RIPK1

Chr 6ADAR

receptor interacting serine/threonine kinase 1

Also known as: AIEFL, IMD57, RIP, RIP-1, RIP1

NCBI Gene: 8737 ENSG00000137275 UniProt: Q13546 OMIM: 603453

The protein is a serine-threonine kinase that regulates TNF-mediated cell death pathways (apoptosis and necroptosis) and inflammatory signaling, functioning both as an enzyme and scaffold protein in cellular survival and immune responses. Mutations cause autoinflammation with episodic fever and lymphadenopathy or immunodeficiency with autoinflammation, following either autosomal dominant or autosomal recessive inheritance patterns. The gene shows high constraint against loss-of-function variants (LOEUF 0.554), reflecting its essential role in development and immune regulation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Autoinflammation with episodic fever and lymphadenopathyMIM #618852

Immunodeficiency 57 with autoinflammationMIM #618108

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · immunodeficiency 57 · AR · ClinGen 2025

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

759

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.55

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.008

Z-score 3.37

OE 0.32 (0.19–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.56Z-score

OE missense 0.77 (0.70–0.85)

293 obs / 378.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.32 (0.19–0.55)

0≤0.351.4

Missense OE?0.77 (0.70–0.85)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 9 / 28.3Missense obs/exp: 293 / 378.5Syn Z: 1.08

Background carrier burden — how many people carry a rare variant somewhere in RIPK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 90

791 rare PASS variants

Rare truncating (LoF)

1 in 4,000

66 rare PASS variants

Rare synonymous (reference)

1 in 120

309 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RIPK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 100	1 in 4,000
South Asian	~43k	1 in 89	1 in 3,100
Remaining (unassigned)	~30k	1 in 75	≈ 1 in 30,000
European (Finnish)	~27k	1 in 380	1 in 2,200
Admixed American	~22k	1 in 74	≈ 1 in 4,500
African / African American	~21k	1 in 72	≈ 1 in 6,400
East Asian	~20k	1 in 100	≈ 1 in 18,000
Ashkenazi Jewish	~13k	1 in 2,100	none seen
Middle Eastern	~2,884	1 in 170	≈ 1 in 2,900

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 8 of 10 coding exons well covered in gnomAD exomes; exons 7, 8 marginal. Genomes: 9 of 10 (exon 2 below).? see exons ↓