RIPK1

protein-coding

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

Gene summary

This gene encodes a member of the receptor-interacting protein (RIP) family of serine/threonine protein kinases. The encoded protein plays a role in inflammation and cell death in response to tissue damage, pathogen recognition, and as part of developmental regulation. RIPK1/RIPK3 kinase-mediated necrosis is referred to as necroptosis. Genetic disruption of this gene in mice results in death shortly after birth. [provided by RefSeq, Aug 2017]

MANE transcript

NM_001354930.2

Inheritance

AR, AD

ClinVar variants

P:34U:320B:151

Top phenotype

Autoinflammation with episodic fever and lymphadenopathy; Immunodeficiency 57 with autoinflammation

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr6:3,063,824-3,115,187

External References & Databases

Ensembl (ENSG00000137275)

Transcript & Mutation Effects

hg38 • Region Span ~51.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

immunodeficiency 57DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020849

Submitter: ClinGen

*RIPK1* was first reported in relation to autosomal recessive immunodeficiency 57 in 2018 (Cuchet-Lourenço et al., PMID: 30026316). The condition is characterized by recurrent bacterial, viral and fungal infections since early childhood, as well as early-onset inflammatory bowel disease and autoinflammatory arthritis. T-cell lymphopenia is typically observed, while B-cell and NK cell counts may be normal or decreased. At least 11 variants (4 missense, 4 nonsense, 1 frameshift, 2 large deletions) have been reported in 13 probands in 5 publications (PMIDs: 30026316, 30591564, 31213653, 32181283, 36466854) that are included in this curation. All patients invariably present with recurrent infection and inflammatory bowel disease during early childhood. The maximum score for genetic evidence (12 pts.) has been reached with all reported cases. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by animal models, biochemical function studies, and in vitro functional assays (PMIDs: 24813849, 24821786, 30026316, 30591564). Studies robustly show that *RIPK1* is involved in MAPK p38 phosphorylation and subsequent stimulation of the production of IL-6, IL-10, TNF-α and IL-12; loss of RIPK1 also leads to excessive production of the proinflammatory cytokine IL-1β. In summary, there is definitive evidence supporting the relationship between *RIPK1* and autosomal recessive immunodeficiency 57. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Primary Immune Regulatory Disorders GCEP on the meeting date 09/16/2025 (SOP Version 11).

immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0033968

Submitter: Orphanet

autoinflammation with episodic fever and lymphadenopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030018

Submitter: Labcorp Genetics (formerly Invitae)

immunodeficiency 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020849

Submitter: Labcorp Genetics (formerly Invitae)

autoinflammation with episodic fever and lymphadenopathySTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030018

Submitter: PanelApp Australia

immunodeficiency 57STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0020849

Submitter: PanelApp Australia

immunodeficiency 57DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0020849

Submitter: Ambry Genetics

autoinflammation with episodic fever and lymphadenopathyMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0030018

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Autoinflammation with episodic fever and lymphadenopathy; Immunodeficiency 57 with autoinflammationAD/AR

Manifestation: Allergy/Immunology/Infectious; Gastrointestinal

Intervention: Allergy/Immunology/Infectious

Rationale: 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

Refs: 30026316; 31827280; 31827281

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to RIPK1 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 513

Inborn genetic diseasesTotal: 95

not specifiedTotal: 48

Immunodeficiency 57Total: 26

RIPK1-related disorderTotal: 24

Autoinflammation with episodic fever and lymphadenopathyTotal: 13

IL10-related early-onset inflammatory bowel diseaseTotal: 5

Inborn error of immunityTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001354930.2. 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	134 clinvar	1 clinvar	137
missense	6 clinvar	4 clinvar	312 clinvar	16 clinvar		338
nonsense	4 clinvar	1 clinvar	1 clinvar			6
start loss			2 clinvar			2
frameshift	6 clinvar	5 clinvar	2 clinvar			13
splice donor/acceptor (+/-2bp)	2 clinvar	6 clinvar	1 clinvar			9
Total	18	16	320	150	1	505

Highest pathogenic variant AF is 0.00011709326

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001354930.2	RefSeq	NP_001341859.1	10	MANE Select
ENST00000259808.9	Ensembl	ENSP00000259808.3	10	MANE Select
NM_001317061.3	RefSeq	NP_001303990.1	7	Standard
NM_001354931.2	RefSeq	NP_001341860.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

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)

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

Molecular Function

protein kinase activity
protein serine/threonine kinase activity
JUN kinase kinase kinase activity
death receptor binding
protein binding

Cellular Component

mitochondrion
cytosol
endosome membrane
death-inducing signaling complex
receptor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000259808
Coding exons: 10
Length: 51197
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.56	293	378	0.774	0.0000201	4483
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000058	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.314

Intolerance Scores

LoFtool: 0.387
RVIS EVS: -1.35
RVIS percentile EVS: 4.58

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.789

Gene Damage Prediction

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