PDIA2

protein-coding

protein disulfide isomerase family A member 2, the group of Protein disulfide isomerases

Gene summary

This gene encodes a member of the disulfide isomerase (PDI) family of endoplasmic reticulum (ER) proteins that catalyze protein folding and thiol-disulfide interchange reactions. The encoded protein has an N-terminal ER-signal sequence, two catalytically active thioredoxin (TRX) domains, two TRX-like domains and a C-terminal ER-retention sequence. The protein plays a role in the folding of nascent proteins in the endoplasmic reticulum by forming disulfide bonds through its thiol isomerase, oxidase, and reductase activity. The encoded protein also possesses estradiol-binding activity and can modulate intracellular estradiol levels. [provided by RefSeq, Sep 2017]

Previous symbols:

PDIP

MANE transcript

NM_006849.4

Inheritance

ClinVar variants

U:171B:23

Top phenotype

—

gnomAD constraint

pLI —, LoF o/e 1.75

Max pathogenic AF

—

Genomic locus

chr16:283,164-287,215

External References & Databases

Ensembl (ENSG00000185615)

Transcript & Mutation Effects

hg38 • Region Span ~4.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

aortic valve disorderLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0003803

Submitter: PanelApp Australia

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PDIA2 variants in ClinVar

2 Conditions Cataloged

not specifiedTotal: 174

not providedTotal: 14

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006849.4. 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			2 clinvar	7 clinvar	2 clinvar	11
missense			168 clinvar	11 clinvar	1 clinvar	180
nonsense						0
start loss						0
frameshift				1 clinvar	1 clinvar	2
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	0	0	171	19	4	194

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006849.4	RefSeq	NP_006840.2	11	MANE Select
ENST00000219406.11	Ensembl	ENSP00000219406.7	11	MANE Select
ENST00000404312.5	Ensembl	ENSP00000384410.1	11	Standard
ENST00000404312.6	Ensembl	ENSP00000384410.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ibuprofen Action Pathway
Phenytoin (Antiarrhythmic) Action Pathway
Ibuprofen Metabolism Pathway
Morphine Metabolism Pathway
Irinotecan Action Pathway

Biological Process

protein folding
protein retention in ER lumen
peptidyl-proline hydroxylation
protein folding in endoplasmic reticulum
response to endoplasmic reticulum stress

Molecular Function

steroid binding
protein binding
disulfide oxidoreductase activity
peptide disulfide oxidoreductase activity

Cellular Component

endoplasmic reticulum
endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000219406
Coding exons: 11
Length: 4064
Individuals with no LoFs: 119718
Homozygous LoFs: 40
Heterozygous LoFs: 5017
Defined: 124775
p: 0.0205

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-1.73	418	330	1.27	0.0000224	3347
Missense (PolyPhen)		134	108.09	1.2397		1264
Synonymous	-5.42	237	152	1.56	0.0000115	1103
Loss of Function	-3.30	39	22.2	1.75	0.00000102	256

Population LoF Frequency

Population	CAF	p-value	Status
African	0.034	0.029	notable
Latino/Admixed American	0.024	0.017	notable
Ashkenazi Jewish	0.060	0.040	notable
East Asian	0.00084	0.00067	rare
Finnish	0.029	0.026	notable
European (Non-Finnish)	0.028	0.020	notable
South Asian	0.033	0.023	notable
Other	0.033	0.025	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as an intracellular estrogen-binding protein. May be involved in modulating cellular levels and biological functions of estrogens in the pancreas. May act as a chaperone that inhibits aggregation of misfolded proteins. {ECO:0000269|PubMed:19150607, ECO:0000269|PubMed:19429457}.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.974
RVIS EVS: 2.7
RVIS percentile EVS: 98.9

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.572

Gene Damage Prediction

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