JAG2

Summary

JAG2 (jagged canonical Notch ligand 2, HGNC:6189) is a protein-coding gene on chromosome 14q32.33, encoding Protein jagged-2 (Q9Y219). Putative Notch ligand involved in the mediation of Notch signaling.

The Notch signaling pathway is an intercellular signaling mechanism that is essential for proper embryonic development. Members of the Notch gene family encode transmembrane receptors that are critical for various cell fate decisions. The protein encoded by this gene is one of several ligands that activate Notch and related receptors. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3714 — RefSeq curated summary.

At a glance

• Gene–disease (curated): muscular dystrophy, limb-girdle, autosomal recessive 27 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 381 total — 1 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 32
• MANE Select transcript: NM_002226

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6189
Approved symbol	JAG2
Name	jagged canonical Notch ligand 2
Location	14q32.33
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000184916
Ensembl biotype	protein_coding
OMIM	602570
Entrez	3714

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 3 retained_intron

ENST00000331782, ENST00000347004, ENST00000546616, ENST00000553051, ENST00000553244, ENST00000938642, ENST00000938643, ENST00000938644, ENST00000966337, ENST00000966338, ENST00000966339, ENST00000966340, ENST00000966341, ENST00000966342, ENST00000966343, ENST00000966344, ENST00000966345

RefSeq mRNA: 2 — MANE Select: NM_002226 NM_002226, NM_145159

CCDS: CCDS9998, CCDS9999

Canonical transcript exons

ENST00000331782 — 26 exons

Exon	Start	End
ENSE00001291747	105149170	105149320
ENSE00001294738	105148745	105148858
ENSE00001297971	105150865	105150911
ENSE00001301167	105167757	105168107
ENSE00001302090	105151626	105151739
ENSE00001306790	105146611	105146724
ENSE00001313304	105147500	105147527
ENSE00001315207	105150991	105151104
ENSE00001317095	105148326	105148439
ENSE00001319156	105150604	105150777
ENSE00001323860	105148937	105149089
ENSE00001325002	105151283	105151396
ENSE00001325832	105147326	105147411
ENSE00002412669	105140995	105143170
ENSE00003461229	105145731	105145973
ENSE00003461958	105143482	105143638
ENSE00003471559	105155562	105155622
ENSE00003481296	105147772	105147888
ENSE00003504868	105152161	105152291
ENSE00003512055	105146385	105146500
ENSE00003517289	105155738	105155989
ENSE00003541630	105144930	105145061
ENSE00003614618	105148116	105148229
ENSE00003683846	105151938	105152057
ENSE00003692427	105157706	105157763
ENSE00003850761	105168355	105168776

Expression profiles

Bgee: expression breadth ubiquitous, 281 present calls, max score 95.47.

FANTOM5 (CAGE): breadth broad, TPM avg 7.4414 / max 175.0997, expressed in 897 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145175	4.3666	788
145174	2.9272	697
145173	0.1476	89

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
nipple	UBERON:0002030	95.47	gold quality
apex of heart	UBERON:0002098	94.26	gold quality
pituitary gland	UBERON:0000007	93.17	gold quality
skin of abdomen	UBERON:0001416	92.90	gold quality
adenohypophysis	UBERON:0002196	92.52	gold quality
skin of leg	UBERON:0001511	91.89	gold quality
zone of skin	UBERON:0000014	91.27	gold quality
endometrium epithelium	UBERON:0004811	90.64	gold quality
cortical plate	UBERON:0005343	90.34	gold quality
endothelial cell	CL:0000115	90.03	gold quality
upper leg skin	UBERON:0004262	90.03	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.03	gold quality
right frontal lobe	UBERON:0002810	89.49	gold quality
trachea	UBERON:0003126	89.33	gold quality
body of tongue	UBERON:0011876	89.33	gold quality
heart left ventricle	UBERON:0002084	89.31	gold quality
cardiac ventricle	UBERON:0002082	88.93	gold quality
esophagus mucosa	UBERON:0002469	88.69	gold quality
lower esophagus mucosa	UBERON:0035834	88.59	gold quality
pharyngeal mucosa	UBERON:0000355	88.56	gold quality
dorsal root ganglion	UBERON:0000044	88.36	gold quality
right uterine tube	UBERON:0001302	88.26	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.02	gold quality
epithelium of mammary gland	UBERON:0003244	87.85	gold quality
hypothalamus	UBERON:0001898	87.75	gold quality
mammary duct	UBERON:0001765	87.74	gold quality
gastrocnemius	UBERON:0001388	87.71	gold quality
tongue	UBERON:0001723	87.63	gold quality
tibia	UBERON:0000979	87.60	gold quality
type B pancreatic cell	CL:0000169	87.57	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	115.68
E-GEOD-135922	yes	41.78
E-ANND-3	yes	9.21
E-MTAB-10137	yes	4.90

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ASCL1, CD46, FOXI3, NEUROG2, SSRP1, TNF, TP53, TP63, TP73

miRNA regulators (miRDB)

102 targeting JAG2, 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-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-12121	99.99	66.64	255
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-605-3P	99.88	69.22	1833

Literature-anchored findings (GeneRIF, showing 40)

• expression required for spermatogenesis in humans and rats (PMID:11700865)
• JAG2 was found to be overexpressed in malignant plasma cells from MM patients; coculture assay demonstrated that JAG2 induced the secretion of IL-6, VEGF, and IGF-1 in stromal cells; JAG2 overexpression may be an early event in the pathogenesis of MM (PMID:15292061)
• The upregulation of Jagged2 expression on BMEC was observed upon TNF-alpha activation. Similarly,activation of endothelial cells in Tie2-tmTNF-alpha mice was characterized by increased expression of Jagged2. (PMID:18439488)
• Results indicate JAG2 may be involved in non-syndromic cleft lip with or without cleft palate etiology in different populations. (PMID:19049519)
• SMRT function restoration induces JAG2 down-regulation as well as multipe myeloma apoptosis. (PMID:19417136)
• Notch signaling may participate in controlling cell differentiation and proliferation in normal bone and COF of the jaws. Notch signaling disorder may be a molecular incident in COF occurrence and development. (PMID:20040020)
• JAG2 is a direct Myc target and Jagged2 and Notch signaling participate in P493-6 lymphomagenesis. (PMID:20133585)
• Expression of Notch3 and Jagged2 were highly correlated in tongue carcinoma tissues. (PMID:20819128)
• we have investigated their influence on early human hematopoiesis and show that Jagged2 affects hematopoietic lineage decisions very similarly as Delta-like-1 and -4, but very different from Jagged1 (PMID:21372153)
• hypoxic induction of JAG2 in tumor cells mediates a hypoxia-regulated cross-talk between tumor and endothelial cells. (PMID:21402725)
• hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis (PMID:21499308)
• The stromal cell-mediated antiapoptotic effect on B- ALL cells is mediated by Notch-3 and -4 or Jagged-1/-2 and DLL-1 in a synergistic manner. (PMID:21602525)
• This study is the first illustration of Notch-1 and Jagged-2 expression in human tissues from non-cancerous disease. (PMID:21892607)
• Notch-1 and Jagged-2 are not expressed in spastic colon segments, which may be associated with the pathogenesis of Hirschsprung disease. (PMID:22030773)
• JAG2 is often expressed by CD138(+) primary cells. Our results indicate that spontaneous clonogenic growth of myeloma cells requires the expression of JAG2. (PMID:22341562)
• Immunohistochemistry showed a reverse correlation between MUC2 and Notch3 or Jagged1 (P = 0.033 and P = 0.005, respectively) and between MUC5AC and Jagged1 or Hes1 (PMID:22691042)
• JAG2-mediated Notch activation confers phenotypic and functional aspects of Langerhans cell histiocytosis to dendritic cells. (PMID:23074278)
• Jagged2 expression status was closely correlated with important histopathologic characteristics (grades and stages) and the recurrence and metastasis of bladder urothelial carcinomas. (PMID:24228105)
• This study demonistrated that NOTCH ligands JAG1 and JAG2 as critical pro-survival factors in childhood medulloblastoma. (PMID:24708907)
• Although Jag1 shares a high degree of homology with Jag2 in the ectodomain region, BACE1 fails to cleave Jag2 effectively, indicating a selective cleavage of Jag1. (PMID:24907271)
• silencing prevents Notch2-driven osteoclast development and bone destruction in multiple myeloma (PMID:25257302)
• Results show that tumor cell migration, invasion, and metastasis are dependent on JAGGED2 independently of NOTCH activation. (PMID:25351917)
• Increased expression of JAG2, a target of miR-1280, is associated with high metastatic dissemination at diagnosis and a poor outcome in medulloblastoma. (PMID:25576913)
• In CL+/-P Malay patients, the prevalence of mutations in the Jagged2 gene was 12.5%. Three variants (g.19779C>T, g.19547G>A, and g.19712C>T) were identified in the Jagged2 gene among nonsyndromic CL+/-P and noncleft patients. Only g.19712C>T showed a significant association with nonsyndromic CL+/-P patients (P = .039). (PMID:26151095)
• Jagged-2 enhances immunomodulatory activity in adipose derived mesenchymal stem cells (PMID:26412454)
• these results show that the Notch signaling pathway in T cells is crucial for the induction of TH2-mediated allergic airway inflammation in an house dust mite -driven asthma model but that expression of Jagged 1 or Jagged 2 on DCs is not required (PMID:28111308)
• The authors present novel structures of human ligands Jagged2 and Delta-like4 and human Notch2, together with functional assays, which suggest that ligand-mediated coupling of membrane recognition and Notch binding is likely to be critical in establishing the optimal context for Notch signalling. (PMID:28572448)
• Results showed that Jagged2 was highly expressed in paclitaxel-resistant triple negative breast cancer (TNBC) tissues and cells. Jagged2 expression was found to be associated with cancer stem cell (CSC) properties of TNBC cells. Jagged2 maintains CSC properties of TNBC cells and paclitaxel resistance via regulating microRNA-200. (PMID:30280784)
• CD14(+) monocytes serve as Langerhans cell histiocytosis (LCH) cell precursor and JAG2-mediated activation of the Notch signaling pathway initiates a differentiation of monocytes toward LCH cells. (PMID:30296338)
• Long noncoding RNA (lncRNA) ENST00000455974 was significantly associated with TNM stage and distant metastasis in patients with DNA mismatch repair-proficient colon cancer. ENST00000455974 was gradually increased across the colonic normal-adenoma-carcinoma-metastasis sequence. ENST00000455974 was mainly located in the nucleus of colon cancer cells and it promoted growth and metastasis through up-regulating JAG2. (PMID:30473216)
• The CT genotype of rs741859 could significantly reduce the risk for NSCLP to 65% (P< 0.05) and the risk for cleft lip with or without cleft palate (CL/P) to 62% (P< 0.05). (PMID:31922603)
• Overexpression of JAG2 is related to poor outcomes in oral squamous cell carcinoma. (PMID:32250571)
• Jagged2 progressively increased expression from Stage I to III of Bladder Cancer and Melatonin-mediated downregulation of Notch/Jagged2 suppresses the Bladder Tumorigenesis via inhibiting PI3K/AKT/mTOR/MMPs signaling. (PMID:32792862)
• A form of muscular dystrophy associated with pathogenic variants in JAG2. (PMID:33861953)
• Splicing factor ESRP1 derived circ_0068162 promotes the progression of oral squamous cell carcinoma via the miR-186/JAG axis. (PMID:37966490)
• miR-541 is associated with the prognosis of liver cirrhosis and directly targets JAG2 to inhibit the activation of hepatic stellate cells. (PMID:38395762)
• ZEB2 alleviates Hirschsprung’s-associated enterocolitis by promoting the proliferation and differentiation of enteric neural precursor cells via the Notch-1/Jagged-2 pathway. (PMID:38485033)
• Ovarian tumor cell-derived JAGGED2 promotes omental metastasis through stimulating the Notch signaling pathway in the mesothelial cells. (PMID:38575576)
• Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages. (PMID:38636522)
• Jag1/2 maintain esophageal homeostasis and suppress foregut tumorigenesis by restricting the basal progenitor cell pool. (PMID:38750026)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	jag1b	ENSDARG00000013168
danio_rerio	jag2b	ENSDARG00000021389
danio_rerio	jag1a	ENSDARG00000030289
danio_rerio	dll4	ENSDARG00000070425
mus_musculus	Jag2	ENSMUSG00000002799
rattus_norvegicus	Jag2	ENSRNOG00000013927
drosophila_melanogaster	Ser	FBGN0004197
caenorhabditis_elegans	paml-2	WBGENE00009114
caenorhabditis_elegans		WBGENE00013498

Paralogs (5): JAG1 (ENSG00000101384), DLL4 (ENSG00000128917), DNER (ENSG00000187957), DLL1 (ENSG00000198719), NOTCH4 (ENSG00000204301)

Protein

Protein identifiers

Protein jagged-2 — Q9Y219 (reviewed: Q9Y219)

All UniProt accessions (1): Q9Y219

UniProt curated annotations — full annotation on UniProt →

Function. Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development.

Subcellular location. Membrane.

Tissue specificity. Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal recessive 27 (LGMDR27) [MIM:619566] An autosomal recessive muscular disorder characterized by progressive muscle weakness most prominent in the proximal lower limb and axial muscles, and resulting in walking difficulty or loss of ambulation. Additional more variable features include neck muscle weakness, scoliosis, and joint contractures. Some affected individuals manifest impaired intellectual development or speech delay, cardiomyopathy, and cardiac arrhythmia. Muscle biopsy shows non-specific dystrophic changes. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y219-1	Long	yes
Q9Y219-2	Short, HJAG2.del-E6

RefSeq proteins (2): NP_002217, NP_660142 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001007	VWF_dom	Domain
IPR001774	DSL	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR011651	Notch_ligand_N	Domain
IPR013032	EGF-like_CS	Conserved_site
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR026219	Jagged/Serrate	Family
IPR049883	NOTCH1_EGF-like	Domain
IPR056986	JAG1_1/2_dom	Domain

Pfam: PF00008, PF01414, PF07645, PF07657, PF12661, PF21700, PF23575

UniProt features (131 total): disulfide bond 51, strand 23, domain 18, sequence variant 14, sequence conflict 6, glycosylation site 5, helix 2, topological domain 2, region of interest 2, compositionally biased region 2, signal peptide 1, chain 1, turn 1, modified residue 1, transmembrane region 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
5MW5	X-RAY DIFFRACTION	2.7
5MW7	X-RAY DIFFRACTION	2.8
5MWF	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y219-F1	72.90	0.13

Functional residue map

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

Post-translational modifications (1): 1123

Disulfide bonds (51): 198–207, 211–223, 231–240, 245–256, 249–262, 264–273, 276–287, 282–293, 295–304, 311–323, 317–333, 335–344, 351–362, 356–371, 373–382, 389–400, 394–409, 411–420, 427–438, 432–447 …

Glycosylation sites (5): 153, 570, 619, 752, 1058

Function

Pathways and Gene Ontology

Reactome pathways

19 pathways

ID	Pathway
R-HSA-2122948	Activated NOTCH1 Transmits Signal to the Nucleus
R-HSA-2644606	Constitutive Signaling by NOTCH1 PEST Domain Mutants
R-HSA-2660826	Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691232	Constitutive Signaling by NOTCH1 HD Domain Mutants
R-HSA-2894862	Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants
R-HSA-2979096	NOTCH2 Activation and Transmission of Signal to the Nucleus
R-HSA-9013507	NOTCH3 Activation and Transmission of Signal to the Nucleus
R-HSA-157118	Signaling by NOTCH
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-1980143	Signaling by NOTCH1
R-HSA-1980145	Signaling by NOTCH2
R-HSA-2644602	Signaling by NOTCH1 PEST Domain Mutants in Cancer
R-HSA-2644603	Signaling by NOTCH1 in Cancer
R-HSA-2660825	Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant
R-HSA-2691230	Signaling by NOTCH1 HD Domain Mutants in Cancer
R-HSA-2894858	Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer
R-HSA-5663202	Diseases of signal transduction by growth factor receptors and second messengers
R-HSA-9012852	Signaling by NOTCH3

MSigDB gene sets: 311 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, REACTOME_SIGNALING_BY_NOTCH, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_RESPIRATORY_GASEOUS_EXCHANGE_BY_RESPIRATORY_SYSTEM, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOBP_THYMIC_T_CELL_SELECTION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_RESPIRATORY_SYSTEM_PROCESS, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_MALE_GAMETE_GENERATION, GOBP_MORPHOGENESIS_OF_EMBRYONIC_EPITHELIUM, GTGCCTT_MIR506

GO Biological Process (18): skeletal system development (GO:0001501), in utero embryonic development (GO:0001701), respiratory system process (GO:0003016), Notch signaling pathway (GO:0007219), spermatogenesis (GO:0007283), auditory receptor cell fate commitment (GO:0009912), morphogenesis of embryonic epithelium (GO:0016331), cell differentiation (GO:0030154), regulation of cell adhesion (GO:0030155), T cell differentiation (GO:0030217), regulation of cell population proliferation (GO:0042127), odontogenesis of dentin-containing tooth (GO:0042475), gamma-delta T cell differentiation (GO:0042492), thymic T cell selection (GO:0045061), positive regulation of Notch signaling pathway (GO:0045747), epithelial cell apoptotic process involved in palatal shelf morphogenesis (GO:1990134), cell communication (GO:0007154), multicellular organism development (GO:0007275)

GO Molecular Function (4): Notch binding (GO:0005112), calcium ion binding (GO:0005509), growth factor activity (GO:0008083), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
Signaling by NOTCH1 in Cancer	4
Signaling by NOTCH	3
Signaling by NOTCH1	1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1
Signaling by NOTCH1 HD Domain Mutants in Cancer	1
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1
Signaling by NOTCH2	1
Signaling by NOTCH3	1
Signal Transduction	1
Diseases of signal transduction by growth factor receptors and second messengers	1
Disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of cellular process	2
system development	1
chordate embryonic development	1
system process	1
respiratory gaseous exchange by respiratory system	1
cell surface receptor signaling pathway	1
developmental process involved in reproduction	1
male gamete generation	1
inner ear auditory receptor cell differentiation	1
inner ear receptor cell fate commitment	1
morphogenesis of an epithelium	1
embryonic morphogenesis	1
cellular developmental process	1
cell adhesion	1
lymphocyte differentiation	1
T cell activation	1
cell population proliferation	1
odontogenesis	1
T cell differentiation	1
gamma-delta T cell activation	1
T cell differentiation in thymus	1
T cell selection	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
apoptotic process involved in morphogenesis	1
secondary palate development	1
epithelial cell apoptotic process	1
cellular process	1
multicellular organismal process	1
anatomical structure development	1
signaling receptor binding	1
metal ion binding	1
receptor ligand activity	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3330 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
JAG2	NOTCH2	Q04721	991
JAG2	NOTCH4	Q99466	991
JAG2	NOTCH3	Q9UM47	988
JAG2	NOTCH1	P46531	988
JAG2	PYCR1	P32322	949
JAG2	SUPT6H	Q7KZ85	895
JAG2	SRRT	Q9BXP5	868
JAG2	PCF11	O94913	864
JAG2	RBPJ	Q06330	836
JAG2	POLR2A	P24928	828
JAG2	MFAP5	Q13361	812
JAG2	CDK9	P50750	779
JAG2	TRIM13	O60858	773
JAG2	EGF	P01133	771
JAG2	SETD2	Q9BYW2	746

IntAct

84 interactions, top by confidence:

A	B	Type	Score
VASN	JAG2	psi-mi:“MI:0407”(direct interaction)	0.700
JAG2	VASN	psi-mi:“MI:0407”(direct interaction)	0.700
JAG2	VASN	psi-mi:“MI:0403”(colocalization)	0.700
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
PLPPR1	STXBP3	psi-mi:“MI:0914”(association)	0.530
VASN	AP3B1	psi-mi:“MI:0914”(association)	0.530
LGALS1	PODXL	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530
CMA1	MANBA	psi-mi:“MI:0914”(association)	0.530
GFI1B	JAG2	psi-mi:“MI:0915”(physical association)	0.510
JAG2	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
JAG2	MBD1	psi-mi:“MI:0915”(physical association)	0.370
JAG2	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
ATXN7	JAG2	psi-mi:“MI:0915”(physical association)	0.370
CACNA1A	JAG2	psi-mi:“MI:0915”(physical association)	0.370
JAG2		psi-mi:“MI:0915”(physical association)	0.370
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
TMEM106A	QSOX1	psi-mi:“MI:0914”(association)	0.350
CLEC12B	GXYLT2	psi-mi:“MI:0914”(association)	0.350
CTLA4	TMEM120B	psi-mi:“MI:0914”(association)	0.350
TCTN2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
KLRC1	METTL15	psi-mi:“MI:0914”(association)	0.350
ST14	LIPT2	psi-mi:“MI:0914”(association)	0.350
ADAM32	GPR89A	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350
PATE1	MANBA	psi-mi:“MI:0914”(association)	0.350
MFAP5	MANBA	psi-mi:“MI:0914”(association)	0.350
DEFB136	MANBA	psi-mi:“MI:0914”(association)	0.350
NTN5	LRP4	psi-mi:“MI:0914”(association)	0.350

BioGRID (132): JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Proximity Label-MS), JAG2 (Proximity Label-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-MS), JAG2 (Affinity Capture-RNA), JAG2 (Affinity Capture-RNA), JAG2 (Affinity Capture-MS)

ESM2 similar proteins: A0JM12, A1A5Y0, A2VCU8, A6BM72, A6QR11, E9QJQ6, O42182, O70534, O88281, P23142, P35555, P35953, P80370, P97607, P98133, P98155, P98156, P98165, P98166, Q08879, Q09163, Q28832, Q2VWQ2, Q5R3Z7, Q5VY43, Q61220, Q61554, Q61555, Q62918, Q62919, Q6DIB5, Q7ZXL5, Q80T14, Q80T91, Q80V70, Q86XX4, Q8C088, Q8R4Y4, Q8VIK5, Q90827

Diamond homologs: A0A1F4, D3ZHH1, G5EDK5, O35474, O43854, O88277, P10040, P13508, P14585, P18168, P78504, P97607, Q06561, Q19319, Q20911, Q501P1, Q53RD9, Q5R7K9, Q5ZQU0, Q63722, Q6R8J2, Q70E20, Q8TER0, Q90Y54, Q90Y57, Q9JLB4, Q9QXX0, Q9QYE5, Q9W332, Q9Y219, A0A2K5V015, A8X481, B8JI71, P21956, P70490, Q5R6R1, Q5T1H1, Q8JZM4, Q8NFT8, Q9NL29

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
MIB2	up-regulates	JAG2	ubiquitination
TNF	“up-regulates quantity by expression”	JAG2	“transcriptional regulation”
JAG2	up-regulates	NOTCH	binding
JAG2	up-regulates	NOTCH2	binding
JAG2	up-regulates	NOTCH3	binding
JAG2	up-regulates	JAG1
JAG2	up-regulates	NOTCH1	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	4
Uncertain significance	255
Likely benign	68
Benign	23

Top pathogenic / likely-pathogenic (5)

Variant ID	HGVS	Classification
1527878	NM_002226.5(JAG2):c.1219_1225del (p.Phe407fs)	Pathogenic
1300192	NM_002226.5(JAG2):c.2515G>A (p.Gly839Arg)	Likely pathogenic
1527879	NM_002226.5(JAG2):c.841G>T (p.Gly281Cys)	Likely pathogenic
1677287	NM_002226.5(JAG2):c.493C>T (p.Arg165Ter)	Likely pathogenic
3064851	NM_002226.5(JAG2):c.312C>A (p.Tyr104Ter)	Likely pathogenic

SpliceAI

3682 predictions. Top by Δscore:

Variant	Effect	Δscore
14:105143168:GACCT:G	acceptor_loss	1.0000
14:105143170:CCT:C	acceptor_loss	1.0000
14:105143171:C:A	acceptor_loss	1.0000
14:105143171:C:CC	acceptor_gain	1.0000
14:105143172:T:C	acceptor_loss	1.0000
14:105143179:C:CT	acceptor_gain	1.0000
14:105143179:C:T	acceptor_gain	1.0000
14:105143180:G:T	acceptor_gain	1.0000
14:105143479:TA:T	donor_loss	1.0000
14:105143480:A:C	donor_loss	1.0000
14:105143481:C:CA	donor_loss	1.0000
14:105143635:AGGA:A	acceptor_gain	1.0000
14:105143636:GGA:G	acceptor_gain	1.0000
14:105143637:GA:G	acceptor_gain	1.0000
14:105143639:C:CC	acceptor_gain	1.0000
14:105143643:G:T	acceptor_gain	1.0000
14:105146381:TCAC:T	donor_loss	1.0000
14:105146382:CACCT:C	donor_loss	1.0000
14:105146383:A:AC	donor_gain	1.0000
14:105146383:A:AG	donor_loss	1.0000
14:105146384:C:CC	donor_gain	1.0000
14:105146384:CCTTG:C	donor_gain	1.0000
14:105146496:GATCA:G	acceptor_gain	1.0000
14:105146497:ATCA:A	acceptor_gain	1.0000
14:105146498:TCA:T	acceptor_gain	1.0000
14:105146498:TCAC:T	acceptor_loss	1.0000
14:105146499:C:CT	acceptor_gain	1.0000
14:105146499:CA:C	acceptor_gain	1.0000
14:105146499:CACTG:C	acceptor_loss	1.0000
14:105146500:AC:A	acceptor_loss	1.0000

AlphaMissense

8146 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:105155760:C:A	W235C	0.999
14:105155760:C:G	W235C	0.999
14:105155845:C:G	C207S	0.999
14:105155845:C:T	C207Y	0.999
14:105155846:A:T	C207S	0.999
14:105155872:C:G	C198S	0.999
14:105155873:A:T	C198S	0.999
14:105167760:C:A	W138C	0.999
14:105167760:C:G	W138C	0.999
14:105167762:A:G	W138R	0.999
14:105167762:A:T	W138R	0.999
14:105167974:C:G	C67S	0.999
14:105167975:A:T	C67S	0.999
14:105147333:G:C	C824W	0.998
14:105150998:G:C	C458W	0.998
14:105152169:C:G	C304S	0.998
14:105152170:A:T	C304S	0.998
14:105155746:C:G	C240S	0.998
14:105155747:A:T	C240S	0.998
14:105155773:C:G	C231S	0.998
14:105155774:A:T	C231S	0.998
14:105155797:C:G	C223S	0.998
14:105155798:A:T	C223S	0.998
14:105155833:C:G	C211S	0.998
14:105155834:A:T	C211S	0.998
14:105155844:G:C	C207W	0.998
14:105155845:C:A	C207F	0.998
14:105155846:A:G	C207R	0.998
14:105155871:G:C	C198W	0.998
14:105155872:C:T	C198Y	0.998

dbSNP variants (sampled 300 via entrez): RS1000061038 (14:105159078 C>A), RS1000088191 (14:105166744 G>A), RS1000329828 (14:105160076 A>C), RS1000367024 (14:105168546 C>A), RS1000382795 (14:105143179 C>A,T), RS1000503759 (14:105140537 G>A), RS1000534417 (14:105140851 C>T), RS1000552851 (14:105165688 G>A), RS1000686252 (14:105142624 G>A), RS1000703971 (14:105167477 G>A), RS1000754513 (14:105167580 C>A,T), RS1000868649 (14:105159224 A>C), RS1000912788 (14:105146919 A>C,T), RS1000931215 (14:105151604 C>T), RS1001098532 (14:105156134 G>A,C)

Disease associations

OMIM: gene MIM:602570 | disease phenotypes: MIM:619566, MIM:614228, MIM:119530

GenCC curated gene-disease

Disease	Classification	Inheritance
muscular dystrophy, limb-girdle, autosomal recessive 27	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive limb-girdle muscular dystrophy	Moderate	AR

Mondo (3): muscular dystrophy, limb-girdle, autosomal recessive 27 (MONDO:0030456), Charcot-Marie-Tooth disease axonal type 2O (MONDO:0013644), orofacial cleft 1 (MONDO:0007335)

Orphanet (2): Autosomal dominant Charcot-Marie-Tooth disease type 2O (Orphanet:284232), Orofacial clefting syndrome (Orphanet:139039)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000729	Autistic behavior
HP:0000750	Delayed speech and language development
HP:0001256	Mild intellectual disability
HP:0001638	Cardiomyopathy
HP:0001716	Wolff-Parkinson-White syndrome
HP:0001771	Achilles tendon contracture
HP:0002505	Loss of ambulation
HP:0002650	Scoliosis
HP:0002987	Elbow flexion contracture
HP:0003044	Shoulder flexion contracture
HP:0003202	Skeletal muscle atrophy
HP:0003236	Elevated circulating creatine kinase concentration
HP:0003306	Spinal rigidity
HP:0003458	EMG: myopathic abnormalities
HP:0003557	Increased variability in muscle fiber diameter
HP:0003560	Muscular dystrophy
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0003676	Progressive
HP:0003712	Skeletal muscle hypertrophy
HP:0006380	Knee flexion contracture
HP:0008959	Distal upper limb muscle weakness
HP:0008994	Proximal lower limb muscle weakness
HP:0008997	Proximal upper limb muscle weakness
HP:0009053	Distal lower limb muscle weakness
HP:0011462	Young adult onset
HP:0011463	Childhood onset

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST009864_7	Fasting plasma glucose	6.000000e-08
GCST010703_198	Brain morphology (MOSTest)	1.000000e-11
GCST90002403_473	Red blood cell count	5.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004305	erythrocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C566121	Orofacial Cleft 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	5
Cadmium Chloride	decreases expression, increases expression, decreases reaction, increases cleavage, increases phosphorylation	4
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance, increases expression	3
Valproic Acid	increases expression, increases methylation, affects expression	3
Particulate Matter	increases expression, decreases expression, increases abundance, affects cotreatment	3
cobaltous chloride	decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Calcitriol	decreases expression, increases expression	2
Cisplatin	increases expression, decreases expression, affects cotreatment	2
Copper	affects binding, increases expression, decreases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol A	decreases expression	1
trichostatin A	affects expression, decreases reaction	1
beta-lapachone	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	decreases expression, increases abundance, affects cotreatment	1
sulindac sulfide	increases expression	1
isobutyl alcohol	increases expression, affects cotreatment, increases abundance	1
phenethyl isothiocyanate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
tebuconazole	decreases expression	1
abrine	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, decreases expression	1
enzalutamide	affects expression	1
jinfukang	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Arsenic Trioxide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1

Cellosaurus cell lines

5 cell lines: 4 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B1UZ	Abcam HeLa JAG2 KO	Cancer cell line	Female
CVCL_D7SX	Ubigene A-549 JAG2 KO	Cancer cell line	Male
CVCL_D8NP	Ubigene HCT 116 JAG2 KO	Cancer cell line	Male
CVCL_D9HQ	Ubigene HEK293 JAG2 KO	Transformed cell line	Female
CVCL_E0FU	Ubigene HeLa JAG2 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease