RIPK4

Summary

RIPK4 (receptor interacting serine/threonine kinase 4, HGNC:496) is a protein-coding gene on chromosome 21q22.3, encoding Receptor-interacting serine/threonine-protein kinase 4 (P57078). Serine/threonine protein kinase.

The protein encoded by this gene is a serine/threonine protein kinase that interacts with protein kinase C-delta. The encoded protein can also activate NFkappaB and is required for keratinocyte differentiation. This kinase undergoes autophosphorylation.

Source: NCBI Gene 54101 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Bartsocas-Papas syndrome 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 328 total — 6 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 103
• Druggable target: yes — 15 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_020639

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:496
Approved symbol	RIPK4
Name	receptor interacting serine/threonine kinase 4
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	DIK, ANKK2, RIP4, PKK
Ensembl gene	ENSG00000183421
Ensembl biotype	protein_coding
OMIM	605706
Entrez	54101

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000332512, ENST00000352483

RefSeq mRNA: 1 — MANE Select: NM_020639 NM_020639

CCDS: CCDS13675

Canonical transcript exons

ENST00000332512 — 8 exons

Exon	Start	End
ENSE00001293079	41743882	41744140
ENSE00001314637	41745759	41745862
ENSE00002459022	41746613	41746771
ENSE00002506003	41751097	41751245
ENSE00002514017	41749154	41749203
ENSE00002730798	41766860	41767052
ENSE00003507261	41756525	41756816
ENSE00003847203	41739373	41741997

Expression profiles

Bgee: expression breadth ubiquitous, 182 present calls, max score 99.06.

FANTOM5 (CAGE): breadth broad, TPM avg 5.0343 / max 171.8972, expressed in 753 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190564	2.7395	586
190565	2.2948	673

Top tissues by expression

261 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.06	gold quality
tongue squamous epithelium	UBERON:0006919	98.30	gold quality
epithelium of esophagus	UBERON:0001976	98.27	gold quality
squamous epithelium	UBERON:0006914	98.13	gold quality
gingival epithelium	UBERON:0001949	97.02	gold quality
palpebral conjunctiva	UBERON:0001812	96.90	gold quality
gingiva	UBERON:0001828	96.83	gold quality
cervix squamous epithelium	UBERON:0006922	96.43	silver quality
oral cavity	UBERON:0000167	94.24	gold quality
lower esophagus mucosa	UBERON:0035834	94.18	gold quality
esophagus mucosa	UBERON:0002469	94.05	gold quality
amniotic fluid	UBERON:0000173	93.31	gold quality
epithelium of bronchus	UBERON:0002031	93.28	gold quality
mucosa of paranasal sinus	UBERON:0005030	93.04	gold quality
oviduct epithelium	UBERON:0004804	93.01	gold quality
nasal cavity epithelium	UBERON:0005384	92.90	gold quality
bronchus	UBERON:0002185	92.73	gold quality
cervix epithelium	UBERON:0004801	92.64	gold quality
bronchial epithelial cell	CL:0002328	92.51	gold quality
pharyngeal mucosa	UBERON:0000355	92.40	gold quality
nephron tubule	UBERON:0001231	92.09	gold quality
hair follicle	UBERON:0002073	91.81	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	91.58	gold quality
epithelium of nasopharynx	UBERON:0001951	91.37	gold quality
parotid gland	UBERON:0001831	90.91	gold quality
seminal vesicle	UBERON:0000998	90.14	gold quality
nasal cavity mucosa	UBERON:0001826	90.12	gold quality
cartilage tissue	UBERON:0002418	89.49	gold quality
mammalian vulva	UBERON:0000997	88.35	gold quality
kidney epithelium	UBERON:0004819	87.75	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.60

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting RIPK4, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-489-3P	99.80	66.46	839
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-3913-3P	99.74	66.53	938
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-1827	99.63	68.57	3265
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-889-3P	99.40	69.76	2103
HSA-MIR-4722-3P	99.35	65.22	1099
HSA-MIR-5582-5P	99.27	71.42	1879
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-3675-3P	99.09	67.70	968
HSA-MIR-10B-3P	99.04	66.98	988
HSA-MIR-452-3P	99.01	66.25	1241
HSA-MIR-421	98.90	67.04	1883
HSA-MIR-6760-5P	98.87	66.73	1515
HSA-MIR-3074-5P	98.82	66.56	1414
HSA-MIR-2276-3P	98.76	67.75	1384

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• PKK may function in both a kinase-dependent as well as a kinase-independent manner to activate NFkappaB (PMID:12676934)
• NF-kappaB activity and keratinocyte differentiation are regulated by the RIP4 protein, which has roles in cutaneous wound repair (PMID:17039240)
• PKK plays a pivotal role in the survival of human Diffuse large B-cell lymphoma (DLBCL) cells and represents a potential target for DLBCL therapy (PMID:18025152)
• Phosphorylation of protein kinase C delta is associated with activation of vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 receptor in lipopolysaccharide induced macrophages (PMID:18511573)
• Data indicate that rip4 gene expression is regulated in a complex manner, which might have therapeutic implications. (PMID:19818768)
• The present study’s findings show that recessive mutations in RIPK4 cause Bartsocas-Papas syndrome and its variant, the autosomal-recessive form of multiple pterygium syndrome (Aslan type). (PMID:22197488)
• phosphorylation of DVL2 by RIPK4 favored canonical Wnt signaling; findings suggest that RIPK4 overexpression may contribute to the growth of certain tumor types (PMID:23371553)
• Data indicate protein-serine-threonine kinases RIPK4 overexpression in transformed fetal hepatocytes. (PMID:24413083)
• Authors found a correlation between RIPK4 expression and TSCC degree of differentiation, age, and gender. (PMID:24519546)
• Suppression of PKK expression by RNA interference inhibits phosphorylation of IKKalpha and IKKbeta as well as activation of NF-kappaB in human cancer cell lines; thus, PKK regulates NF-kappaB activation by modulating activation of IKKalpha and IKKbeta. (PMID:25096806)
• we identified an epithelial ovarian cancer susceptibility loci at 10p11.21 (rs1192691 near ANKRD30A, P(meta) = 2.62 x 10(-8)) (PMID:25134534)
• Ser-413 and Ser-424 in IRF6 are important for its activation by RIPK4 (PMID:25246526)
• The protein kinase C-associated kinase (PKK), which is also known as the receptor-interacting protein kinase 4, is a suppressor of tumor growth in squamous cell carcinoma of the skin. (PMID:25285922)
• The p.Ser376X mutation in RIPK4 impaired its induction of IRF6 transactivator function. (PMID:25784454)
• CHAND and Bartsocas-Papas syndrome might be allelic disorders or RIPK4 mutations could confer varying degrees of phenotypic severity, depending on their localization within or outside functionally important domains. (PMID:26129644)
• CCL5 and CXCL11 expression were also induced in response to the activation of the PKC pathway, and gene silencing experiments indicated that their inducible expression was dependent on RIPK4 and IRF6. Moreover, gene reporter assays suggested that RIPK4 induces CCL5 and CXCL11 expression by stimulating the transactivation of their promoters by IRF6. (PMID:27014863)
• These findings position RIPK4 upstream of a hierarchal IRF6-GRHL3-ELF3 transcription factor pathway in keratinocytes. (PMID:27667567)
• Overexpression of EZH2 was found in 30 patients (76.9%) and was associated with FIGO stage, histological type, and lymph node metastasis (p < 0.05). In conclusion, our data suggest that RIPK4/EZH2 markers might be used as potential predictors of prognosis in cervical cancer. (PMID:27697098)
• that loss of RIP4 enhances STAT3 signaling in lung cancer cells (PMID:28574510)
• The patient with CHAND syndrome harbored the same mutation as the one identified in the family previously reported. We thus confirm the implication of RIPK4 gene in CHAND syndrome in addition to Bartsocas-Papas syndrome and discuss genotype/phenotype correlations. (PMID:28940926)
• Silencing RIPK4 promoted the proliferation and inhibited the apoptosis of chondrocytes. In addition, silencing RIPK4 blocked the Wnt/betacatenin signaling pathway, thus contributing to alleviating the osteoarthritis pathogenesis. (PMID:29257245)
• Data show that the SCF(beta-TrCP) ubiquitin E3 ligase complex responsible for regulating the active protein kinase C-associated kinase (RIPK4) level. (PMID:29435596)
• RIPK4 was upregulated in the subgroup of pancreatic cancer with a high metastatic potential (PMID:29436617)
• A20 regulates canonical wnt-signaling through an interaction with RIPK4 (PMID:29718933)
• Data highlighted the molecular aetiology and clinical significance of RIPK4 in BC: upregulation of RIPK4 contributes to NF-kappaB activation, and upregulates VEGF-A, and BC progression. (PMID:29867225)
• Taken together, these findings indicate that IL-17 increased RIP4-mediated STAT3 phosphorylation by directly interacting with STAT3. Thus, transcriptional activation of STAT3 promotes the expression of CCL20. Thus, activations of these signalling pathways by RIP4 may contribute to epithermal inflammation in psoriatic keratinocytes. (PMID:30044012)
• This study demonstrated the oncogenic roles of RIPK4 in nasopharyngeal carcinoma. (PMID:30212707)
• RIPK4 suppresses the TGF-beta1 signaling pathway in HaCaT cells. (PMID:31825120)
• Silencing of RIPK4 inhibits epithelialmesenchymal transition by inactivating the Wnt/betacatenin signaling pathway in osteosarcoma. (PMID:32016450)
• MicroRNA miR-330-3p suppresses the progression of ovarian cancer by targeting RIPK4. (PMID:33487072)
• A novel homozygous RIPK4 variant in a family with severe Bartsocas-Papas syndrome. (PMID:33713555)
• Downregulation of RIPK4 Expression Inhibits Epithelial-Mesenchymal Transition in Ovarian Cancer through IL-6. (PMID:33855091)
• Overexpression of RIPK4 Predicts Poor Prognosis and Promotes Metastasis in Ovarian Cancer. (PMID:34124253)
• Receptor interacting protein kinase 4 promotes cell proliferation, migration, and invasion in ovarian cancer via targeting protein kinase C delta. (PMID:34414590)
• Deciphering the Functional Role of RIPK4 in Melanoma. (PMID:34768934)
• Depletion of RIPK4 parallels higher malignancy potential in cutaneous squamous cell carcinoma. (PMID:35186499)
• RIPK4 regulates cell-cell adhesion in epidermal development and homeostasis. (PMID:35220430)
• LncRNA MIR31HG promotes cell proliferation and invasive properties of the MCF-7 cell line by regulation of receptor-interacting serine-threonine kinase 4. (PMID:38064252)
• m6A-modified RIPK4 facilitates proliferation and cisplatin resistance in epithelial ovarian cancer. (PMID:38086167)
• RIPK4 Promotes Cell Invasion and the Epithelial-Mesenchymal Transition in Ovarian Cancer. (PMID:38179758)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ripk4	ENSDARG00000043211
mus_musculus	Ripk4	ENSMUSG00000005251
rattus_norvegicus	Ripk4	ENSRNOG00000001618

Paralogs (1): ANKK1 (ENSG00000170209)

Protein

Protein identifiers

Receptor-interacting serine/threonine-protein kinase 4 — P57078 (reviewed: P57078)

Alternative names: Ankyrin repeat domain-containing protein 3, PKC-delta-interacting protein kinase

All UniProt accessions (1): P57078

UniProt curated annotations — full annotation on UniProt →

Function. Serine/threonine protein kinase. Required for embryonic skin development and correct skin homeostasis in adults, via phosphorylation of PKP1 and subsequent promotion of keratinocyte differentiation and cell adhesion. It is a direct transcriptional target of TP63. Plays a role in NF-kappa-B activation.

Subunit / interactions. Interacts with PRKCB. Interacts with TRAF1, TRAF2, TRAF3 and TRAF5. Interacts with BIRC2/c-IAP1, BIRC3/c-IAP2 and XIAP/BIRC4.

Subcellular location. Cytoplasm. Membrane.

Tissue specificity. Expressed in hair follicles and skin.

Post-translational modifications. May be phosphorylated by MAP3K2 and MAP3K3. Proteolytically cleaved by during Fas-induced apoptosis. Cleavage at Asp-388 and Asp-426. Polyubiquitinated with ‘Lys-48’ and ‘Lys-63’-linked chains by BIRC2/c-IAP1 and BIRC3/c-IAP2, leading to activation of NF-kappa-B.

Disease relevance. Bartsocas-Papas syndrome (BPS) [MIM:263650] An autosomal recessive disorder characterized by multiple popliteal pterygia leading to severe arthrogryposis, ankyloblepharon filiforme adnatum, filiform bands between the jaws, synostosis of the carpal/tarsal and phalangeal bones in the hands and feet, digital hypoplasia/aplasia, complete soft-tissue syndactyly, lack of nails, lack of scalp hair, eyebrows and eyelashes, blepharophimosis, cleft lip and/or palate, and hypoplastic external genitalia. Early lethality is common, although survival into childhood and beyond has been reported. The disease is caused by variants affecting the gene represented in this entry. CHAND syndrome (CHANDS) [MIM:214350] An autosomal recessive syndrome characterized by ankyloblepharon, sparse, curly and woolly hair, nail dysplasia, and oral frenula. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P57078-1	1	yes
P57078-2	2

RefSeq proteins (1): NP_065690* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR002110	Ankyrin_rpt	Repeat
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily

Pfam: PF00069, PF12796, PF13637

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (41 total): sequence variant 15, repeat 10, compositionally biased region 3, region of interest 2, binding site 2, site 2, cross-link 2, chain 1, domain 1, active site 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P57078-F1	75.41	0.48

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 143 (proton acceptor); 388–389 (cleavage); 426–427 (cleavage)

Ligand- & substrate-binding residues (2): 28–36; 51

Post-translational modifications (2): 51, 145

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 387 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, AREB6_03, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, CREBP1_Q2, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, CREB_Q4, NKX62_Q2, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION, MARTINEZ_RB1_TARGETS_DN, MODULE_301, WTGAAAT_UNKNOWN, HFH4_01

GO Biological Process (4): morphogenesis of an epithelium (GO:0002009), skin development (GO:0043588), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), protein phosphorylation (GO:0006468)

GO Molecular Function (8): protein serine/threonine kinase activity (GO:0004674), ATP binding (GO:0005524), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein kinase activity (GO:0004672), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein kinase activity	2
tissue morphogenesis	1
epithelium development	1
animal organ development	1
phosphorylation	1
protein modification process	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

5681 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RIPK4	PRKCD	Q05655	893
RIPK4	IRF6	O14896	705
RIPK4	KDF1	Q8NAX2	526
RIPK4	GRHL3	Q8TE85	476
RIPK4	ZBTB21	Q9ULJ3	448
RIPK4	OVOL1	O14753	437
RIPK4	LRRC19	Q9H756	426
RIPK4	GRK3	P35626	420
RIPK4	KNG1	P01042	408
RIPK4	FICD	Q9BVA6	401
RIPK4	KBTBD8	Q8NFY9	390
RIPK4	PTCHD1	Q96NR3	385
RIPK4	PRDM15	P57071	382
RIPK4	NWD2	Q9ULI1	380
RIPK4	LIMS2	Q7Z4I7	380

IntAct

57 interactions, top by confidence:

A	B	Type	Score
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
DVL2	RIPK4	psi-mi:“MI:0915”(physical association)	0.600
DVL2	RIPK4	psi-mi:“MI:0217”(phosphorylation reaction)	0.600
RIPK4	BIRC3	psi-mi:“MI:0915”(physical association)	0.600
BIRC2	RIPK4	psi-mi:“MI:0915”(physical association)	0.600
BIRC3	RIPK4	psi-mi:“MI:0915”(physical association)	0.600
XIAP	RIPK4	psi-mi:“MI:0915”(physical association)	0.540
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
HIF1AN	RIPK4	psi-mi:“MI:0915”(physical association)	0.500
BIRC3	UBE2D1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
BIRC2	UBE2D1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
RIPK4	UBE2D1	psi-mi:“MI:0220”(ubiquitination reaction)	0.440
RIPK4	LRP6	psi-mi:“MI:0915”(physical association)	0.400
RIPK4	H1-1	psi-mi:“MI:0915”(physical association)	0.400
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
RIPK4	PRKCB	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
RIPK4	TBCA	psi-mi:“MI:0914”(association)	0.350
YWHAE	DEPDC5	psi-mi:“MI:0914”(association)	0.350
AFG2A	ESYT2	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
RIPK4	ASB3	psi-mi:“MI:0915”(physical association)	0.000
RIPK4	TNPO2	psi-mi:“MI:0915”(physical association)	0.000
RIPK4	PREPL	psi-mi:“MI:0915”(physical association)	0.000

ESM2 similar proteins: A0M8T3, A0PJZ0, A1X154, A4D7T3, A6NHY2, C7B178, P57078, Q00PJ3, Q07DV3, Q07DX6, Q07DY6, Q07DZ7, Q07E17, Q07E30, Q07E43, Q09YH1, Q09YI3, Q09YJ5, Q09YK6, Q09YN0, Q108U1, Q14DN9, Q2IBB1, Q2IBB4, Q2IBE3, Q2IBF5, Q2IBG0, Q2QL84, Q2QLA4, Q2QLB5, Q2QLC6, Q2QLG0, Q2QLH1, Q4R3S3, Q5EA33, Q5RCK5, Q8NFD2, Q8VD46, Q8VE42, Q8WMX6

Diamond homologs: A1Z9X0, A2CI34, A2CI35, A8KBH6, A8XW88, F1M7Y5, O70146, P00542, P00543, P04409, P05126, P05128, P05129, P05696, P05771, P05772, P07332, P09215, P0CD62, P10102, P10829, P13678, P14238, P16054, P16879, P17252, P20444, P21137, P22612, P23298, P24723, P28867, P32866, P41743, P43057, P48562, P50527, P57078, P63318, P63319

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
BIRC2	“up-regulates activity”	RIPK4	polyubiquitination
BIRC3	“up-regulates activity”	RIPK4	polyubiquitination
XIAP	“up-regulates activity”	RIPK4	polyubiquitination
RIPK4	“up-regulates activity”	DVL2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 53 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	5	92.8×	2e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	81.9×	2e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	81.9×	2e-07
Activation of BH3-only proteins	5	60.5×	9e-07
RHO GTPases activate PKNs	5	38.7×	8e-06
Intrinsic Pathway for Apoptosis	5	35.7×	1e-05
Apoptosis	7	28.7×	3e-07
Programmed Cell Death	8	28.6×	1e-07

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of protein ubiquitination	5	21.3×	4e-04
intracellular protein localization	7	14.7×	7e-05
protein polyubiquitination	5	11.5×	3e-03
Wnt signaling pathway	5	10.0×	5e-03
endocytosis	5	9.5×	5e-03
ubiquitin-dependent protein catabolic process	6	8.9×	2e-03
regulation of apoptotic process	5	8.3×	8e-03
proteasome-mediated ubiquitin-dependent protein catabolic process	7	7.3×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

328 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	2
Uncertain significance	184
Likely benign	61
Benign	41

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
30511	NM_020639.3(RIPK4):c.1127C>A (p.Ser376Ter)	Pathogenic
30512	NM_020639.3(RIPK4):c.242T>A (p.Ile81Asn)	Pathogenic
30513	NM_020639.3(RIPK4):c.362T>A (p.Ile121Asn)	Pathogenic
30514	NM_020639.3(RIPK4):c.777dup (p.Arg260fs)	Pathogenic
585264	NM_020639.3(RIPK4):c.850G>A (p.Glu284Lys)	Pathogenic
585265	NM_020639.3(RIPK4):c.1074dup (p.Glu359Ter)	Pathogenic
1285557	NM_020639.3(RIPK4):c.722G>A (p.Arg241His)	Likely pathogenic
1325006	NM_020639.3(RIPK4):c.121del (p.His41fs)	Likely pathogenic

SpliceAI

1170 predictions. Top by Δscore:

Variant	Effect	Δscore
21:41741993:CAGAT:C	acceptor_gain	1.0000
21:41741994:AGAT:A	acceptor_gain	1.0000
21:41741996:ATCT:A	acceptor_loss	1.0000
21:41741997:TC:T	acceptor_loss	1.0000
21:41741998:CTGC:C	acceptor_loss	1.0000
21:41741999:T:A	acceptor_loss	1.0000
21:41743878:TCA:T	donor_loss	1.0000
21:41743879:CAC:C	donor_loss	1.0000
21:41743880:A:AC	donor_gain	1.0000
21:41743880:ACCGC:A	donor_loss	1.0000
21:41743881:C:A	donor_loss	1.0000
21:41743881:C:CC	donor_gain	1.0000
21:41743881:CCG:C	donor_gain	1.0000
21:41744137:CCAC:C	acceptor_gain	1.0000
21:41744138:CACC:C	acceptor_gain	1.0000
21:41744141:CTG:C	acceptor_loss	1.0000
21:41744142:T:A	acceptor_loss	1.0000
21:41745754:GTTAC:G	donor_loss	1.0000
21:41745755:TTAC:T	donor_loss	1.0000
21:41745756:TACC:T	donor_loss	1.0000
21:41745757:ACCTC:A	donor_loss	1.0000
21:41745758:CCTC:C	donor_loss	1.0000
21:41745758:CCTCG:C	donor_gain	1.0000
21:41745858:AATTT:A	acceptor_gain	1.0000
21:41745859:ATTT:A	acceptor_gain	1.0000
21:41745860:TTT:T	acceptor_gain	1.0000
21:41745861:TT:T	acceptor_gain	1.0000
21:41745862:TC:T	acceptor_loss	1.0000
21:41745863:C:CC	acceptor_gain	1.0000
21:41745863:C:CG	acceptor_loss	1.0000

AlphaMissense

5096 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:41741823:A:G	L505P	0.999
21:41751238:T:A	D161V	0.999
21:41766899:A:G	L48P	0.999
21:41741625:A:G	L571P	0.998
21:41741820:A:G	L506P	0.998
21:41741916:A:G	L474P	0.998
21:41741928:A:G	L470P	0.998
21:41741956:C:G	A461P	0.998
21:41756529:A:T	V157D	0.998
21:41756544:T:A	D152V	0.998
21:41756550:A:G	L150P	0.998
21:41756568:A:G	L144P	0.998
21:41756617:C:G	G128R	0.998
21:41756628:T:A	E124V	0.998
21:41756754:A:G	L82P	0.998
21:41756765:A:C	F78L	0.998
21:41756765:A:T	F78L	0.998
21:41756767:A:G	F78L	0.998
21:41766893:A:T	I50N	0.998
21:41766896:G:T	A49D	0.998
21:41741580:C:G	R586P	0.997
21:41741658:G:T	A560D	0.997
21:41741761:C:G	A526P	0.997
21:41741859:G:T	A493E	0.997
21:41741964:A:G	L458P	0.997
21:41749184:C:G	G215R	0.997
21:41749187:A:G	W214R	0.997
21:41749187:A:T	W214R	0.997
21:41749192:A:T	V212D	0.997
21:41749203:G:C	S208R	0.997

dbSNP variants (sampled 300 via entrez): RS1000105303 (21:41756948 C>T), RS1000119709 (21:41746348 C>T), RS1000264477 (21:41751798 G>A,T), RS1000315605 (21:41762284 G>A,C), RS1000496549 (21:41747326 C>G), RS1000718844 (21:41767228 C>A,G,T), RS1000850472 (21:41753508 T>A,C), RS1000900246 (21:41759359 T>C), RS1001091772 (21:41748566 T>G), RS1001444216 (21:41754117 T>C), RS1001495459 (21:41742520 A>G), RS1001829118 (21:41743674 G>A), RS1002206479 (21:41754408 T>C), RS1002268677 (21:41767155 C>A,G,T), RS1002375700 (21:41762540 G>A,T)

Disease associations

OMIM: gene MIM:605706 | disease phenotypes: MIM:263650, MIM:214350

GenCC curated gene-disease

Disease	Classification	Inheritance
Bartsocas-Papas syndrome 1	Definitive	Autosomal recessive
ectodermal dysplasia syndrome	Strong	Autosomal recessive

Mondo (3): Bartsocas-Papas syndrome 1 (MONDO:0009901), CHAND syndrome (MONDO:0008959), ectodermal dysplasia syndrome (MONDO:0019287)

Orphanet (2): Bartsocas-Papas syndrome (Orphanet:1234), CHAND syndrome (Orphanet:1401)

HPO phenotypes

103 total (30 of 103 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000042	Absent external genitalia
HP:0000050	Hypoplastic male external genitalia
HP:0000054	Micropenis
HP:0000059	Hypoplastic labia majora
HP:0000062	Ambiguous genitalia
HP:0000072	Hydroureter
HP:0000086	Ectopic kidney
HP:0000160	Narrow mouth
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000190	Abnormal oral frenulum morphology
HP:0000204	Cleft upper lip
HP:0000252	Microcephaly
HP:0000298	Mask-like facies
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000430	Underdeveloped nasal alae
HP:0000470	Short neck
HP:0000561	Absent eyelashes
HP:0000568	Microphthalmia
HP:0000581	Blepharophimosis
HP:0000582	Upslanted palpebral fissure
HP:0000625	Eyelid coloboma
HP:0000652	Lower eyelid coloboma
HP:0000656	Ectropion

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST004068_75	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	3.000000e-06
GCST012490_139	Femur bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D004476	Ectodermal Dysplasia	C16.131.077.350; C16.131.831.350; C16.320.850.250; C17.800.804.350; C17.800.827.250
C538074	Curly hair-ankyloblepharon-nail dysplasia syndrome (supp.)
C564874	Popliteal Pterygium Syndrome, Lethal Type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6083 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

15 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 292,764 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1287853	FEDRATINIB	4	3,554
CHEMBL1289926	AXITINIB	4	15,732
CHEMBL1789941	RUXOLITINIB	4	11,547
CHEMBL24828	VANDETANIB	4	42,230
CHEMBL502835	NINTEDANIB	4	8,545
CHEMBL535	SUNITINIB	4	79,020
CHEMBL553	ERLOTINIB	4	108,300
CHEMBL601719	CRIZOTINIB	4	14,403
CHEMBL603469	LESTAURTINIB	3
CHEMBL1230609	FORETINIB	2	3,096
CHEMBL230011	TG100-115	2	1,504
CHEMBL475251	R-406	2	762
CHEMBL572878	TOZASERTIB	2	2,998
CHEMBL1908397	KW-2449	1	622
CHEMBL574738	AST-487	1	451

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Receptor interacting protein kinase (RIPK) family

ChEMBL bioactivities

27 potent at pChembl≥5 of 27 total, top 23 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.89	Kd	13	nM	LESTAURTINIB
7.04	IC50	92	nM	CHEMBL1835063
7.01	Kd	97	nM	TG100-115
6.96	Kd	110	nM	STAUROSPORINE
6.89	Kd	130	nM	KW-2449
6.85	Kd	140	nM	CHEMBL4554938
6.75	Kd	180	nM	AST-487
6.66	Kd	220	nM	R-406
6.54	Kd	290	nM	CHEMBL1241674
6.52	Kd	300	nM	TOZASERTIB
6.36	Kd	440	nM	NINTEDANIB
6.21	Kd	620	nM	VANDETANIB
6.05	Kd	900	nM	FORETINIB
6.00	IC50	1000	nM	TP-030n
5.85	Kd	1400	nM	AXITINIB
5.68	Kd	2100	nM	SUNITINIB
5.68	Kd	2100	nM	CRIZOTINIB
5.68	Kd	2100	nM	RUXOLITINIB
5.64	Kd	2300	nM	CHEMBL5177284
5.50	Kd	3200	nM	TAE-684
5.31	Kd	4900	nM	ERLOTINIB
5.25	IC50	5690	nM	CHEMBL4635883
5.01	Kd	9800	nM	FEDRATINIB

PubChem BioAssay actives

24 with measured affinity, of 189 total; 22 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(15S,16S,18R)-16-hydroxy-16-(hydroxymethyl)-15-methyl-28-oxa-4,14,19-triazaoctacyclo[12.11.2.115,18.02,6.07,27.08,13.019,26.020,25]octacosa-1,6,8,10,12,20,22,24,26-nonaen-3-one	508067: Binding affinity to RIPK4	kd	0.0130	uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[3-(trifluoromethyl)anilino]pyrimidine-5-carboxamide	1668837: Inhibition of human RIPK4 using histone H2A as substrate in presence of [gamma-33P]-ATP by hotspot kinase assay	ic50	0.0920	uM
3-[2,4-diamino-7-(3-hydroxyphenyl)pteridin-6-yl]phenol	624763: Binding constant for RIPK4 kinase domain	kd	0.0970	uM
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	624763: Binding constant for RIPK4 kinase domain	kd	0.1100	uM
[4-[(E)-2-(1H-indazol-3-yl)ethenyl]phenyl]-piperazin-1-ylmethanone	624763: Binding constant for RIPK4 kinase domain	kd	0.1300	uM
4-[(2,9-dimethyl-8-oxo-6-thia-2,9,12,14-tetrazatricyclo[8.4.0.03,7]tetradeca-1(14),3(7),4,10,12-pentaen-13-yl)amino]benzenesulfonamide	2189157: Binding affinity to RIPK4 (unknown origin) assessed as dissociation constant	kd	0.1400	uM
1-[4-[(4-ethylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]-3-[4-[6-(methylamino)pyrimidin-4-yl]oxyphenyl]urea	624763: Binding constant for RIPK4 kinase domain	kd	0.1800	uM
6-[[5-fluoro-2-(3,4,5-trimethoxyanilino)pyrimidin-4-yl]amino]-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one	624763: Binding constant for RIPK4 kinase domain	kd	0.2200	uM
2-(4-amino-1-propan-2-ylpyrazolo[3,4-d]pyrimidin-3-yl)-1H-indol-5-ol	624763: Binding constant for RIPK4 kinase domain	kd	0.2900	uM
N-[4-[4-(4-methylpiperazin-1-yl)-6-[(5-methyl-1H-pyrazol-3-yl)amino]pyrimidin-2-yl]sulfanylphenyl]cyclopropanecarboxamide	624763: Binding constant for RIPK4 kinase domain	kd	0.3000	uM
methyl 2-hydroxy-3-[N-[4-[methyl-[2-(4-methylpiperazin-1-yl)acetyl]amino]phenyl]-C-phenylcarbonimidoyl]-1H-indole-6-carboxylate	624763: Binding constant for RIPK4 kinase domain	kd	0.4400	uM
Vandetanib	624763: Binding constant for RIPK4 kinase domain	kd	0.6200	uM
1-N’-[3-fluoro-4-[6-methoxy-7-(3-morpholin-4-ylpropoxy)quinolin-4-yl]oxyphenyl]-1-N-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide	624763: Binding constant for RIPK4 kinase domain	kd	0.9000	uM
Axitinib	624763: Binding constant for RIPK4 kinase domain	kd	1.4000	uM
Crizotinib	624763: Binding constant for RIPK4 kinase domain	kd	2.1000	uM
Ruxolitinib	624763: Binding constant for RIPK4 kinase domain	kd	2.1000	uM
Sunitinib	508067: Binding affinity to RIPK4	kd	2.1000	uM
7-(4-aminocyclohexyl)-5-(2-fluoro-4-methylphenyl)pyrrolo[2,3-d]pyrimidin-4-amine	1880921: Binding affinity to human RIPK4	kd	2.3000	uM
5-chloro-2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)pyrimidine-2,4-diamine	624763: Binding constant for RIPK4 kinase domain	kd	3.2000	uM
Erlotinib	624763: Binding constant for RIPK4 kinase domain	kd	4.9000	uM
2-[(3S)-3-aminopiperidin-1-yl]-4-[[2,6-di(propan-2-yl)-4-pyridinyl]amino]pyrimidine-5-carboxamide	1668837: Inhibition of human RIPK4 using histone H2A as substrate in presence of [gamma-33P]-ATP by hotspot kinase assay	ic50	5.6900	uM
Fedratinib	624763: Binding constant for RIPK4 kinase domain	kd	9.8000	uM

CTD chemical–gene interactions

38 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	6
trichostatin A	affects cotreatment, increases expression	3
sodium arsenite	decreases expression, increases expression	3
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Calcitriol	increases expression, affects cotreatment	2
Smoke	decreases expression, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
urushiol	decreases expression	1
lead acetate	decreases expression	1
potassium chromate(VI)	decreases expression	1
cupric chloride	decreases expression	1
nickel sulfate	increases expression	1
monomethylarsonous acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
PCI 5002	affects cotreatment, increases expression	1
1-(2-chlorobenzyl)-5’-phenyl-3’H-spiro(indoline-3,2’-(1,3,4)thiadiazol)-2-one	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Polychlorinated Biphenyls	affects expression	1
Silicon Dioxide	increases expression	1
Testosterone	affects cotreatment, increases expression	1

ChEMBL screening assays

91 unique, capped per target: 91 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1052949	Binding	Inhibition of RIPK4 assessed as enzyme activity at 1 uM relative to untreated control	Selective inhibitors of the mutant B-Raf pathway: discovery of a potent and orally bioavailable aminoisoquinoline. — J Med Chem

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00001211	Not specified	COMPLETED	Clinical Study of Oral Endosseous Titanium Implants in Edentulous Subjects
NCT00266513	Not specified	TERMINATED	Studies of Disorders in Antibody Production and Related Primary Immunodeficiency States
NCT01108770	Not specified	COMPLETED	Evaluation of Phenotypic and Genetic Properties in Male Subjects Affected By Hypohidrotic Ectodermal Dysplasia
NCT02896387	Not specified	TERMINATED	Ability of a Molecule (Prima) to Restore Physiological Differentiation in Epithelium Expressing Gene p63
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07468019	Not specified	RECRUITING	Organization’s Unique Protocol ID