Immunodeficiency 57

Summary

Immunodeficiency 57 (MONDO:0020849) is a disease caused by RIPK1 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: RIPK1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 22

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	immunodeficiency 57
Mondo ID	MONDO:0020849
OMIM	618108
DOID	DOID:0111952
UMLS	C4748212
MedGen	1648306
Is cancer (heuristic)	no

Also known as: IMD57 · immunodeficiency 57 with autoinflammation

Data availability: 22 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › immunodeficiency disease › immunodeficiency 57

Related subtypes (94): B cell deficiency, T-cell immunodeficiency, complement deficiency, myalgic encephalomeyelitis/chronic fatigue syndrome, hypoproteinemia, hypercatabolic, X-linked lymphoproliferative syndrome, Wiskott-Aldrich syndrome, autosomal dominant form, immunodeficiency due to CD25 deficiency, immunodeficiency 67, primary immunodeficiency with natural-killer cell deficiency and adrenal insufficiency, immunodeficiency 35, pyogenic bacterial infections due to MyD88 deficiency, lymphoproliferative syndrome 1, FADD-related immunodeficiency, immunodeficiency 31B, Wiskott-Aldrich syndrome 2, cryptosporidiosis-chronic cholangitis-liver disease syndrome, idiopathic CD4 lymphocytopenia, immunodeficiency 23, DOCK2 deficiency, immunodeficiency 45, TFRC-related combined immunodeficiency, combined immunodeficiency, autoimmune hemolytic anemia-autoimmune thrombocytopenia-primary immunodeficiency syndrome, immunodeficiency due to selective anti-polysaccharide antibody deficiency, immunodeficiency 14b, autosomal recessive, immunodeficiency 98 with autoinflammation, X-linked, immunodeficiency 102, immunodeficiency 74, COVID-19-related, X-linked, immunodeficiency 66, immunodeficiency 80 with or without congenital cardiomyopathy, immunodeficiency 81, immunodeficiency 82 with systemic inflammation, immunodeficiency 84, immunodeficiency 85 and autoimmunity, immunodeficiency 86, immunodeficiency 87 and autoimmunity, immunodeficiency 88, immunodeficiency 89 and autoimmunity, immunodeficiency 91 and hyperinflammation, immunodeficiency 92, immunodeficiency 93 and hypertrophic cardiomyopathy, immunodeficiency 95, immunodeficiency 96, immunodeficiency 97 with autoinflammation, immunodeficiency 99 with hypogammaglobulinemia and autoimmune cytopenias, immunodeficiency 101 (varicella zoster virus-specific), immunodeficiency 75, immunodeficiency 76, immunodeficiency 106, susceptibility to viral infections, immunodeficiency 78 with autoimmunity and developmental delay, immunodeficiency 77, immunodeficiency 107, susceptibility to invasive staphylococcus aureus infection, immunodeficiency 15a, immunodeficiency 60, immunodeficiency 62, immunodeficiency 63 with lymphoproliferation and autoimmunity, immunodeficiency 64, immunodeficiency 65, susceptibility to viral infections, immunodeficiency 69, immunodeficiency 70, immunodeficiency 72 with autoinflammation, GATA2 deficiency with susceptibility to MDS/AML, Shwachman-Diamond syndrome 1, immunodeficiency 53, immunodeficiency 11b with atopic dermatitis, IKBKG-related immunodeficiency with or without ectodermal dysplasia, FNIP1-associated syndrome, FASLG-related immunodeficiency, TNFRSF9-related immunodeficiency, DNAJC21-related Shwachman Diamond syndrome, IRF4-related immune disorder, PTEN harmartoma tumor syndrome with immune disorder, primary immunodeficiency due to calcium channel deficiency, chronic mucocutaneous candidiasis and connective tissue disease due to JNK1 haploinsufficiency, immune deficiency due to impaired neutrophil phagocytosis and migration, hatipoglu immunodeficiency syndrome, immunodeficiency 112, immunodeficiency 113 with autoimmunity and autoinflammation, immunodeficiency 114, folate-responsive, immunodeficiency 115 with autoinflammation, immunodeficiency 117, immunodeficiency 118, immunodeficiency 119, immunodeficiency 121 with autoinflammation, immunodeficiency 122, immunodeficiency 123 with HPV-related verrucosis, immunodeficiency 125, immunodeficiency 126, susceptibility to, immunodeficiency 127, immunodeficiency 128, immunodeficiency 132b, immunodeficiency 133 with ectodermal dysplasia with or without peripheral neuropathy, immunodeficiency 134 (Epstein-Barr virus-specific)

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

22 retrieved; paginated sample, class counts are floors:

7 conflicting classifications of pathogenicity, 7 uncertain significance, 5 pathogenic, 1 benign, 1 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1457300	NM_001354930.2(RIPK1):c.528_532del (p.Arg177fs)	RIPK1	Pathogenic	criteria provided, multiple submitters, no conflicts
561164	NM_001354930.2(RIPK1):c.867_870del (p.Phe288_Tyr289insTer)	RIPK1	Pathogenic	no assertion criteria provided
561165	NM_001354930.2(RIPK1):c.688_688+20del	RIPK1	Pathogenic	no assertion criteria provided
561166	NM_001354930.2(RIPK1):c.460-133_689-244del	RIPK1	Pathogenic	no assertion criteria provided
598790	NM_001354930.2(RIPK1):c.954del (p.Met318fs)	RIPK1	Pathogenic/Likely pathogenic	no assertion criteria provided
1929382	NM_006929.5(SKIC2):c.2479C>T (p.Arg827Ter)	SKIC2	Pathogenic	criteria provided, multiple submitters, no conflicts
1029752	NM_001354930.2(RIPK1):c.1194G>C (p.Gln398His)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029754	NM_001354930.2(RIPK1):c.931G>A (p.Glu311Lys)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1409194	NM_001354930.2(RIPK1):c.607G>T (p.Ala203Ser)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1536099	NM_001354930.2(RIPK1):c.1335T>A (p.His445Gln)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1806739	NM_001354930.2(RIPK1):c.1966T>C (p.Cys656Arg)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1961792	NM_001354930.2(RIPK1):c.1682_1683insAAAA (p.Asn561fs)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
598788	NM_001354930.2(RIPK1):c.1934C>T (p.Thr645Met)	RIPK1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029753	NM_001354930.2(RIPK1):c.464C>G (p.Ala155Gly)	RIPK1	Uncertain significance	criteria provided, single submitter
1034027	NM_001354930.2(RIPK1):c.1862G>A (p.Arg621Gln)	RIPK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1368739	NM_001354930.2(RIPK1):c.368T>C (p.Ile123Thr)	RIPK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1445799	NM_001354930.2(RIPK1):c.82T>C (p.Phe28Leu)	RIPK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2810139	NM_001354930.2(RIPK1):c.1122_1123delinsAA (p.Gln375Lys)	RIPK1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3892289	NM_001354930.2(RIPK1):c.665T>C (p.Phe222Ser)	RIPK1	Uncertain significance	criteria provided, single submitter
4813553	NM_001354930.2(RIPK1):c.271_273del (p.Val91del)	RIPK1	Uncertain significance	criteria provided, single submitter
1166905	NM_001354930.2(RIPK1):c.84T>C (p.Phe28=)	RIPK1	Benign	criteria provided, multiple submitters, no conflicts
712317	NM_001354930.2(RIPK1):c.1935G>A (p.Thr645=)	RIPK1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RIPK1	Definitive	Autosomal recessive	immunodeficiency 57	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RIPK1	Orphanet:529977	Immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome
SKIC2	Orphanet:84064	Trichohepatoenteric syndrome

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RIPK1	HGNC:10019	ENSG00000137275	Q13546	Receptor-interacting serine/threonine-protein kinase 1	gencc,clinvar
SKIC2	HGNC:10898	ENSG00000204351	Q15477	Superkiller complex protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RIPK1	Receptor-interacting serine/threonine-protein kinase 1	Serine-threonine kinase which is a key regulator of TNF-mediated apoptosis, necroptosis and inflammatory pathways.
SKIC2	Superkiller complex protein 2	Helicase component of the SKI complex, a multiprotein complex that assists the RNA-degrading exosome during the mRNA decay and quality-control pathways.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RIPK1	Kinase	yes	2.7.10.2	Death_dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
SKIC2	Other/Unknown	no		Helicase_C-like, DEAD/DEAH_box_helicase_dom, Ski2/MTR4_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	2
granulocyte	1
sural nerve	1
adenohypophysis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RIPK1	238	ubiquitous	marker	granulocyte, sural nerve, right lobe of liver
SKIC2	134	ubiquitous	yes	right lobe of liver, pituitary gland, adenohypophysis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RIPK1	4,129
SKIC2	2,818

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RIPK1	Q13546	39
SKIC2	Q15477	11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 31. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
SARS-CoV-1-mediated effects on programmed cell death	1	1903.3×	0.007	RIPK1
Microbial modulation of RIPK1-mediated regulated necrosis	1	1427.5×	0.007	RIPK1
TLR3-mediated TICAM1-dependent programmed cell death	1	951.7×	0.007	RIPK1
Defective RIPK1-mediated regulated necrosis	1	951.7×	0.007	RIPK1
TRIF-mediated programmed cell death	1	634.4×	0.007	RIPK1
Regulation by c-FLIP	1	519.1×	0.007	RIPK1
CASP8 activity is inhibited	1	519.1×	0.007	RIPK1
Dimerization of procaspase-8	1	519.1×	0.007	RIPK1
Deadenylation-dependent mRNA decay	1	439.2×	0.007	SKIC2
NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10	1	439.2×	0.007	RIPK1
Caspase activation via Death Receptors in the presence of ligand	1	380.7×	0.007	RIPK1
mRNA decay by 3’ to 5’ exoribonuclease	1	356.9×	0.007	SKIC2
Dengue virus modulates apoptosis	1	356.9×	0.007	RIPK1
RIP-mediated NFkB activation via ZBP1	1	335.9×	0.007	RIPK1
TICAM1, RIP1-mediated IKK complex recruitment	1	300.5×	0.007	RIPK1
IKK complex recruitment mediated by RIP1	1	248.3×	0.007	RIPK1
RIPK1-mediated regulated necrosis	1	228.4×	0.007	RIPK1
TNFR1-induced proapoptotic signaling	1	219.6×	0.007	RIPK1
Regulation of necroptotic cell death	1	219.6×	0.007	RIPK1
TNF signaling	1	211.5×	0.007	RIPK1
TRP channels	1	203.9×	0.007	RIPK1
TNFR1-induced NF-kappa-B signaling pathway	1	167.9×	0.008	RIPK1
Chaperonin-mediated protein folding	1	150.3×	0.009	SKIC2
Association of TriC/CCT with target proteins during biosynthesis	1	146.4×	0.009	SKIC2
Ovarian tumor domain proteases	1	139.3×	0.009	RIPK1
Protein folding	1	129.8×	0.009	SKIC2
Regulation of TNFR1 signaling	1	112.0×	0.010	RIPK1
Potential therapeutics for SARS	1	57.1×	0.019	RIPK1
Ub-specific processing proteases	1	26.6×	0.040	RIPK1
Metabolism of RNA	1	20.8×	0.049	SKIC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
ripoptosome assembly	1	8426.0×	0.003	RIPK1
positive regulation of miRNA processing	1	8426.0×	0.003	RIPK1
positive regulation of interleukin-6-mediated signaling pathway	1	2808.7×	0.003	RIPK1
nuclear-transcribed mRNA catabolic process, 3’-5’ exonucleolytic nonsense-mediated decay	1	2808.7×	0.003	SKIC2
ripoptosome assembly involved in necroptotic process	1	2808.7×	0.003	RIPK1
positive regulation of programmed necrotic cell death	1	2106.5×	0.003	RIPK1
nuclear-transcribed mRNA catabolic process, non-stop decay	1	2106.5×	0.003	SKIC2
peptidyl-serine autophosphorylation	1	1685.2×	0.004	RIPK1
positive regulation of necroptotic process	1	1404.3×	0.004	RIPK1
programmed necrotic cell death	1	1053.2×	0.004	RIPK1
necroptotic signaling pathway	1	1053.2×	0.004	RIPK1
T cell apoptotic process	1	648.1×	0.006	RIPK1
positive regulation of macrophage differentiation	1	601.9×	0.006	RIPK1
positive regulation of programmed cell death	1	561.7×	0.006	RIPK1
necroptotic process	1	526.6×	0.006	RIPK1
positive regulation of tumor necrosis factor-mediated signaling pathway	1	526.6×	0.006	RIPK1
negative regulation of necroptotic process	1	495.6×	0.006	RIPK1
positive regulation of execution phase of apoptosis	1	421.3×	0.007	RIPK1
response to tumor necrosis factor	1	312.1×	0.008	RIPK1
amyloid fibril formation	1	300.9×	0.008	RIPK1
positive regulation of reactive oxygen species metabolic process	1	255.3×	0.010	RIPK1
rescue of stalled cytosolic ribosome	1	240.7×	0.010	SKIC2
positive regulation of extrinsic apoptotic signaling pathway	1	227.7×	0.010	RIPK1
negative regulation of extrinsic apoptotic signaling pathway	1	210.7×	0.010	RIPK1
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	205.5×	0.010	RIPK1
canonical NF-kappaB signal transduction	1	183.2×	0.011	RIPK1
tumor necrosis factor-mediated signaling pathway	1	165.2×	0.011	RIPK1
cellular response to growth factor stimulus	1	159.0×	0.011	RIPK1
extrinsic apoptotic signaling pathway	1	153.2×	0.011	RIPK1
positive regulation of protein phosphorylation	1	138.1×	0.012	RIPK1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RIPK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIPK1	24	4
SKIC2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	RIPK1
FEDRATINIB	4	RIPK1
AXITINIB	4	RIPK1
SORAFENIB	4	RIPK1
DABRAFENIB	4	RIPK1
PAZOPANIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
CRIZOTINIB	4	RIPK1
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1
SU-014813	2	RIPK1
REBASTINIB	2	RIPK1
FEXAGRATINIB	2	RIPK1
GSK2982772	2	RIPK1
ECLITASERTIB	2	RIPK1
FLIZASERTIB	2	RIPK1
OCADUSERTIB	2	RIPK1
RAF-265	2	RIPK1
TOZASERTIB	2	RIPK1
KW-2449	1	RIPK1
AST-487	1	RIPK1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RIPK1	400	Binding:391, ADMET:7, Functional:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RIPK1	2.7.10.2	non-specific protein-tyrosine kinase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RIPK1	400

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

24 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	RIPK1
FEDRATINIB	4	RIPK1
AXITINIB	4	RIPK1
SORAFENIB	4	RIPK1
DABRAFENIB	4	RIPK1
PAZOPANIB	4	RIPK1
NINTEDANIB	4	RIPK1
SUNITINIB	4	RIPK1
QUIZARTINIB	4	RIPK1
CRIZOTINIB	4	RIPK1
LINIFANIB	3	RIPK1
DOVITINIB	3	RIPK1
FORETINIB	2	RIPK1
SU-014813	2	RIPK1
REBASTINIB	2	RIPK1
FEXAGRATINIB	2	RIPK1
GSK2982772	2	RIPK1
ECLITASERTIB	2	RIPK1
FLIZASERTIB	2	RIPK1
OCADUSERTIB	2	RIPK1
RAF-265	2	RIPK1
TOZASERTIB	2	RIPK1
KW-2449	1	RIPK1
AST-487	1	RIPK1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RIPK1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SKIC2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SKIC2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.