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RIPK1

receptor interacting serine/threonine kinase 1, the group of Ripoptosome

Basic information

Region (hg38): 6:3063823-3115187

Links

ENSG00000137275NCBI:8737OMIM:603453HGNC:10019Uniprot:Q13546AlphaFoldGenCCjaxSfariGnomADPubmedClinVar

Phenotypes

GenCC

Source: genCC

  • immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome (Supportive), mode of inheritance: AR
  • autoinflammation with episodic fever and lymphadenopathy (Strong), mode of inheritance: AD
  • immunodeficiency 57 (Strong), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

ConditionInheritanceIntervention CategoriesIntervention/Rationale Manifestation CategoriesReferences
Autoinflammation with episodic fever and lymphadenopathy; Immunodeficiency 57 with autoinflammationAD/ARAllergy/Immunology/InfectiousAutoinflammation with episodic fever and lymphadenopathy may involve recurrent fevers and accompanying symptoms, and medical management (eg, with anti-IL6R treatment) has been desrcribed as beneficial; Immunodeficiency 57 can include early-onset, recurrent bacterial, viral, and fungal infections, and awareness preventative measures and early and aggressive treatment of infections (e.g., IVIG has been described as beneficial); HSCT has been describedAllergy/Immunology/Infectious; Gastrointestinal30026316; 31827280; 31827281

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the RIPK1 gene.

  • not provided (292 variants)
  • Inborn genetic diseases (25 variants)
  • Immunodeficiency 57 (8 variants)
  • See cases (4 variants)
  • RIPK1-related condition (3 variants)
  • Immunodeficiency 57;Autoinflammation with episodic fever and lymphadenopathy (3 variants)
  • not specified (2 variants)
  • Autoinflammation with episodic fever and lymphadenopathy (2 variants)
  • Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections syndrome;Inborn error of immunity (1 variants)
  • Hereditary breast ovarian cancer syndrome (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the RIPK1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type Pathogenic Likely pathogenic VUS Likely benign Benign Sum
synonymous
81
clinvar
4
clinvar
85
missense
160
clinvar
3
clinvar
2
clinvar
165
nonsense
2
clinvar
2
start loss
1
clinvar
1
frameshift
3
clinvar
1
clinvar
1
clinvar
5
inframe indel
3
clinvar
3
splice donor/acceptor (+/-2bp)
1
clinvar
1
splice region
5
4
9
non coding
1
clinvar
28
clinvar
4
clinvar
33
Total 5 2 166 112 10

Variants in RIPK1

This is a list of pathogenic ClinVar variants found in the RIPK1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position Type Phenotype Significance ClinVar
6-3076825-T-A Uncertain significance (Mar 20, 2021)1432706
6-3076850-C-G Likely benign (Dec 18, 2023)1533206
6-3076863-T-G Likely benign (Oct 31, 2023)1610301
6-3076864-C-T Uncertain significance (Jun 14, 2022)2006477
6-3076865-C-T Likely benign (Jan 13, 2024)1580741
6-3076894-A-C Uncertain significance (May 25, 2022)1999073
6-3076898-C-T Likely benign (Dec 11, 2023)2200552
6-3076899-G-A Uncertain significance (Jul 05, 2022)2099403
6-3076905-T-C Immunodeficiency 57;Autoinflammation with episodic fever and lymphadenopathy Uncertain significance (Jan 28, 2024)1445799
6-3076905-TTT-CTC RIPK1-related condition Uncertain significance (Jan 02, 2024)3061239
6-3076907-T-C not specified • Immunodeficiency 57 • Autoinflammation with episodic fever and lymphadenopathy Benign (Feb 01, 2024)1166905
6-3076907-TG-CA Uncertain significance (Oct 25, 2022)1520162
6-3076918-C-T Uncertain significance (Dec 19, 2023)2980626
6-3076922-G-A Likely benign (Jul 06, 2022)1153124
6-3076937-C-T Likely benign (Jun 05, 2022)2046084
6-3076940-G-A Likely benign (Sep 24, 2022)1900774
6-3076949-G-A Uncertain significance (Jul 19, 2022)1523087
6-3076950-A-T Uncertain significance (Oct 16, 2023)809859
6-3076953-A-C Uncertain significance (Nov 20, 2023)2697539
6-3076967-C-T Likely benign (May 26, 2021)1661610
6-3076973-G-A Likely benign (Oct 13, 2023)2021608
6-3076974-C-T Uncertain significance (Mar 26, 2021)1405393
6-3076978-A-G Inborn genetic diseases Uncertain significance (Nov 18, 2023)2164101
6-3076984-T-C Uncertain significance (Aug 17, 2023)2105213
6-3077000-CA-C Benign (Dec 21, 2023)1658447

GnomAD

Source: gnomAD

GeneTypeBio TypeTranscript Coding Exons Length
RIPK1protein_codingprotein_codingENST00000259808 1051197
pLI Probability
LOF Intolerant
pRec Probability
LOF Recessive
Individuals with
no LOFs
Individuals with
Homozygous LOFs
Individuals with
Heterozygous LOFs
Defined p
0.007940.9921257320161257480.0000636
Z-Score Observed Expected Observed/Expected Mutation Rate Total Possible in Transcript
Missense1.562933780.7740.00002014483
Missense in Polyphen88138.690.634521618
Synonymous1.081311480.8870.000009141223
Loss of Function3.37928.30.3180.00000128364

LoF frequencies by population

EthnicitySum of pLOFs p
African & African-American0.00005800.0000580
Ashkenazi Jewish0.000.00
East Asian0.000.00
Finnish0.00004620.0000462
European (Non-Finnish)0.0001150.000114
Middle Eastern0.000.00
South Asian0.000.00
Other0.000.00

dbNSFP

Source: dbNSFP

Function
FUNCTION: Serine-threonine kinase which transduces inflammatory and cell-death signals (programmed necrosis) following death receptors ligation, activation of pathogen recognition receptors (PRRs), and DNA damage (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Upon activation of TNFR1 by the TNF-alpha family cytokines, TRADD and TRAF2 are recruited to the receptor (PubMed:11101870, PubMed:17389591, PubMed:19524512, PubMed:19524513). Phosphorylates DAB2IP at 'Ser-728' in a TNF- alpha-dependent manner, and thereby activates the MAP3K5-JNK apoptotic cascade (PubMed:17389591). Ubiquitination by TRAF2 via 'Lys-63'-link chains acts as a critical enhancer of communication with downstream signal transducers in the mitogen-activated protein kinase pathway and the NF-kappa-B pathway, which in turn mediate downstream events including the activation of genes encoding inflammatory molecules (PubMed:15258597). Polyubiquitinated protein binds to IKBKG/NEMO, the regulatory subunit of the IKK complex, a critical event for NF-kappa-B activation. Interaction with other cellular RHIM-containing adapters initiates gene activation and cell death (PubMed:15258597). RIPK1 and RIPK3 association, in particular, forms a necrosis-inducing complex (PubMed:19524513, PubMed:19524512). {ECO:0000269|PubMed:11101870, ECO:0000269|PubMed:15258597, ECO:0000269|PubMed:17389591, ECO:0000269|PubMed:19524512, ECO:0000269|PubMed:19524513}.;
Pathway
TNF signaling pathway - Homo sapiens (human);Cytosolic DNA-sensing pathway - Homo sapiens (human);Necroptosis - Homo sapiens (human);Toll-like receptor signaling pathway - Homo sapiens (human);NOD-like receptor signaling pathway - Homo sapiens (human);Hepatitis C - Homo sapiens (human);Apoptosis - Homo sapiens (human);NF-kappa B signaling pathway - Homo sapiens (human);Epstein-Barr virus infection - Homo sapiens (human);RIG-I-like receptor signaling pathway - Homo sapiens (human);Regulation of toll-like receptor signaling pathway;Apoptosis Modulation and Signaling;TNF related weak inducer of apoptosis (TWEAK) Signaling Pathway;TNF alpha Signaling Pathway;Integrated Lung Cancer Pathway;Nanoparticle triggered regulated necrosis;Apoptosis;Apoptotic Signaling Pathway;Apoptosis Modulation by HSP70;RIG-I-like Receptor Signaling;p38 MAPK Signaling Pathway;Toll-like Receptor Signaling Pathway;TWEAK;Signal Transduction;tnfr1 signaling pathway;tnfr2 signaling pathway;induction of apoptosis through dr3 and dr4/5 death receptors;hiv-1 nef: negative effector of fas and tnf;tnf/stress related signaling;nf-kb signaling pathway;keratinocyte differentiation;TICAM1, RIP1-mediated IKK complex recruitment ;Toll Like Receptor 3 (TLR3) Cascade;ZBP1(DAI) mediated induction of type I IFNs;Toll-Like Receptors Cascades;NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10;Post-translational protein modification;DDX58/IFIH1-mediated induction of interferon-alpha/beta;Metabolism of proteins;Regulation of necroptotic cell death;Dimerization of procaspase-8;Regulation by c-FLIP;Ligand-dependent caspase activation;Caspase activation via extrinsic apoptotic signalling pathway;Innate Immune System;Immune System;Apoptosis;CASP8 activity is inhibited;Regulated Necrosis;Programmed Cell Death;RIPK1-mediated regulated necrosis;ceramide signaling pathway;RIP-mediated NFkB activation via ZBP1;IL-7 signaling;TNFR1-induced NFkappaB signaling pathway;TNFR1-induced proapoptotic signaling;EGFR1;TNF signaling;TLR3-mediated TICAM1-dependent programmed cell death;sodd/tnfr1 signaling pathway;Ub-specific processing proteases;JAK STAT pathway and regulation;Ovarian tumor domain proteases;Deubiquitination;EPO signaling;Death Receptor Signalling;Regulation of TNFR1 signaling;TNFalpha;Cytosolic sensors of pathogen-associated DNA ;IKK complex recruitment mediated by RIP1;TRIF-mediated programmed cell death;TRIF(TICAM1)-mediated TLR4 signaling ;MyD88-independent TLR4 cascade ;Toll Like Receptor 4 (TLR4) Cascade;TNF;VEGF;Caspase Cascade in Apoptosis;HIV-1 Nef: Negative effector of Fas and TNF-alpha;TRAIL signaling pathway;TNF receptor signaling pathway ;Regulation of p38-alpha and p38-beta;FAS (CD95) signaling pathway;Ceramide signaling pathway (Consensus)

Recessive Scores

pRec
0.314

Intolerance Scores

loftool
0.387
rvis_EVS
-1.35
rvis_percentile_EVS
4.58

Haploinsufficiency Scores

pHI
0.130
hipred
Y
hipred_score
0.601
ghis
0.568

Essentials

essential_gene_CRISPR
N
essential_gene_CRISPR2
N
essential_gene_gene_trap
gene_indispensability_pred
E
gene_indispensability_score
0.789

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium

Mouse Genome Informatics

Gene name
Ripk1
Phenotype
digestive/alimentary phenotype; immune system phenotype; liver/biliary system phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); hematopoietic system phenotype; growth/size/body region phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); homeostasis/metabolism phenotype; cellular phenotype; endocrine/exocrine gland phenotype;

Gene ontology

Biological process
MAPK cascade;positive regulation of protein phosphorylation;MyD88-independent toll-like receptor signaling pathway;apoptotic process;activation of cysteine-type endopeptidase activity involved in apoptotic process;I-kappaB kinase/NF-kappaB signaling;activation of JNKK activity;activation of JUN kinase activity;regulation of tumor necrosis factor-mediated signaling pathway;positive regulation of necrotic cell death;viral process;protein deubiquitination;positive regulation of interleukin-8 production;positive regulation of tumor necrosis factor production;tumor necrosis factor-mediated signaling pathway;toll-like receptor 3 signaling pathway;response to tumor necrosis factor;TRIF-dependent toll-like receptor signaling pathway;peptidyl-serine autophosphorylation;positive regulation of apoptotic process;positive regulation of programmed cell death;positive regulation of I-kappaB kinase/NF-kappaB signaling;negative regulation of I-kappaB kinase/NF-kappaB signaling;cellular protein catabolic process;positive regulation of macrophage differentiation;positive regulation of transcription by RNA polymerase II;positive regulation of JNK cascade;protein autophosphorylation;positive regulation of NF-kappaB transcription factor activity;protein homooligomerization;protein heterooligomerization;positive regulation of necroptotic process;T cell apoptotic process;necroptotic process;regulation of ATP:ADP antiporter activity;cellular response to tumor necrosis factor;cellular response to growth factor stimulus;death-inducing signaling complex assembly;apoptotic signaling pathway;extrinsic apoptotic signaling pathway;ripoptosome assembly;necroptotic signaling pathway;ripoptosome assembly involved in necroptotic process;regulation of extrinsic apoptotic signaling pathway via death domain receptors;negative regulation of extrinsic apoptotic signaling pathway via death domain receptors;positive regulation of hydrogen peroxide-induced cell death;amyloid fibril formation;positive regulation of reactive oxygen species metabolic process;negative regulation of extrinsic apoptotic signaling pathway;positive regulation of extrinsic apoptotic signaling pathway;negative regulation of extrinsic apoptotic signaling pathway in absence of ligand
Cellular component
mitochondrion;cytosol;endosome membrane;death-inducing signaling complex;receptor complex;membrane raft;ripoptosome
Molecular function
protein kinase activity;protein serine/threonine kinase activity;JUN kinase kinase kinase activity;death receptor binding;protein binding;ATP binding;ubiquitin protein ligase binding;identical protein binding;protein-containing complex binding;death domain binding