082	rare
Other	0.00087	0.00065	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Calcium-dependent cell-adhesion protein involved in cells self-recognition and non-self discrimination. Thereby, it is involved in the establishment and maintenance of specific neuronal connections in the brain. {ECO:0000250|UniProtKB:O88689}.;

Recessive Scores

pRec: 0.203

Intolerance Scores

LoFtool: 0.956
RVIS EVS: 0.83
RVIS percentile EVS: 88.13

Essentials

Essential (CRISPR): N
Indispensability pred.: E
Indispensability score: 0.572

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High