PCDHA1

protein-coding

protocadherin alpha 1, 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_018900.4

Inheritance

—

ClinVar variants

U:135B:16

Top phenotype

PCDHA9-related disorder

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr5:140,786,136-141,012,347

External References & Databases

Ensembl (ENSG00000204970)

Transcript & Mutation Effects

hg38 • Region Span ~226.2 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 PCDHA1 variants in ClinVar

12 Conditions Cataloged

not specifiedTotal: 2189

not providedTotal: 98

PCDHA9-related disorderTotal: 35

PCDHA3-related disorderTotal: 15

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

PCDHA13-related disorderTotal: 2

PCDHA2-related disorderTotal: 2

Prostate cancerTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018900.4. 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				4 clinvar	2 clinvar	6
missense			135 clinvar	10 clinvar		145
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)						0
Total	0	0	135	14	2	151

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018900.4	RefSeq	NP_061723.1	4	MANE Select
ENST00000504120.4	Ensembl	ENSP00000420840.3	4	MANE Select
NM_031410.3	RefSeq	NP_113598.1	1	Standard
NM_031411.3	RefSeq	NP_113599.1	4	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

Cellular Component

extracellular region
endoplasmic reticulum
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000504120
Coding exons: 4
Length: 226054
Individuals with no LoFs: 125675
Homozygous LoFs: 1
Heterozygous LoFs: 72
Defined: 125748
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.334	603	580	1.04	0.0000406	6084
Missense (PolyPhen)		126	131.07	0.96134		1511
Synonymous	-0.628	294	281	1.05	0.0000239	2073
Loss of Function	2.06	16	27.7	0.577	0.00000142	334

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.00041	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00054	0.00054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00029	0.00027	rare
South Asian	0.00046	0.00042	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Potential calcium-dependent cell-adhesion protein. May be involved in the establishment and maintenance of specific neuronal connections in the brain.;

Intolerance Scores

LoFtool: 0.720
RVIS EVS: 0.21
RVIS percentile EVS: 67.55

Essentials

Essential (CRISPR): N
Indispensability pred.: N
Indispensability score: 0.107

Gene Damage Prediction

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