RIPK2
protein-codingreceptor interacting serine/threonine kinase 2, the group of Caspase recruitment domain containing
Gene summary
This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein contains a C-terminal caspase activation and recruitment domain (CARD), and is a component of signaling complexes in both the innate and adaptive immune pathways. It is a potent activator of NF-kappaB and inducer of apoptosis in response to various stimuli. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~33.3 kbGenCC 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 RIPK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_003821.6. 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 | 1 | 2 | |||
| missense | 48 | 4 | 1 | 53 | ||
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 8 | 8 | ||||
| Total | 0 | 0 | 56 | 5 | 2 | 63 |
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_003812.1 | 11 | MANE Select | |
| Ensembl | ENSP00000220751.4 | 11 | MANE Select | |
| RefSeq | NP_001362289.1 | 9 | Standard | |
| Ensembl | ENSP00000427736.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neurotrophin signaling pathway - Homo sapiens (human)
- NOD-like receptor signaling pathway - Homo sapiens (human)
- Tuberculosis - Homo sapiens (human)
- Shigellosis - Homo sapiens (human)
- Nucleotide-binding Oligomerization Domain (NOD) pathway
Biological Process
- MAPK cascade
- activation of MAPK activity
- positive regulation of cytokine-mediated signaling pathway
- adaptive immune response
- apoptotic process
Molecular Function
- protein serine/threonine kinase activity
- JUN kinase kinase kinase activity
- non-membrane spanning protein tyrosine kinase activity
- signaling receptor binding
- protein binding
Cellular Component
- cytoplasm
- cytosol
- cytoskeleton
- vesicle
- protein-containing complex
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000220751
- Coding exons
- 11
- Length
- 33317
- Individuals with no LoFs
- 125646
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 6
- Defined
- 125652
- p
- 0.0000239
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 2.16 | 172 | 272 | 0.632 | 0.0000127 | 3518 |
| Missense (PolyPhen) | 41 | 120.54 | 0.34014 | 1569 | ||
| Synonymous | 1.20 | 81 | 95.9 | 0.845 | 0.00000445 | 1010 |
| Loss of Function | 3.73 | 6 | 26.8 | 0.224 | 0.00000138 | 345 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0.000032 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000027 | 0.000026 | rare |
| South Asian | 0.000066 | 0.000065 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Serine/threonine/tyrosine kinase that plays an essential role in modulation of innate and adaptive immune responses. Upon stimulation by bacterial peptidoglycans, NOD1 and NOD2 are activated, oligomerize and recruit RIPK2 through CARD-CARD domains. Contributes to the tyrosine phosphorylation of the guanine exchange factor ARHGEF2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Once recruited, RIPK2 autophosphorylates and undergoes 'Lys-63'-linked polyubiquitination by E3 ubiquitin ligases XIAP, BIRC2 and BIRC3. The polyubiquitinated protein mediates the recruitment of MAP3K7/TAK1 to IKBKG/NEMO and induces 'Lys-63'-linked polyubiquitination of IKBKG/NEMO and subsequent activation of IKBKB/IKKB. In turn, NF-kappa-B is released from NF-kappa-B inhibitors and translocates into the nucleus where it activates the transcription of hundreds of genes involved in immune response, growth control, or protection against apoptosis. Plays also a role during engagement of the T-cell receptor (TCR) in promoting BCL10 phosphorylation and subsequent NF-kappa-B activation. {ECO:0000269|PubMed:14638696, ECO:0000269|PubMed:17054981, ECO:0000269|PubMed:18079694, ECO:0000269|PubMed:21123652, ECO:0000269|PubMed:21887730}.;
Recessive Scores
- pRec
- 0.232
Intolerance Scores
- LoFtool
- 0.490
- RVIS EVS
- 0.42
- RVIS percentile EVS
- 76.96
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.918
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |