NELL1

Summary

NELL1 (neural EGFL like 1, HGNC:7750) is a protein-coding gene on chromosome 11p15.1, encoding Protein kinase C-binding protein NELL1 (Q92832). Plays a role in the control of cell growth and differentiation.

This gene encodes a cytoplasmic protein that contains epidermal growth factor (EGF)-like repeats. The encoded heterotrimeric protein may be involved in cell growth regulation and differentiation. A similar protein in rodents is involved in craniosynostosis. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 4745 — RefSeq curated summary.

At a glance

• GWAS associations: 20
• Clinical variants (ClinVar): 152 total
• MANE Select transcript: NM_006157

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7750
Approved symbol	NELL1
Name	neural EGFL like 1
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	IDH3GL, FLJ45906
Ensembl gene	ENSG00000165973
Ensembl biotype	protein_coding
OMIM	602319
Entrez	4745

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 7 protein_coding, 7 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000298925, ENST00000325319, ENST00000357134, ENST00000524738, ENST00000527873, ENST00000528046, ENST00000528495, ENST00000529218, ENST00000529595, ENST00000530672, ENST00000532434, ENST00000534263, ENST00000860940, ENST00000918540, ENST00000963666

RefSeq mRNA: 4 — MANE Select: NM_006157 NM_001288713, NM_001288714, NM_006157, NM_201551

CCDS: CCDS44555, CCDS73267, CCDS73268, CCDS7855

Canonical transcript exons

ENST00000357134 — 20 exons

Exon	Start	End
ENSE00001098565	20677932	20678060
ENSE00001138218	21560189	21560382
ENSE00001138237	21229332	21229454
ENSE00001138282	20928377	20928479
ENSE00001138289	20927308	20927442
ENSE00001138296	20919252	20919334
ENSE00002144364	21574972	21575686
ENSE00002192410	20669586	20669778
ENSE00003462759	20885444	20885540
ENSE00003466842	21370853	21370948
ENSE00003478566	21534374	21534514
ENSE00003489596	21573185	21573409
ENSE00003505714	20847583	20847753
ENSE00003522964	20960432	20960560
ENSE00003533769	20783680	20783830
ENSE00003593067	21113589	21113714
ENSE00003604997	20918182	20918254
ENSE00003656471	20947336	20947435
ENSE00003673516	20937786	20937859
ENSE00003693871	21570764	21570940

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 92.60.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9081 / max 217.7475, expressed in 210 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113434	1.4440	192
113435	0.3595	96
113438	0.0564	31
113433	0.0385	20
113436	0.0068	2
113437	0.0029	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	92.60	gold quality
buccal mucosa cell	CL:0002336	91.69	gold quality
ventricular zone	UBERON:0003053	88.89	gold quality
orbitofrontal cortex	UBERON:0004167	88.79	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.39	gold quality
middle temporal gyrus	UBERON:0002771	86.50	gold quality
prefrontal cortex	UBERON:0000451	85.32	gold quality
sperm	CL:0000019	85.06	gold quality
male germ cell	CL:0000015	82.09	gold quality
Brodmann (1909) area 10	UBERON:0013541	82.05	gold quality
frontal cortex	UBERON:0001870	81.94	gold quality
frontal lobe	UBERON:0016525	81.94	gold quality
superior frontal gyrus	UBERON:0002661	81.58	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	81.48	gold quality
cortical plate	UBERON:0005343	81.23	gold quality
frontal pole	UBERON:0002795	80.96	gold quality
entorhinal cortex	UBERON:0002728	80.95	gold quality
secondary oocyte	CL:0000655	80.81	gold quality
neocortex	UBERON:0001950	80.74	gold quality
Brodmann (1909) area 23	UBERON:0013554	80.74	gold quality
postcentral gyrus	UBERON:0002581	80.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	80.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.12	gold quality
cerebral cortex	UBERON:0000956	79.74	gold quality
primary visual cortex	UBERON:0002436	79.08	gold quality
parietal lobe	UBERON:0001872	78.97	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.64	gold quality
oocyte	CL:0000023	77.29	gold quality
right frontal lobe	UBERON:0002810	77.20	gold quality
ganglionic eminence	UBERON:0004023	76.45	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-ANND-2	yes	4815.00
E-CURD-119	yes	41.61
E-ANND-3	yes	5.68

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX2, SP7

miRNA regulators (miRDB)

31 targeting NELL1, 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-7110-3P	100.00	73.18	2486
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-383-3P	99.85	65.84	1359
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-370-5P	99.78	66.81	706
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-451B	99.55	68.28	1380
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-297	99.40	69.58	1418
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-640	98.44	66.93	644
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-1302	97.92	67.27	844
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-4298	97.26	66.59	765
HSA-MIR-627-5P	95.51	66.80	509

Literature-anchored findings (GeneRIF, showing 40)

• Transgenic mice overexpressing Nell-1 develop craniosynostosis. (PMID:12235118)
• Runx2 directly binds to the osteoblast specific binding elements 2 elements and transactivates the human NELL-1 promoter. (PMID:17042739)
• Promoter hypermethylation of NELL1 is a common, tissue-specific event in human EAC, occurs early during Barrett’s-associated esophageal neoplastic progression, and is a potential biomarker of poor prognosis in early-stage EAC (PMID:17452981)
• Data indicate that NELL1 is a ubiquitous inflammatory bowel disease susceptibility locus. (PMID:17684544)
• findings suggest that upon binding to a specific receptor NELL1 transduces an osteogenic signal through activation of certain Tyr-kinases associated with the Ras-MAPK cascade, and finally leads to the osteogenic differentiation (PMID:18082140)
• a potent growth factor that is highly specific to the osteochondral lineage, and has demonstrated robust induction of bone in multiple in vivo models [review] (PMID:20647499)
• The osteogenic effects of NELL1 on femoral distraction osteogenesis, was investigated. (PMID:20959151)
• Genome-wide association studies-reported associations between the NELL1, NCF4, and FAM92B genes and susceptibility to Crohn’s disease could not be replicated in Canadian children and young adults. (PMID:21472827)
• Nell-1 is a candidate growth factor able to induce pericyte osteogenic differentiation. (PMID:21615216)
• the effects of NELL-1 on osteoblastic differentiation and proliferation are partly through binding to APR3 (PMID:21723284)
• NELL-1 may produce functional cartilage with properties similar to native cartilage. (PMID:21902605)
• Results suggest that Osterix is a direct transcriptional regulator with repressive effect on NELL-1 gene expression, contributing to a delicate balance of regulatory effects on NELL-1 transcription with Runx2. (PMID:21931789)
• SHH and NELL-1 directed signaling produced additive effects on the pro-osteogenic and antiadipogenic differentiation of adipose derived stem cells. (PMID:22264144)
• Prediction of radiographic severity in Ankolysing Spondylitis based on clinical variables can be significantly improved by including SNPs at ADRB1 (rs1801253), NELL1 (rs8176785) and MHC (rs1634747, rs9270986, rs7451962 and rs241453) genes. (PMID:22495925)
• These results identify one potential mechanism of action for rhNELL-1 induced osteogenesis and highlight a fundamental difference between NELL-1 and BMP-2 signaling. (PMID:22580275)
• NELL1 is able to promote the osteogenic differentiation of periodontal ligament stem cells, which may be related to the downregulation of Msx2 expression. (PMID:22767336)
• Activation of the JNK pathway is necessary to mediate terminal osteogenic different-iation of Saos-2 osteosarcoma cells by rhNELL-1. (PMID:22797704)
• Data indicate that LvNELL1 infection promoted the osteogenic differentiation of hADSCs, and the effect was comparable with that of LvBMP2. (PMID:23017834)
• Two single-nucleotide polymorphisms of the NELL1 gene may represent a novel mechanism underlying hydrochlorothiazide-induced adverse metabolic effects (meta-analysis). (PMID:23400010)
• NELL1 overexpression greatly enhanced the osteogenic differentiation and mineral synthesis of iPSC-MSCs on RGD-grafted CPC scaffold for the first time. (PMID:25220281)
• CpG islands in the NELL1 and NELL2 promoters are hypermethylated in renal cell carcinoma.NELL1 and NELL2 protein expression is downregulated in clear cell renal carcinoma. (PMID:25726761)
• NELL-1 demonstrates diffuse and reliable expression in benign but not malignant bone-forming skeletal tumors (PMID:25791475)
• NELL-1 signaling activates Wnt/beta-catenin signaling. (PMID:26082355)
• We also detected lower relative expression of Nell-1 by real-time PCR. Furthermore, immunohistochemical analyses revealed that Nell-1 staining was less intense in cancer tissue relative to normal tissue and that the tumor cells had spread to the muscle (PMID:26090379)
• Data suggest that TSPN (N-terminal thrombospondin-1-like) domain of NELL1 exhibits major heparin-binding sites which may be involved in interaction of NELL1 with cell surface heparan sulfate proteoglycans. (PMID:26627376)
• lipoaspirate-derived hPSCs present a novel and abundant cell source of MSCs for cartilage regeneration, and the combinatorial application of NELL-1, TGF-beta3, and BMP-6 with hPSCs may remarkably enhance and accelerate cartilage repair. (PMID:26700847)
• establish the feasibility of combining NELL-1 with BMP2 to improve clinical bone regeneration and provide mechanistic insight into canonical Wnt pathway activity during NELL-1 and BMP2 osteogenesis (PMID:26772960)
• Results demonstrate that NELL1 is differentially expressed in fusion-positive alveolar rhabdomyosarcoma (ARMS) and in embryonal rhabdomyosarcoma (ERMS) samples, and they show that this transcriptional difference partially depends on genomic DNA methylation. The study also found that high NELL1 levels are correlated with negative RMS prognostic factors and with poor tumor outcomes. (PMID:28380437)
• This work indicates that NELL-1, HMGB1, and CCN2 might enhance bone defect healing via the recruitment of endogenous cells and induction of vascularization and act via different processes than BMP2. (PMID:28463604)
• NELL1 variant is associated with tobacco- and HPV-mediated oral oncogenesis. (PMID:30091681)
• Results show that NELL1 methylation level was 6.8% higher in renal cell cancer (RCC) tissues associated with advanced disease of distant metastases, and shorter RFS. Analyses suggested that NELL1 DNA methylation is a promising candidate prognostic epigenetic biomarker for more detailed analyses of RCC disease. (PMID:30272321)
• Study results suggest that NELL1 induces lung cancer stemlike cell differentiation, which provides a new potential therapeutic target for cancer stem cells. (PMID:30628703)
• results suggest that Robo2 functions as a receptor for NELL1/2, particularly under circumstances where Robo2 undergoes proteolytic digestion (PMID:30700556)
• The expression levels of neural markers were increased in rat pulp and in cultured human dental pulp stem cells stimulated with Nell-1 protein. This is the first study to demonstrate the effect of Nell-1 on dental pulp cells neural-like differentiation. (PMID:30979495)
• Nell-1 could reciprocally interact with APR3 and stimulate the differentiation and mineralization of human dental pulp cells. (PMID:31416616)
• Neural epidermal growth factor-like 1 protein (NELL-1) associated membranous nephropathy. (PMID:31901340)
• NELL1 is a target antigen in malignancy-associated membranous nephropathy. (PMID:32828756)
• NELL-1 Increased the Osteogenic Differentiation and mRNA Expression of Spheroids Composed of Stem Cells. (PMID:34201046)
• Anoctamin 5 promotes osteosarcoma development by increasing degradation of Nel-like proteins 1 and 2. (PMID:34238763)
• METTL3-Mediated lncRNA m(6)A Modification in the Osteogenic Differentiation of Human Adipose-Derived Stem Cells Induced by NEL-Like 1 Protein. (PMID:34505967)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nell3	ENSDARG00000096932
mus_musculus	Nell1	ENSMUSG00000055409
rattus_norvegicus	Nell1	ENSRNOG00000015675

Paralogs (1): NELL2 (ENSG00000184613)

Protein

Protein identifiers

Protein kinase C-binding protein NELL1 — Q92832 (reviewed: Q92832)

Alternative names: NEL-like protein 1, Nel-related protein 1

All UniProt accessions (3): Q92832, F5H6I3, J3KNC5

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in the control of cell growth and differentiation. Promotes osteoblast cell differentiation and terminal mineralization.

Subunit / interactions. Homotrimer. Binds to PKC beta-1. Interacts with ATRAID; the interaction promotes osteoblast cell differentiation and mineralization. Interacts with ROBO3.

Subcellular location. Cytoplasm. Nucleus envelope. Secreted.

Miscellaneous. It has been demonstrated that ROBO3 binds to both NELL1 and NELL2. However, NELL1 is not expressed in the spinal cord at the time of commissural axon growth to the midline and has no significant effect on commissural axon repulsion in vitro, suggesting that NELL1 is not a functional ligand for ROBO3 in commissural axons. It remains possible, however, that NELL1 functions as a ligand for ROBO3 at another spatiotemporal location.

Isoforms (2)

UniProt ID	Names	Canonical?
Q92832-1	1	yes
Q92832-2	2

RefSeq proteins (4): NP_001275642, NP_001275643, NP_006148, NP_963845 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000152	EGF-type_Asp/Asn_hydroxyl_site	PTM
IPR000742	EGF	Domain
IPR001007	VWF_dom	Domain
IPR001791	Laminin_G	Domain
IPR001881	EGF-like_Ca-bd_dom	Domain
IPR009030	Growth_fac_rcpt_cys_sf	Homologous_superfamily
IPR013320	ConA-like_dom_sf	Homologous_superfamily
IPR018097	EGF_Ca-bd_CS	Conserved_site
IPR024731	NELL2-like_EGF	Domain
IPR048287	TSPN-like_N	Domain
IPR049883	NOTCH1_EGF-like	Domain
IPR051586	PKC-binding_NELL	Family

Pfam: PF00093, PF02210, PF07645, PF12947

UniProt features (70 total): disulfide bond 18, strand 13, glycosylation site 12, domain 8, binding site 6, sequence variant 5, sequence conflict 3, signal peptide 1, chain 1, splice variant 1, helix 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6POL	X-RAY DIFFRACTION	1.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92832-F1	79.34	0.12

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 (6): 434; 435; 437; 453; 454; 457

Disulfide bonds (18): 395–407, 401–416, 418–432, 438–451, 445–460, 462–474, 480–493, 487–502, 504–515, 519–529, 523–535, 537–546, 553–566, 560–575, 577–594, 600–613, 607–622, 624–630

Glycosylation sites (12): 40, 53, 83, 224, 294, 372, 511, 562, 609, 708, 732, 758

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, BENPORATH_ES_WITH_H3K27ME3, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_OSTEOBLAST_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, DAVICIONI_RHABDOMYOSARCOMA_PAX_FOXO1_FUSION_UP, MORF_ZNF10, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_BONE_MINERALIZATION, GOBP_POSITIVE_REGULATION_OF_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEIN_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_METABOLIC_PROCESS, MORF_EPHA7, GOBP_OSSIFICATION, GOMF_GLYCOSAMINOGLYCAN_BINDING

GO Biological Process (9): nervous system development (GO:0007399), regulation of gene expression (GO:0010468), cell differentiation (GO:0030154), positive regulation of bone mineralization (GO:0030501), negative regulation of osteoblast proliferation (GO:0033689), negative regulation of protein catabolic process (GO:0042177), regulation of osteoblast differentiation (GO:0045667), positive regulation of osteoblast differentiation (GO:0045669), positive regulation of ossification (GO:0045778)

GO Molecular Function (4): protein kinase C binding (GO:0005080), calcium ion binding (GO:0005509), heparin binding (GO:0008201), protein binding (GO:0005515)

GO Cellular Component (6): obsolete extracellular space (GO:0005615), nuclear envelope (GO:0005635), cytoplasm (GO:0005737), perinuclear region of cytoplasm (GO:0048471), extracellular region (GO:0005576), nucleus (GO:0005634)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
osteoblast differentiation	2
system development	1
gene expression	1
regulation of macromolecule biosynthetic process	1
cellular developmental process	1
bone mineralization	1
regulation of bone mineralization	1
positive regulation of ossification	1
positive regulation of biomineral tissue development	1
negative regulation of cell population proliferation	1
osteoblast proliferation	1
regulation of osteoblast proliferation	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
regulation of cell differentiation	1
positive regulation of cell differentiation	1
regulation of osteoblast differentiation	1
ossification	1
regulation of ossification	1
positive regulation of multicellular organismal process	1
protein kinase binding	1
metal ion binding	1
glycosaminoglycan binding	1
sulfur compound binding	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2339 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NELL1	ANO6	Q4KMQ2	895
NELL1	ANO5	Q75V66	870
NELL1	THSD7A	Q9UPZ6	764
NELL1	PLA2R1	Q13018	718
NELL1	ANO1	Q5XXA6	563
NELL1	TNXB	P22105	562
NELL1	EXT2	Q93063	552
NELL1	EXT1	Q16394	545
NELL1	RUNX2	Q13950	535
NELL1	BMP2	P12643	523
NELL1	SEMA3B	Q13214	519
NELL1	PCDH7	O60245	439
NELL1	LCN9	Q8WX39	433
NELL1	TTLL11	Q8NHH1	427
NELL1	ZSCAN20	P17040	423

IntAct

47 interactions, top by confidence:

A	B	Type	Score
ARRDC1	WWP2	psi-mi:“MI:0914”(association)	0.850
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
NELL1	ATRAID	psi-mi:“MI:0915”(physical association)	0.610
NELL1	ATRAID	psi-mi:“MI:0403”(colocalization)	0.610
MEOX2	NELL1	psi-mi:“MI:0915”(physical association)	0.560
NELL1	EIF4B	psi-mi:“MI:0915”(physical association)	0.400
EEF1A1	NELL1	psi-mi:“MI:0915”(physical association)	0.400
NELL1	EIF5B	psi-mi:“MI:0915”(physical association)	0.400
PLCG1	NELL1	psi-mi:“MI:0915”(physical association)	0.400
NELL1	PPP4R3A	psi-mi:“MI:0915”(physical association)	0.400
NELL1	SLTM	psi-mi:“MI:0915”(physical association)	0.400
NELL1	NOL10	psi-mi:“MI:0915”(physical association)	0.400
SSRP1	NELL1	psi-mi:“MI:0915”(physical association)	0.400
NELL1	DNTTIP2	psi-mi:“MI:0915”(physical association)	0.400
NELL1	NEXN	psi-mi:“MI:0915”(physical association)	0.400
NELL1	HOXA1	psi-mi:“MI:0915”(physical association)	0.370
NELL1	MBD1	psi-mi:“MI:0915”(physical association)	0.370
NELL1	NUFIP2	psi-mi:“MI:0915”(physical association)	0.370
NELL1	ATXN7	psi-mi:“MI:0915”(physical association)	0.370
CACNA1A	NELL1	psi-mi:“MI:0915”(physical association)	0.370
ECE1	NELL1	psi-mi:“MI:0915”(physical association)	0.370
NELL1		psi-mi:“MI:0915”(physical association)	0.370
Mecom	ESYT2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
HCN1	USP27X	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350

BioGRID (53): NELL1 (Affinity Capture-MS), MATN2 (Affinity Capture-MS), PFKP (Affinity Capture-MS), FBXO27 (Affinity Capture-MS), PXDN (Affinity Capture-MS), ZNF260 (Affinity Capture-MS), TRMT2B (Affinity Capture-MS), EMILIN2 (Affinity Capture-MS), TP53RK (Affinity Capture-MS), TIMP3 (Affinity Capture-MS), EGFL7 (Affinity Capture-MS), C4orf48 (Affinity Capture-MS), POLRMT (Affinity Capture-MS), TYW3 (Affinity Capture-MS), LTBP4 (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: A1A5Y0, A2VCU8, A4IGL7, A5A8Y8, A6QR11, B5DFC9, O75095, O88322, P07996, P10493, P14585, P35441, P35448, P82279, P98118, Q14112, Q20911, Q24025, Q28178, Q2PC93, Q2VWQ2, Q3MHH9, Q5FW85, Q5R3Z7, Q61220, Q62918, Q62919, Q6AZ60, Q6GUQ1, Q6MG84, Q75N90, Q7T3Q2, Q7ZXL5, Q80T14, Q8AVH7, Q8AWW5, Q8VHS2, Q90827, Q90ZD5, Q91X17

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	126
Likely benign	7
Benign	10

Top pathogenic / likely-pathogenic (0)

SpliceAI

4476 predictions. Top by Δscore:

Variant	Effect	Δscore
11:20677930:A:AG	acceptor_gain	1.0000
11:20677930:AGT:A	acceptor_gain	1.0000
11:20677930:AGTG:A	acceptor_gain	1.0000
11:20677931:G:GT	acceptor_gain	1.0000
11:20677931:GT:G	acceptor_gain	1.0000
11:20677931:GTG:G	acceptor_gain	1.0000
11:20677931:GTGG:G	acceptor_gain	1.0000
11:20677931:GTGGT:G	acceptor_gain	1.0000
11:20678057:CAAG:C	donor_loss	1.0000
11:20678058:AAGG:A	donor_loss	1.0000
11:20678059:AGGT:A	donor_loss	1.0000
11:20678060:GGT:G	donor_loss	1.0000
11:20678061:G:A	donor_loss	1.0000
11:20783670:T:A	acceptor_gain	1.0000
11:20783677:TA:T	acceptor_loss	1.0000
11:20783678:A:AG	acceptor_gain	1.0000
11:20783679:G:GG	acceptor_gain	1.0000
11:20783679:GAC:G	acceptor_gain	1.0000
11:20783828:CAGGT:C	donor_loss	1.0000
11:20783829:AGGT:A	donor_loss	1.0000
11:20783830:GGTA:G	donor_loss	1.0000
11:20783831:G:GG	donor_gain	1.0000
11:20783832:T:A	donor_loss	1.0000
11:20885438:TTACA:T	acceptor_loss	1.0000
11:20885439:TACAG:T	acceptor_loss	1.0000
11:20885440:ACAGG:A	acceptor_loss	1.0000
11:20885441:CAGG:C	acceptor_loss	1.0000
11:20885442:A:AG	acceptor_gain	1.0000
11:20885442:AG:A	acceptor_gain	1.0000
11:20885442:AGG:A	acceptor_loss	1.0000

AlphaMissense

5391 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:20927309:T:C	L254P	0.999
11:20927406:G:C	W286C	0.998
11:20927406:G:T	W286C	0.998
11:21113600:T:A	C438S	0.998
11:21113601:G:C	C438S	0.998
11:21534457:T:A	C577S	0.998
11:21534458:G:C	C577S	0.998
11:21570863:T:A	C694S	0.998
11:21570864:G:C	C694S	0.998
11:21570910:G:C	W709C	0.998
11:21570910:G:T	W709C	0.998
11:21570935:T:A	C718S	0.998
11:21570936:G:C	C718S	0.998
11:21113622:G:A	C445Y	0.997
11:21113623:T:G	C445W	0.997
11:21113639:T:A	C451S	0.997
11:21113639:T:C	C451R	0.997
11:21113640:G:A	C451Y	0.997
11:21113640:G:C	C451S	0.997
11:21113666:T:A	C460S	0.997
11:21113667:G:C	C460S	0.997
11:21113708:T:A	C474S	0.997
11:21113709:G:C	C474S	0.997
11:21229448:T:A	C515S	0.997
11:21229448:T:C	C515R	0.997
11:21229449:G:C	C515S	0.997
11:21370939:T:A	C546S	0.997
11:21370940:G:A	C546Y	0.997
11:21370940:G:C	C546S	0.997
11:21370941:C:G	C546W	0.997

dbSNP variants (sampled 300 via entrez): RS1000004746 (11:20902163 G>C,T), RS1000005276 (11:21075030 T>G), RS1000007339 (11:20694421 C>A,G,T), RS1000010102 (11:21308610 G>A), RS1000010429 (11:21227411 G>A), RS1000011365 (11:21499811 A>G), RS1000019522 (11:20747571 C>A), RS1000021510 (11:20928401 A>T), RS1000023587 (11:21075632 A>G), RS1000025048 (11:21502600 A>G), RS1000029482 (11:21272407 AG>A), RS1000029754 (11:21188262 G>A), RS1000032626 (11:21269695 A>T), RS1000033597 (11:21150284 A>G), RS1000038309 (11:20761118 G>A,T)

Disease associations

OMIM: gene MIM:602319 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): prostate cancer (MONDO:0008315)

Orphanet (1): Familial prostate cancer (Orphanet:1331)

HPO phenotypes

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

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000066_2	Crohn’s disease	3.000000e-06
GCST001431_12	Adverse response to lamotrigine and phenytoin	5.000000e-06
GCST001616_3	Cannabis use (initiation)	4.000000e-06
GCST001651_89	Response to amphetamines	9.000000e-06
GCST001762_179	Obesity-related traits	7.000000e-06
GCST001762_922	Obesity-related traits	5.000000e-06
GCST002589_15	Hippocampal sclerosis	2.000000e-06
GCST002734_3	Fibrinogen levels (smoking status, alcohol consumption or body mass index interaction)	2.000000e-06
GCST003025_23	Attention function in attention deficit hyperactive disorder	7.000000e-06
GCST003744_2	Chronic periodontitis (mean interproximal clinical attachment level)	1.000000e-07
GCST003943_1	Hepcidin levels	1.000000e-06
GCST003945_10	Hepcidin/transferrin saturation ratio	7.000000e-07
GCST004136_35	Methadone dose in opioid dependence	9.000000e-06
GCST004639_18	Prudent dietary pattern	3.000000e-06
GCST005214_2	Bone mineral density change response to combined chemotherapy in acute lymphoblastic leukemia	4.000000e-06
GCST006055_1	Response to long-chain n-3 polyunsaturated fatty acid supplementation (change in triglyceride levels)	4.000000e-06
GCST007538_4	Cellular nuclear factor (erythroid-derived 2)-like 2 levels	4.000000e-07
GCST008152_43	Weight	7.000000e-07
GCST011742_60	Triglyceride levels in HIV infection	9.000000e-06
GCST012490_244	Femur bone mineral density x serum urate levels interaction	7.000000e-09

EFO canonical traits (13, from GWAS)

EFO ID	Trait name
EFO:0005118	IGFBP-1 measurement
EFO:0004340	body mass index
EFO:0007636	attention function measurement
EFO:0007780	periodontal measurement
EFO:0007902	hepcidin:transferrin saturation ratio
EFO:0007907	methadone dose measurement
EFO:0008111	diet measurement
EFO:0007965	response to combination chemotherapy
EFO:0007681	triglyceride change measurement
EFO:0009794	NRF2 measurement
EFO:0004338	body weight
EFO:0004530	triglyceride measurement
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011471	Prostatic Neoplasms	C04.588.945.440.770; C12.100.500.260.750; C12.100.500.565.625; C12.200.294.260.750; C12.200.294.565.625; C12.200.758.409.750; C12.900.619.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12279250	NELL1		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	6
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases methylation, increases mutagenesis	2
Ethinyl Estradiol	decreases expression, affects expression	2
Tretinoin	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation	2
methylmercuric chloride	increases expression	1
bisphenol A	affects methylation	1
terbufos	increases methylation	1
arsenite	increases methylation	1
sodium arsenite	affects methylation	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases reaction, increases expression	1
bathocuproine sulfonate	increases expression, affects cotreatment, decreases reaction	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	increases 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
Decitabine	affects methylation, affects expression	1
Acetaminophen	decreases expression	1
Dust	decreases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Tetradecanoylphorbol Acetate	affects cotreatment, decreases reaction, increases expression	1
Triclosan	increases expression	1
Ionomycin	affects cotreatment, decreases reaction, increases expression	1
Antirheumatic Agents	decreases expression	1
Copper Sulfate	decreases expression	1
Genistein	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00029224	PHASE4	COMPLETED	Treatment With Zoledronic Acid in Patients With Breast Cancer, Multiple Myeloma, and Prostate Cancer With Cancer Related Bone Lesions
NCT00035997	PHASE4	COMPLETED	Open-label Trial on the Effect of I.V. Zoledronic Acid 4 mg on Bone Density in Hormone Sensitive Prostate Cancer Patients With Bone Metastasis
NCT00063609	PHASE4	COMPLETED	The Effect of Zoledronic Acid on Bone Loss in Prostate Cancer Patients Undergoing Androgen Deprivation Therapy
NCT00103623	PHASE4	SUSPENDED	The Plenaxis® Experience Study
NCT00106392	PHASE4	COMPLETED	A Safety and Efficacy Study of Prograf in the Prevention of Erectile Dysfunction After Radical Prostatectomy
NCT00185029	PHASE4	UNKNOWN	MR-Lymphography and Lymph Node Staging in Prostate Cancer
NCT00199485	PHASE4	COMPLETED	Angelica Sinensis for the Treatment of Hot Flashes in Men Undergoing LHRH Therapy for Prostate Cancer
NCT00219219	PHASE4	COMPLETED	Zoledronic Acid in the Prevention of Skeletal-related Events in Hormone Refractory and Hormone-sensitive Prostate Cancer Patients With Bone Metastases
NCT00219271	PHASE4	COMPLETED	Effect Of Zoledronic Acid On Circulating And Bone Marrow-Residing Prostate Cancer Cells In Patients With Clinically Localized Prostate Cancer
NCT00237146	PHASE4	COMPLETED	Study to Evaluate Zoledronic Acid on Quality of Life and Skeletal-related Events as Adjuvant Treatment in Patients With Hormone-naïve Prostate Cancer and Bone Metastasis Who Have Undergone Orchiectomy
NCT00242554	PHASE4	COMPLETED	Open-label Phase IV Clinical Trial to Evaluate the Safety and Tolerability of Zoledronic Acid in Patients With Prostate Cancer and Bone Metastases
NCT00280098	PHASE4	COMPLETED	Docetaxel in the Treatment of Hormone Refractory Prostate Cancer
NCT00293696	PHASE4	COMPLETED	Casodex/Zoladex Biomarkers in Localised Prostate Cancer
NCT00334139	PHASE4	COMPLETED	Effect of Zoledronic Acid on Bone Metabolism in Patients With Bone Metastasis and Prostate or Breast Cancer
NCT00375765	PHASE4	COMPLETED	Effects On Dihydrotestosterone Regulated Gene Expression In Benign Prostatic Hyperplasia Or Prostate Cancer
NCT00391690	PHASE4	COMPLETED	Evaluation of Bone Markers as Diagnostic Tools for Early Detection of Bone Metastases in Patients With High Risk Prostate Cancer
NCT00422708	PHASE4	COMPLETED	Local Anesthesia for Prostate Biopsy
NCT00526331	PHASE4	COMPLETED	Evaluation of Arterial Pressure Based Cardiac Output for Goal-Directed Perioperative Therapy
NCT00590213	PHASE4	COMPLETED	Compare the Value of Prophylactic Versus Therapeutic Breast Radiotherapy in CASODEX
NCT00629330	PHASE4	TERMINATED	Dissemination of Prostate Cancer Screening to PCP’s in African American Communities
NCT00771966	PHASE4	COMPLETED	Radical Prostatectomy and Perioperative Fluid Therapy
NCT00805701	PHASE4	COMPLETED	Study Assessing The Efficacy And Safety Of Avodart (Dutasteride) At Improving Urinary Symptoms In Men With Prostate Cancer Who Are Undergoing Seed Implantation
NCT00859027	PHASE4	COMPLETED	Effect Of Risedronate On Bone Mass In Older Men Receiving Neoadjuvant Therapy For Prostate Cancer
NCT00906269	PHASE4	UNKNOWN	Can Hyperbaric Oxygen Improve Erectile Function Following Surgery for Prostate Cancer
NCT00953277	PHASE4	COMPLETED	Study of Nerve Reconstruction Using AVANCE in Subjects Who Undergo Robotic Assisted Prostatectomy for Treatment of Prostate Cancer
NCT00982800	PHASE4	COMPLETED	Does Postoperative Gabapentin Reduce Pain, Opioid Consumption and Anxiety and Have a Positive Effect on Health Related Quality of Life After Radical Prostatectomy?
NCT01083199	PHASE4	COMPLETED	Global Performance Evaluation of the AMS CONTINUUM™ Device
NCT01136226	PHASE4	COMPLETED	Evaluate Recovery of Testosterone for Patients Using Eligard
NCT01161563	PHASE4	COMPLETED	Randomized Crossover Trial to Assess the Tolerability of Gonadotropin Releasing Hormone (GnRH) Analogue Administration
NCT01230905	PHASE4	COMPLETED	Study to Monitor the Effects of Androgen Suppression Treatment on the Heart
NCT01296672	PHASE4	COMPLETED	3 Month Finasteride Challenge Test Can Significantly Improve the Performance of Screening for Prostate Cancer
NCT01365143	PHASE4	TERMINATED	Prospective Randomized Trial Comparing Robotic Versus Open Radical Prostatectomy
NCT01379742	PHASE4	UNKNOWN	Comparison of Between ThinSeed™ and OncoSeed™ for Permanent Prostate Brachytherapy
NCT01486563	PHASE4	COMPLETED	Hydroxyethyl Starch and Renal Function After Radical Prostatectomy
NCT01511874	PHASE4	COMPLETED	Efficacy and Safety Study of ELIGARD 22.5mg With Prostate Cancer
NCT01512472	PHASE4	TERMINATED	Firmagon (Degarelix) Intermittent Therapy
NCT01547416	PHASE4	COMPLETED	The Effect of Combined General/Epidural Anesthesia Versus General Anesthesia on Diaphragmatic Function
NCT01571544	PHASE4	COMPLETED	The Use of Thermal Suits as Preventing Hypothermia During Surgery
NCT01581749	PHASE4	UNKNOWN	Evaluation of Truebeam for Low-Intermediate Risk Prostate Cancer
NCT01649635	PHASE4	COMPLETED	Study of Cabazitaxel Combined With Prednisone and Prophylaxis of Neutropenia Complications in the Treatment of Patients With Metastatic Castration-resistant Prostate Cancer