NUCB2

Summary

NUCB2 (nucleobindin 2, HGNC:8044) is a protein-coding gene on chromosome 11p15.1, encoding Nucleobindin-2 (P80303). Calcium-binding protein which may have a role in calcium homeostasis.

This gene encodes a protein with a suggested role in calcium level maintenance, eating regulation in the hypothalamus, and release of tumor necrosis factor from vascular endothelial cells. This protein binds calcium and has EF-folding domains.

Source: NCBI Gene 4925 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 59 total
• Druggable target: yes
• MANE Select transcript: NM_005013

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8044
Approved symbol	NUCB2
Name	nucleobindin 2
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	NEFA
Ensembl gene	ENSG00000070081
Ensembl biotype	protein_coding
OMIM	608020
Entrez	4925

Gene structure

Transcript identifiers

Ensembl transcripts: 79 — 72 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron, 2 nonsense_mediated_decay

ENST00000323688, ENST00000525637, ENST00000526120, ENST00000527580, ENST00000527735, ENST00000528644, ENST00000529010, ENST00000529313, ENST00000530527, ENST00000530964, ENST00000531172, ENST00000531242, ENST00000532240, ENST00000533511, ENST00000533738, ENST00000533773, ENST00000533926, ENST00000620945, ENST00000646648, ENST00000909713, ENST00000909714, ENST00000909715, ENST00000909716, ENST00000909717, ENST00000909718, ENST00000909719, ENST00000909720, ENST00000909721, ENST00000909722, ENST00000909723, ENST00000909724, ENST00000909725, ENST00000909726, ENST00000909727, ENST00000909728, ENST00000909729, ENST00000909730, ENST00000909731, ENST00000909732, ENST00000909733, ENST00000909734, ENST00000909735, ENST00000909736, ENST00000909737, ENST00000909738, ENST00000909739, ENST00000909740, ENST00000909741, ENST00000909742, ENST00000909743, ENST00000909744, ENST00000909745, ENST00000909746, ENST00000909747, ENST00000909748, ENST00000909749, ENST00000935684, ENST00000950418, ENST00000950419, ENST00000950420, ENST00000950421, ENST00000950422, ENST00000950423, ENST00000950424, ENST00000950425, ENST00000950426, ENST00000950427, ENST00000950428, ENST00000950429, ENST00000950430, ENST00000950431, ENST00000950432, ENST00000950433, ENST00000950434, ENST00000950435, ENST00000950436, ENST00000950437, ENST00000950438, ENST00000950439

RefSeq mRNA: 14 — MANE Select: NM_005013 NM_001330227, NM_001352661, NM_001352662, NM_001352663, NM_001352664, NM_001352665, NM_001352666, NM_001352667, NM_001352668, NM_001352669, NM_001352670, NM_001352671, NM_001352672, NM_005013

CCDS: CCDS41623

Canonical transcript exons

ENST00000529010 — 14 exons

Exon	Start	End
ENSE00000886091	17311193	17311283
ENSE00001538067	17282789	17282943
ENSE00002161760	17331412	17332211
ENSE00002165521	17276739	17276828
ENSE00003303058	17301744	17301870
ENSE00003355164	17309572	17309675
ENSE00003359747	17310825	17311010
ENSE00003389700	17311872	17311930
ENSE00003428011	17296104	17296211
ENSE00003467633	17295324	17295467
ENSE00003471049	17330902	17330983
ENSE00003483697	17312028	17312120
ENSE00003492541	17315386	17315475
ENSE00003673097	17330127	17330297

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.81.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.1114 / max 985.0416, expressed in 1798 samples.

FANTOM5 promoters (14 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113264	24.4279	1750
113263	10.2171	1649
113268	9.0009	1337
113265	1.0666	483
113269	0.7278	369
113259	0.6856	253
113266	0.6678	297
113255	0.4291	184
113258	0.3437	88
113267	0.3135	146

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	99.81	gold quality
tendon of biceps brachii	UBERON:0008188	99.67	gold quality
bronchial epithelial cell	CL:0002328	99.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	99.50	gold quality
seminal vesicle	UBERON:0000998	99.34	gold quality
bone marrow cell	CL:0002092	99.32	gold quality
corpus epididymis	UBERON:0004359	99.29	gold quality
calcaneal tendon	UBERON:0003701	99.21	gold quality
tendon	UBERON:0000043	99.20	gold quality
epithelium of bronchus	UBERON:0002031	99.17	gold quality
bronchus	UBERON:0002185	99.17	gold quality
trabecular bone tissue	UBERON:0002483	99.11	gold quality
body of pancreas	UBERON:0001150	99.08	gold quality
mucosa of paranasal sinus	UBERON:0005030	99.07	gold quality
tongue squamous epithelium	UBERON:0006919	99.07	gold quality
nasal cavity mucosa	UBERON:0001826	99.04	gold quality
oral cavity	UBERON:0000167	98.88	gold quality
bone marrow	UBERON:0002371	98.79	gold quality
cauda epididymis	UBERON:0004360	98.70	gold quality
islet of Langerhans	UBERON:0000006	98.64	gold quality
lower esophagus mucosa	UBERON:0035834	98.51	gold quality
pituitary gland	UBERON:0000007	98.44	gold quality
pharyngeal mucosa	UBERON:0000355	98.39	gold quality
pancreas	UBERON:0001264	98.38	gold quality
epithelium of nasopharynx	UBERON:0001951	98.38	gold quality
pericardium	UBERON:0002407	98.38	gold quality
stromal cell of endometrium	CL:0002255	98.26	gold quality
adenohypophysis	UBERON:0002196	98.16	gold quality
pylorus	UBERON:0001166	98.14	gold quality
left testis	UBERON:0004533	97.90	gold quality

Single-cell (SCXA)

Detected in 24 experiment(s), a significant marker in 20.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	1895.98
E-MTAB-9801	yes	877.30
E-CURD-88	yes	227.67
E-HCAD-4	yes	81.98
E-CURD-122	yes	42.25
E-HCAD-1	yes	35.84
E-CURD-46	yes	35.78
E-CURD-112	yes	30.82
E-HCAD-13	yes	24.70
E-MTAB-8410	yes	24.49
E-GEOD-125970	yes	22.99
E-MTAB-9067	yes	19.40
E-HCAD-11	yes	16.34
E-GEOD-130148	yes	14.27
E-MTAB-8498	yes	13.80

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX1

miRNA regulators (miRDB)

19 targeting NUCB2, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-3691-3P	97.90	65.97	791
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-148B-5P	97.29	66.30	992
HSA-MIR-6874-3P	97.29	66.34	975
HSA-MIR-610	96.84	67.98	905
HSA-MIR-6726-5P	95.97	63.72	841
HSA-MIR-920	95.97	63.95	811
HSA-MIR-4300	95.85	64.56	1003
HSA-MIR-5591-5P	95.85	64.76	1002
HSA-MIR-4633-3P	93.85	63.56	534
HSA-MIR-6500-5P	93.85	63.64	522

Literature-anchored findings (GeneRIF, showing 40)

• Calcium-dependent ARTS-1-nucleobindin 2 complexes associate with TNFR1 prior to the commitment of TNFR1 to pathways that result in the constitutive release of TNFR1 exosome-like vesicles or the inducible proteolytic cleavage of TNFR1 ectodomains. (PMID:16407280)
• NUCB2-ARTS-1 complexes play an important role in mediating tumor necrosis factor receptor 1 release to the extracellular compartment. (PMID:16407280)
• results suggest that the functions of nucleobindins could be modulated by caspase-mediated cleavage in apoptosis (PMID:18154733)
• low ghrelin and especially the dramatically elevated nesfatin-1 levels might contribute to the pathophyisology of epilepsy[Nesfatin-1] (PMID:19262995)
• NUCB2 may be implicated in gastric secretion by establishing an agonist-releasable Ca2+ store in ER or Golgi apparatus, signalling via heterotrimeric Galpha proteins and/or mediating the exocytosis of the secretory granules. (PMID:19351608)
• nucb2 is the direct target gene of AML1 and AML1-ETO, the transcription regulation of AML1, AML1-ETO on nucb2 is carried out via repressing its promoter activity. (PMID:20030931)
• The release of NUCB2 from isolated islets was significantly elevated following glucose challenge. (PMID:20032201)
• Data report that nesfatin-1 is a novel depot specific adipokine preferentially produced by sc tissue, with obesity- and food deprivation-regulated expression. (PMID:20427481)
• lack of nesfatin-1 response to the exercise protocols may be partially due to the fasting condition (PMID:20625762)
• Apelins and nesfatin-1 concentrations were higher in mature milk than in colostrum (P<0.05). The concentration of apelins, ghrelins and nesfatin-1 in serum and milk in gestational diabetic lactating women was lower than in control samples (PMID:20813143)
• nesfatin-1 levels may be regulated by nutrition status and response to starvation. (PMID:20937336)
• Potential weight-reducing actions of nesfatin-1/NUCB-2 treatment. (PMID:21252251)
• polymorphisms in the NUCB2 gene could play an important role in the protection against the development of obesity in male subjects (PMID:21459029)
• Increased serum prolactin and nesfatin-1 concentrations, decreased ghrelin concentrations could be used as markers to identify patients that have suffered a recent epileptic seizure or other paroxysmal event (psychogenic). (PMID:21554911)
• structural basis for the properties of Calnuc and NUCB2 binding to Galpha subunits and its regulation by calcium ions. (PMID:21653697)
• This study demonistrated thatsex difference in NUCB2 dynamic expressions in the midbrain of drug-free depressed suicide victims. (PMID:21803054)
• High NUCB2 is associated with recurrence and metastasis in breast carcinoma. (PMID:21988594)
• Plasma nesfatin-1 concentrations were found to be elevated in subjects with both impaired glucose tolerance and newly diagnosed T2 diabetes mellitus. (PMID:22020667)
• nesfatin-1 levels did not differ between hemodialysis patients and healthy subjects and negatively correlated with protein intake (PMID:22036920)
• Human islet NUCB2 mRNA was reduced in T2D subjects but upregulated after culture in glucolipotoxic conditions. Furthermore, a positive correlation between NUCB2 and glucagon and insulin gene expression, as well as insulin secretory capacity, was evident. (PMID:22108805)
• Data suggest that maternal serum levels of nesfatin-1 (derived from NUCB2) are lower in patients with gestational diabetes compared with control pregnant women; however, the cord blood nesfatin-1 levels are similar. (PMID:22203468)
• the details of nesfatin-1 physiology ought to be clarified, and it may be considered suitable in the future, as a potential drug in the pharmacotherapy of obesity–{REVIEW} (PMID:22225987)
• We have demonstrated that the Wa antigen is NEFA or nucleobindin-2, which binds specific tRNA species, and is distributed in specific human tissues. (PMID:22270345)
• NUCB2 may operate directly at the testicular level to link energy homeostasis, puberty onset, and gonadal function (PMID:22334726)
• Lower nesfatin-1 concentration may plays a very important role in the development of polycystic ovary syndrome (PMID:22367584)
• Nesfatin-1 concentrations were reduced in non-alcoholic fatty liver disease. (PMID:22950627)
• we have identified the first rare genetic variants in the NUCB2 gene in obese individuals (frequency 0.2%), suggesting that NUCB2 might indeed be involved in the regulation of energy homeostasis and food intake. (PMID:23141462)
• Nesfatin-1 is involved in the physiological regulation of intrauterine and postnatal growth and development in small for gestational ages infants. (PMID:23155701)
• nesfatin-1 levels are decreased in large for gestational age compared to appropriate for gestational age fetuses. (PMID:23178145)
• The NUCB2 variant c.1012C>G (Q338E) is associated with childhood adiposity. The GG genotype may be protective against excessive weight gain. (PMID:23266808)
• Loss of fat mass may decrease serum nesfatin-1 level in lung cancer patients with weight loss. (PMID:23269222)
• In advanced cystic fibrosis and low fat mass, nesfatin-1 plasma levels are significantly increased and inversely correlated with the fat mass. (PMID:23306670)
• Data suggest that serum nesfatin-1 are significantly lower in obese youth than in healthy control youth; no association was found with insulin resistance in obese subjects. (PMID:23346951)
• Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects. (PMID:23515787)
• A statistically significant correlation was found between the serum nesfatin-1 level and supraventricular tachycardia. (PMID:23524986)
• pro-osteogenic activity of NUCB2(1-83) (PMID:23613885)
• Nesfatin-1 levels were lower in children with untreated autoimmune thyroid diseases, however, the mechanism is also unknown. (PMID:23739643)
• This study provides a novel regulatory signaling pathway of nesfatin-1-regulated ovarian epithelial carcinoma growth and may contribute to ovarian cancer prevention and therapy, especially in obese patients. (PMID:23764403)
• Increased nucleobindin-2 (NUCB2) transcriptional activity links the regulation of insulin sensitivity in Type 2 diabetes mellitus. (PMID:23765387)
• Circulating nesfatin-1 may modulate glucose homeostasis during diabetes remission in gastric bypass and sleeve gastrectomy, and participate in regulating body weight in sleeve gastrectomy (PMID:23768444)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	nucb2b	ENSDARG00000036291
danio_rerio	nucb2a	ENSDARG00000036299
mus_musculus	Nucb2	ENSMUSG00000030659
rattus_norvegicus	Nucb2	ENSRNOG00000020456
drosophila_melanogaster	NUCB1	FBGN0052190
caenorhabditis_elegans		WBGENE00009674

Paralogs (1): NUCB1 (ENSG00000104805)

Protein

Protein identifiers

Nucleobindin-2 — P80303 (reviewed: P80303)

Alternative names: DNA-binding protein NEFA, Epididymis secretory protein Li 109, Gastric cancer antigen Zg4, Prepronesfatin

All UniProt accessions (12): P80303, A0A1B0GXJ7, A0A2R8Y6G7, E9PJP3, E9PKG6, E9PLE9, E9PLR0, E9PLR5, E9PM22, E9PRQ3, H0YD18, H0YEG8

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-binding protein which may have a role in calcium homeostasis. Acts as a non-receptor guanine nucleotide exchange factor which binds to and activates guanine nucleotide-binding protein (G-protein) alpha subunit GNAI3. Anorexigenic peptide, seems to play an important role in hypothalamic pathways regulating food intake and energy homeostasis, acting in a leptin-independent manner. May also exert hypertensive roles and modulate blood pressure through directly acting on peripheral arterial resistance. In intestinal epithelial cells, plays a role in the inhibition of hepatic glucose production via MC4R receptor leading to increased cyclic adenosine monophosphate (cAMP) levels and glucagon-like peptide 1 (GLP-1) secretion.

Subunit / interactions. Interacts (via GBA motif) with guanine nucleotide-binding protein G(i) alpha subunit GNAI3. Preferentially interacts with inactive rather than active GNAI3. Interaction with GNAI3 is inhibited when NUCB2 binds calcium, probably due to a conformational change which renders the GBA motif inaccessible. Binds to the postmitotic growth suppressor NDN; coexpression abolishes NUCB2 secretion. Interacts with MC4R.

Subcellular location. Golgi apparatus. Membrane. Cytoplasm. Secreted. Endoplasmic reticulum. Nucleus envelope Secreted.

Tissue specificity. Predominantly expressed in spleen, testis and normal stomach.

Domain organisation. The GBA (G-alpha binding and activating) motif mediates binding to the alpha subunits of guanine nucleotide-binding proteins (G proteins).

Polymorphism. Deletion of Gln-402 is frequent.

Miscellaneous. NEFA stands for N=DNA-binding; EF=EF-hand; A=Acidic region.

Similarity. Belongs to the nucleobindin family.

Isoforms (2)

UniProt ID	Names	Canonical?
P80303-1	1	yes
P80303-2	2

RefSeq proteins (14): NP_001317156, NP_001339590, NP_001339591, NP_001339592, NP_001339593, NP_001339594, NP_001339595, NP_001339596, NP_001339597, NP_001339598, NP_001339599, NP_001339600, NP_001339601, NP_005004* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR040250	Nucleobindin	Family
IPR057576	NUCB1_N	Domain

Pfam: PF13499, PF25434

UniProt features (25 total): binding site 8, region of interest 3, chain 2, modified residue 2, sequence variant 2, domain 2, signal peptide 1, compositionally biased region 1, splice variant 1, sequence conflict 1, DNA-binding region 1, short sequence motif 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P80303-F1	84.43	0.57

Functional residue map

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

Ligand- & substrate-binding residues (8): 254; 256; 258; 265; 306; 308; 310; 317

Post-translational modifications (2): 257, 332

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 296 (showing top): GRUETZMANN_PANCREATIC_CANCER_DN, GOZGIT_ESR1_TARGETS_DN, HOEGERKORP_CD44_TARGETS_TEMPORAL_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, CAFFAREL_RESPONSE_TO_THC_UP, RACCACAR_AML_Q6, WANG_ESOPHAGUS_CANCER_VS_NORMAL_DN, ONKEN_UVEAL_MELANOMA_UP, HUTTMANN_B_CLL_POOR_SURVIVAL_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM3, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN, MODULE_206, HESS_TARGETS_OF_HOXA9_AND_MEIS1_UP, DELYS_THYROID_CANCER_DN, CAFFAREL_RESPONSE_TO_THC_24HR_5_UP

GO Biological Process (1): small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (6): G-protein alpha-subunit binding (GO:0001965), DNA binding (GO:0003677), guanyl-nucleotide exchange factor activity (GO:0005085), calcium ion binding (GO:0005509), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (14): obsolete extracellular space (GO:0005615), nuclear outer membrane (GO:0005640), endoplasmic reticulum (GO:0005783), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), extracellular region (GO:0005576), nucleus (GO:0005634), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
intracellular membrane-bounded organelle	4
endomembrane system	3
intracellular signaling cassette	1
protein binding	1
nucleic acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
metal ion binding	1
binding	1
cation binding	1
nuclear membrane	1
organelle outer membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
membrane	1
cell periphery	1
extracellular vesicle	1
nucleus	1
organelle envelope	1
intracellular anatomical structure	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

898 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NUCB2	ERAP1	Q9NZ08	924
NUCB2	LEP	P41159	761
NUCB2	POMC	P01189	748
NUCB2	GHRL	Q9UBU3	717
NUCB2	LEPR	P48357	672
NUCB2	OXT	P01178	612
NUCB2	CRH	P06850	591
NUCB2	CARTPT	Q16568	591
NUCB2	NPY	P01303	583
NUCB2	PYY	P10082	541
NUCB2	PMCH	P20382	531
NUCB2	NENF	Q9UMX5	521
NUCB2	HCRT	O43612	516
NUCB2	KCNJ11	Q14654	513
NUCB2	INS	P01308	510

IntAct

60 interactions, top by confidence:

A	B	Type	Score
JUN	ATF2	psi-mi:“MI:0914”(association)	0.950
JUNB	FOS	psi-mi:“MI:0914”(association)	0.950
TNNI2	TNNC1	psi-mi:“MI:0914”(association)	0.590
KXD1	HIP1	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
NUCB2	GADD45A	psi-mi:“MI:0915”(physical association)	0.510
GADD45A	NUCB2	psi-mi:“MI:0915”(physical association)	0.510
NUCB1	NUCB2	psi-mi:“MI:0915”(physical association)	0.500
NUCB1	NUCB2	psi-mi:“MI:0914”(association)	0.500
NUCB2	CASP8	psi-mi:“MI:0194”(cleavage reaction)	0.440
CASP7	NUCB2	psi-mi:“MI:0194”(cleavage reaction)	0.440
CASP6	NUCB2	psi-mi:“MI:0194”(cleavage reaction)	0.440
NUCB2	CASP3	psi-mi:“MI:0194”(cleavage reaction)	0.440
ZNF280A	NUCB2	psi-mi:“MI:0915”(physical association)	0.400
NUCB2		psi-mi:“MI:0915”(physical association)	0.370
GNAI3	NUCB2	psi-mi:“MI:0915”(physical association)	0.370
NUCB2	GNAS	psi-mi:“MI:0915”(physical association)	0.370
NUCB2	SMARCD1	psi-mi:“MI:0915”(physical association)	0.370
XPO1	NUCB2	psi-mi:“MI:0915”(physical association)	0.370
CUL2	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
NDUFS3	ACOT7	psi-mi:“MI:0914”(association)	0.350
XPNPEP3	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
	GAPDH	psi-mi:“MI:0914”(association)	0.350
CAPZB	ENAH	psi-mi:“MI:0914”(association)	0.350
COPA	ESYT2	psi-mi:“MI:0914”(association)	0.350
COPE	ESYT2	psi-mi:“MI:0914”(association)	0.350
YIPF5	EI24	psi-mi:“MI:0914”(association)	0.350
CSTL1	DENND11	psi-mi:“MI:0914”(association)	0.350

BioGRID (134): NUCB2 (Affinity Capture-MS), CALU (Co-fractionation), SPTAN1 (Co-fractionation), SSSCA1 (Co-fractionation), NUCB2 (Proximity Label-MS), NUCB2 (Proximity Label-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-MS), NUCB2 (Affinity Capture-RNA), NUCB2 (Affinity Capture-RNA), NUCB2 (Two-hybrid)

ESM2 similar proteins: A0A7J6K452, A5PJN0, A5YVD9, A8WQT4, D4QD81, G5ED46, O54998, O74903, O76038, O77636, O81223, P10731, P14925, P19021, P34714, P39931, P45961, P78536, P80303, P81117, P97467, Q06BR2, Q2L6K8, Q3HRN7, Q3ZBZ1, Q4R585, Q5BKL9, Q5QIT3, Q5ZKE5, Q61112, Q66JA6, Q6AXZ3, Q6DJ05, Q6R556, Q75KU4, Q7ZUC2, Q803V3, Q869S9, Q8VZQ4, Q91WD9

Diamond homologs: P80303, P81117, Q02818, Q02819, Q0P569, Q5R4U1, Q63083, Q9JI85

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 83 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
Apoptotic execution phase	5	44.1×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2574 predictions. Top by Δscore:

Variant	Effect	Δscore
11:17276828:GG:G	donor_loss	1.0000
11:17276830:T:A	donor_loss	1.0000
11:17286714:GTAG:G	donor_gain	1.0000
11:17295323:GAT:G	acceptor_gain	1.0000
11:17295372:T:G	acceptor_gain	1.0000
11:17295463:CACCA:C	donor_gain	1.0000
11:17295464:ACCAG:A	donor_loss	1.0000
11:17295465:CCA:C	donor_gain	1.0000
11:17295466:CA:C	donor_gain	1.0000
11:17295467:AG:A	donor_loss	1.0000
11:17295468:G:GG	donor_gain	1.0000
11:17295468:GT:G	donor_loss	1.0000
11:17295469:TA:T	donor_loss	1.0000
11:17295470:AA:A	donor_loss	1.0000
11:17296208:AAAG:A	donor_loss	1.0000
11:17296210:AGGT:A	donor_loss	1.0000
11:17296212:G:T	donor_loss	1.0000
11:17296213:T:A	donor_loss	1.0000
11:17301743:GA:G	acceptor_gain	1.0000
11:17309570:A:AG	acceptor_gain	1.0000
11:17309571:G:GA	acceptor_gain	1.0000
11:17309571:GA:G	acceptor_gain	1.0000
11:17309571:GAT:G	acceptor_gain	1.0000
11:17309571:GATA:G	acceptor_gain	1.0000
11:17309571:GATAT:G	acceptor_gain	1.0000
11:17309673:GCG:G	donor_gain	1.0000
11:17309674:CGG:C	donor_loss	1.0000
11:17309675:GGTG:G	donor_loss	1.0000
11:17309676:G:C	donor_loss	1.0000
11:17309676:G:GG	donor_gain	1.0000

AlphaMissense

2858 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:17296132:T:C	L58P	1.000
11:17301799:T:A	L103H	1.000
11:17301799:T:C	L103P	1.000
11:17301812:A:C	K107N	1.000
11:17301812:A:T	K107N	1.000
11:17309665:T:C	L158P	1.000
11:17296128:T:C	Y57H	0.999
11:17296129:A:G	Y57C	0.999
11:17296132:T:A	L58H	0.999
11:17296153:T:A	L65Q	0.999
11:17296153:T:C	L65P	0.999
11:17296183:T:C	L75P	0.999
11:17301766:T:C	L92P	0.999
11:17301808:T:C	L106P	0.999
11:17301810:A:G	K107E	0.999
11:17301811:A:T	K107I	0.999
11:17309640:T:C	F150L	0.999
11:17309641:T:C	F150S	0.999
11:17309641:T:G	F150C	0.999
11:17309642:T:A	F150L	0.999
11:17309642:T:G	F150L	0.999
11:17309656:T:C	L155S	0.999
11:17309665:T:A	L158Q	0.999
11:17310838:T:C	L166P	0.999
11:17311220:T:A	W233R	0.999
11:17311220:T:C	W233R	0.999
11:17311222:G:C	W233C	0.999
11:17311222:G:T	W233C	0.999
11:17315470:T:A	W333R	0.999
11:17315470:T:C	W333R	0.999

dbSNP variants (sampled 300 via entrez): RS1000007812 (11:17298842 G>A,T), RS1000012915 (11:17337283 C>T), RS1000095942 (11:17276441 A>G), RS1000156132 (11:17294322 G>T), RS1000189111 (11:17343995 G>C), RS1000258952 (11:17302286 G>C), RS1000314559 (11:17294070 C>G,T), RS1000402767 (11:17309158 TA>T,TAA), RS1000438872 (11:17345309 T>C), RS1000469200 (11:17281339 TG>T), RS1000469911 (11:17345471 G>A), RS1000490522 (11:17329013 A>G,T), RS1000561303 (11:17281507 G>A,T), RS1000615951 (11:17336488 A>C), RS1000618509 (11:17336124 G>A)

Disease associations

OMIM: gene MIM:608020 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST000817_141	Height	5.000000e-09
GCST004562_111	Waist circumference adjusted for body mass index	5.000000e-06
GCST004562_143	Waist circumference adjusted for body mass index	3.000000e-08
GCST004562_38	Waist circumference adjusted for body mass index	4.000000e-08
GCST004562_58	Waist circumference adjusted for body mass index	3.000000e-06
GCST004563_120	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	2.000000e-07
GCST004563_124	Waist circumference adjusted for BMI (joint analysis main effects and physical activity interaction)	4.000000e-07
GCST004564_40	Waist circumference adjusted for BMI in active individuals	3.000000e-07
GCST004564_41	Waist circumference adjusted for BMI in active individuals	3.000000e-07
GCST004776_58	Systolic blood pressure	4.000000e-06
GCST005951_67	Body mass index	6.000000e-09
GCST005951_68	Body mass index	3.000000e-09
GCST007096_18	Pulse pressure	8.000000e-08
GCST007099_3	Systolic blood pressure	5.000000e-11
GCST011011_67	Youthful appearance (self-reported)	3.000000e-08
GCST012226_343	Waist circumference adjusted for body mass index	7.000000e-10
GCST90002395_81	Mean platelet volume	3.000000e-13

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007789	BMI-adjusted waist circumference
EFO:0008002	physical activity measurement
EFO:0006335	systolic blood pressure
EFO:0004340	body mass index
EFO:0005763	pulse pressure measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067290 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs757081	Efficacy	3	hydrochlorothiazide	Hypertension

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs757081	NUCB2	3	3.00	1	hydrochlorothiazide

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	5
Cyclosporine	affects expression, increases expression	5
Tunicamycin	increases expression	3
Valproic Acid	increases expression	3
bisphenol A	affects expression, increases expression	2
trichostatin A	affects cotreatment, decreases expression	2
perfluorooctane sulfonic acid	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
belinostat	decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Testosterone	affects cotreatment, increases expression, decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cadmium Chloride	decreases expression, increases expression	2
Thapsigargin	increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
sodium arsenate	decreases expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
nickel chloride	decreases expression	1
cupric chloride	increases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one	decreases reaction, increases stability	1
K 7174	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651938	Binding	Binding affinity to human NUCB2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1PE	Abcam K-562 NUCB2 KO	Cancer cell line	Female
CVCL_D2L0	Abcam Raji NUCB2 KO	Cancer cell line	Male
CVCL_WQ17	Abcam Jurkat NUCB2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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