RIPK1

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

Basic information

Region (hg38): 6:3063823-3115187

Links

ENSG00000137275 ∙ NCBI:8737 ∙ OMIM:603453 ∙ HGNC:10019 ∙ Uniprot:Q13546 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

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

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Autoinflammation with episodic fever and lymphadenopathy; Immunodeficiency 57 with autoinflammation	AD/AR	Allergy/Immunology/Infectious	Autoinflammation 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 described	Allergy/Immunology/Infectious; Gastrointestinal	30026316; 31827280; 31827281

ClinVar

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

• not provided (6 variants)
• Immunodeficiency 57 (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			1	100	4	105
missense			203	4	2	209
nonsense	2		1			3
start loss			1			1
frameshift	5	1	1			7
inframe indel			3			3
splice donor/acceptor (+/-2bp)		2				2
splice region			6	6		12
non coding			1	37	4	42
Total	7	3	211	141	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)
6-3076850-C-G			Likely benign (Dec 18, 2023)
6-3076863-T-G			Likely benign (Oct 31, 2023)
6-3076864-C-T			Uncertain significance (Jun 14, 2022)
6-3076865-C-T			Likely benign (Jan 13, 2024)
6-3076894-A-C			Uncertain significance (May 25, 2022)
6-3076898-C-T			Likely benign (Dec 11, 2023)
6-3076899-G-A			Uncertain significance (Jul 05, 2022)
6-3076905-T-C		Immunodeficiency 57;Autoinflammation with episodic fever and lymphadenopathy	Uncertain significance (Jan 28, 2024)
6-3076905-TTT-CTC		RIPK1-related disorder	Uncertain significance (Jan 02, 2024)
6-3076907-T-C		Autoinflammation with episodic fever and lymphadenopathy • Immunodeficiency 57 • not specified	Benign (Feb 01, 2024)
6-3076907-TG-CA			Uncertain significance (Oct 25, 2022)
6-3076918-C-T			Uncertain significance (Dec 19, 2023)
6-3076922-G-A			Likely benign (Jul 06, 2022)
6-3076937-C-T			Likely benign (Jun 05, 2022)
6-3076940-G-A			Likely benign (Sep 24, 2022)
6-3076949-G-A			Uncertain significance (Jul 19, 2022)
6-3076950-A-T			Uncertain significance (Oct 16, 2023)
6-3076953-A-C			Uncertain significance (Nov 20, 2023)
6-3076963-T-C		Inborn genetic diseases	Uncertain significance (Nov 29, 2023)
6-3076967-C-T			Likely benign (May 26, 2021)
6-3076973-G-A			Likely benign (Oct 13, 2023)
6-3076974-C-T			Uncertain significance (Mar 26, 2021)
6-3076978-A-G		Inborn genetic diseases	Uncertain significance (Nov 18, 2023)
6-3076984-T-C			Uncertain significance (Aug 17, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
RIPK1	protein_coding	protein_coding	ENST00000259808	10	51197

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00794	0.992	125732	0	16	125748	0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.56	293	378	0.774	0.0000201	4483
Missense in Polyphen		88	138.69	0.63452		1618
Synonymous	1.08	131	148	0.887	0.00000914	1223
Loss of Function	3.37	9	28.3	0.318	0.00000128	364

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000580	0.0000580
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.000115	0.000114
Middle Eastern	0.00	0.00
South Asian	0.00	0.00
Other	0.00	0.00

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
• gene_indispensability_pred: E
• gene_indispensability_score: 0.789

Gene Damage Prediction

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

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