GeneBe

PTPN22

protein-coding

protein tyrosine phosphatase non-receptor type 22, the group of Protein tyrosine phosphatases non-receptor type

Gene summary

This gene encodes of member of the non-receptor class 4 subfamily of the protein-tyrosine phosphatase family. The encoded protein is a lymphoid-specific intracellular phosphatase that associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. Mutations in this gene may be associated with a range of autoimmune disorders including Type 1 Diabetes, rheumatoid arthritis, systemic lupus erythematosus and Graves' disease. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Mar 2009]

Previous symbols:
  • PTPN8

MANE transcript

NM_015967.8

Inheritance

AD, AR

ClinVar variants

U:104B:24

Top phenotype

systemic lupus erythematosus

gnomAD constraint

pLI —, LoF o/e 0.82

Max pathogenic AF

—

Genomic locus

chr1:113,813,811-113,871,753

External References & Databases

Ensembl (ENSG00000134242)NCBI Gene (26191)OMIM (600716)HGNC:9652GenCCUniProt (Q9Y2R2)AlphaFoldClinVar (PTPN22)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~57.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autoimmune diseaseLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007179

Submitter: PanelApp Australia

systemic lupus erythematosusSUPPORTIVE

Inheritance Pattern: Unknown

Disease ID:MONDO:0007915

Submitter: Orphanet

type 1 diabetes mellitus 1LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0009100

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

rheumatoid arthritisLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0008383

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTPN22 variants in ClinVar

6 Conditions Cataloged
not specifiedTotal: 86
not providedTotal: 26
PTPN22-related disorderTotal: 9
Diabetes mellitus type 1Total: 2
Rheumatoid arthritisTotal: 2
Systemic lupus erythematosusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015967.8. 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.

EffectPLPVUSLBBSum
synonymous
12
clinvar
2
clinvar
 14
missense
95
clinvar
7
clinvar
2
clinvar
 104
nonsense
3
clinvar
 3
start loss
0
frameshift
1
clinvar
 1
splice donor/acceptor (+/-2bp)
5
clinvar
1
clinvar
 6
Total00104195128
Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_015967.8RefSeqNP_057051.421MANE Select
ENST00000359785.10EnsemblENSP00000352833.521MANE Select
NM_001193431.3RefSeqNP_001180360.221Standard
NM_001308297.2RefSeqNP_001295226.220Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Phosphorylation of CD3 and TCR zeta chains
  • Translocation of ZAP-70 to Immunological synapse
  • TCR signaling
  • TCR
  • Immune System

Biological Process

  • protein dephosphorylation
  • autophagy
  • negative regulation of autophagy
  • positive regulation of gene expression
  • negative regulation of gene expression

Molecular Function

  • protein tyrosine phosphatase activity
  • protein binding
  • phosphatase activity
  • SH3 domain binding
  • kinase binding

Cellular Component

  • nucleus
  • cytoplasm
  • cytosol
  • cytoplasmic side of plasma membrane
  • perinuclear region of cytoplasm

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000359785
Coding exons
21
Length
57949
Individuals with no LoFs
125359
Homozygous LoFs
3
Heterozygous LoFs
385
Defined
125747
p
0.00154
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense0.8693564050.8780.00001915308
Missense (PolyPhen)93130.090.714891710
Synonymous-0.6221451361.070.000006041483
Loss of Function1.073643.70.8250.00000199587

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00120.0012notable
Latino/Admixed American0.000960.00084rare
Ashkenazi Jewish0.000110.000099rare
East Asian0.000830.00082rare
Finnish0.00400.0039notable
European (Non-Finnish)0.000470.00045rare
South Asian0.00600.0059notable
Other0.00160.0015notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Acts as negative regulator of T-cell receptor (TCR) signaling by direct dephosphorylation of the Src family kinases LCK and FYN, ITAMs of the TCRz/CD3 complex, as well as ZAP70, VAV, VCP and other key signaling molecules (PubMed:16461343, PubMed:18056643). Associates with and probably dephosphorylates CBL. Dephosphorylates LCK at its activating 'Tyr-394' residue (PubMed:21719704). Dephosphorylates ZAP70 at its activating 'Tyr- 493' residue (PubMed:16461343). Dephosphorylates the immune system activator SKAP2 (PubMed:21719704). Positively regulates toll-like receptor (TLR)-induced type 1 interferon production (PubMed:23871208). Promotes host antiviral responses mediated by type 1 interferon (By similarity). Regulates NOD2-induced pro- inflammatory cytokine secretion and autophagy (PubMed:23991106). {ECO:0000250|UniProtKB:P29352, ECO:0000269|PubMed:16461343, ECO:0000269|PubMed:18056643, ECO:0000269|PubMed:19167335, ECO:0000269|PubMed:21719704, ECO:0000269|PubMed:23871208, ECO:0000269|PubMed:23991106}.;
Disease
DISEASE: Systemic lupus erythematosus (SLE) [MIM:152700]: A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. {ECO:0000269|PubMed:15273934}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Diabetes mellitus, insulin-dependent (IDDM) [MIM:222100]: A multifactorial disorder of glucose homeostasis that is characterized by susceptibility to ketoacidosis in the absence of insulin therapy. Clinical features are polydipsia, polyphagia and polyuria which result from hyperglycemia-induced osmotic diuresis and secondary thirst. These derangements result in long-term complications that affect the eyes, kidneys, nerves, and blood vessels. {ECO:0000269|PubMed:15004560}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Rheumatoid arthritis (RA) [MIM:180300]: An inflammatory disease with autoimmune features and a complex genetic component. It primarily affects the joints and is characterized by inflammatory changes in the synovial membranes and articular structures, widespread fibrinoid degeneration of the collagen fibers in mesenchymal tissues, and by atrophy and rarefaction of bony structures. {ECO:0000269|PubMed:15208781}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.; DISEASE: Vitiligo (VTLG) [MIM:193200]: A pigmentary disorder of the skin and mucous membranes. It is characterized by circumscribed depigmented macules and patches, commonly on extensor aspects of extremities, on the face or neck and in skin folds. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. It is a multifactorial disorder with a complex etiology probably including autoimmune mechanisms, and is associated with an elevated risk of other autoimmune diseases. {ECO:0000269|PubMed:16015369}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.355

Intolerance Scores

LoFtool
0.607
RVIS EVS
0.27
RVIS percentile EVS
70.64

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.322

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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