NRARP

Summary

NRARP (NOTCH regulated ankyrin repeat protein, HGNC:33843) is a protein-coding gene on chromosome 9q34.3, encoding Notch-regulated ankyrin repeat-containing protein (Q7Z6K4). Downstream effector of Notch signaling.

Involved in Notch signaling pathway. Acts upstream of or within negative regulation of Notch signaling pathway and positive regulation of canonical Wnt signaling pathway.

Source: NCBI Gene 441478 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 1 total
• MANE Select transcript: NM_001004354

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33843
Approved symbol	NRARP
Name	NOTCH regulated ankyrin repeat protein
Location	9q34.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC61598
Ensembl gene	ENSG00000198435
Ensembl biotype	protein_coding
OMIM	619987
Entrez	441478

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000356628

RefSeq mRNA: 1 — MANE Select: NM_001004354 NM_001004354

CCDS: CCDS35188

Canonical transcript exons

ENST00000356628 — 1 exons

Exon	Start	End
ENSE00001401563	137299631	137302271

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 96.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.4225 / max 291.2185, expressed in 1018 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
103354	10.9816	1015
103353	0.3441	136
103352	0.0968	39

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of sigmoid colon	UBERON:0004993	96.96	gold quality
colonic mucosa	UBERON:0000317	96.82	gold quality
ileal mucosa	UBERON:0000331	96.47	gold quality
mucosa of transverse colon	UBERON:0004991	95.71	gold quality
upper arm skin	UBERON:0004263	95.04	gold quality
lower esophagus mucosa	UBERON:0035834	94.22	gold quality
epithelial cell of pancreas	CL:0000083	93.33	silver quality
pharyngeal mucosa	UBERON:0000355	93.28	gold quality
pancreatic ductal cell	CL:0002079	92.10	gold quality
trachea	UBERON:0003126	91.67	gold quality
gingival epithelium	UBERON:0001949	91.51	gold quality
nipple	UBERON:0002030	91.43	gold quality
sperm	CL:0000019	91.08	gold quality
rectum	UBERON:0001052	91.00	gold quality
amniotic fluid	UBERON:0000173	90.89	gold quality
gingiva	UBERON:0001828	90.48	gold quality
palpebral conjunctiva	UBERON:0001812	89.97	gold quality
upper leg skin	UBERON:0004262	89.97	gold quality
left ventricle myocardium	UBERON:0006566	89.18	silver quality
body of tongue	UBERON:0011876	89.00	gold quality
transverse colon	UBERON:0001157	88.64	gold quality
esophagus squamous epithelium	UBERON:0006920	88.37	gold quality
pylorus	UBERON:0001166	88.34	gold quality
kidney epithelium	UBERON:0004819	87.80	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.68	gold quality
heart right ventricle	UBERON:0002080	87.51	silver quality
ventricular zone	UBERON:0003053	87.02	gold quality
vena cava	UBERON:0004087	87.00	silver quality
duodenum	UBERON:0002114	86.72	gold quality
skin of abdomen	UBERON:0001416	86.59	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-CURD-114	yes	66.21
E-GEOD-125970	yes	42.84
E-ANND-3	yes	13.35
E-MTAB-6678	no	2.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NOTCH1, RBPJ

miRNA regulators (miRDB)

146 targeting NRARP, 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-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787

Literature-anchored findings (GeneRIF, showing 5)

• NRARP may stimulate cell proliferation in human breast cancer. (PMID:24778018)
• Downregulation of NRARP expression exerts significant antitumor activities against cell growth and invasion of thyroid cancer, that suggests a potential role of NRARP in thyroid cancer targeted therapy. (PMID:27364790)
• High NRARP expression is associated with papillary thyroid carcinoma progression. (PMID:28207739)
• NRARP displays either pro- or anti-tumoral roles in T-cell acute lymphoblastic leukemia depending on Notch and Wnt signaling. (PMID:31586130)
• Extension of the Notch intracellular domain ankyrin repeat stack by NRARP promotes feedback inhibition of Notch signaling. (PMID:31690634)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrarpb	ENSDARG00000018958
danio_rerio	nrarpa	ENSDARG00000091419
mus_musculus	Nrarp	ENSMUSG00000078202
rattus_norvegicus	Nrarp	ENSRNOG00000009354

Paralogs (2): ANKRD10 (ENSG00000088448), ANKRD6 (ENSG00000135299)

Protein

Protein identifiers

Notch-regulated ankyrin repeat-containing protein — Q7Z6K4 (reviewed: Q7Z6K4)

All UniProt accessions (1): Q7Z6K4

UniProt curated annotations — full annotation on UniProt →

Function. Downstream effector of Notch signaling. Involved in the regulation of liver cancer cells self-renewal. Involved in angiogenesis acting downstream of Notch at branch points to regulate vascular density. Proposed to integrate endothelial Notch and Wnt signaling to control stalk cell proliferation and to stablilize new endothelial connections during angiogenesis. During somitogenesis involved in maintenance of proper somite segmentation and proper numbers of somites and vertebrae. Required for proper anterior-posterior somite patterning. Proposed to function in a negative feedback loop to destabilize Notch 1 intracellular domain (NICD) and down-regulate the Notch signal, preventing expansion of the Notch signal into the anterior somite domain.

Subunit / interactions. Interacts with LEF1.

Induction. In endothelial cells by Notch signaling.

Similarity. Belongs to the NRARP family.

RefSeq proteins (1): NP_001004354* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002110	Ankyrin_rpt	Repeat
IPR036770	Ankyrin_rpt-contain_sf	Homologous_superfamily
IPR051226	PP1_Regulatory_Subunit	Family

Pfam: PF12796

UniProt features (3 total): repeat 2, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6PY8	X-RAY DIFFRACTION	3.75

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z6K4-F1	84.17	0.49

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 233 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, HORIUCHI_WTAP_TARGETS_DN, ACTACCT_MIR196A_MIR196B, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_AXIS_SPECIFICATION, GOBP_EMBRYONIC_AXIS_SPECIFICATION, PEREZ_TP63_TARGETS, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_NEGATIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, GOBP_CELL_CELL_ADHESION, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION

GO Biological Process (15): negative regulation of transcription by RNA polymerase II (GO:0000122), branching involved in blood vessel morphogenesis (GO:0001569), blood vessel endothelial cell proliferation involved in sprouting angiogenesis (GO:0002043), Notch signaling pathway (GO:0007219), T cell differentiation (GO:0030217), somite rostral/caudal axis specification (GO:0032525), negative regulation of T cell differentiation (GO:0045581), negative regulation of Notch signaling pathway (GO:0045746), positive regulation of canonical Wnt signaling pathway (GO:0090263), vascular endothelial cell proliferation (GO:0101023), positive regulation of vascular endothelial cell proliferation (GO:1905564), somitogenesis (GO:0001756), endothelial cell proliferation (GO:0001935), sprouting angiogenesis (GO:0002040), regulation of cell-cell adhesion (GO:0022407)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
angiogenesis	2
endothelial cell proliferation	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
blood vessel morphogenesis	1
branching morphogenesis of an epithelial tube	1
sprouting angiogenesis	1
cell surface receptor signaling pathway	1
lymphocyte differentiation	1
T cell activation	1
embryonic axis specification	1
somitogenesis	1
anterior/posterior axis specification	1
T cell differentiation	1
regulation of T cell differentiation	1
negative regulation of lymphocyte differentiation	1
negative regulation of T cell activation	1
Notch signaling pathway	1
regulation of Notch signaling pathway	1
negative regulation of signal transduction	1
positive regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
regulation of canonical Wnt signaling pathway	1
positive regulation of endothelial cell proliferation	1
vascular endothelial cell proliferation	1
regulation of vascular endothelial cell proliferation	1
anterior/posterior pattern specification	1
segmentation	1
chordate embryonic development	1
anatomical structure formation involved in morphogenesis	1
somite development	1
epithelial cell proliferation	1
regulation of cell adhesion	1
cell-cell adhesion	1
binding	1

Protein interactions and networks

STRING

1312 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRARP	HEY1	Q9Y5J3	809
NRARP	DTX1	Q86Y01	770
NRARP	NOTCH1	P46531	745
NRARP	JAG1	P78504	726
NRARP	HES5	Q5TA89	726
NRARP	DLL4	Q9NR61	698
NRARP	LFNG	Q8NES3	694
NRARP	MAML1	Q92585	687
NRARP	NOTCH3	Q9UM47	673
NRARP	LEF1	Q9UJU2	631
NRARP	DUSP6	Q16828	621
NRARP	NKD1	Q969G9	617
NRARP	RBPJ	Q06330	605
NRARP	DLL1	O00548	572
NRARP	HES4	Q9HCC6	571

IntAct

5 interactions, top by confidence:

A	B	Type	Score
GTF2E1	NRARP	psi-mi:“MI:0915”(physical association)	0.560
NRARP	GTF2E1	psi-mi:“MI:0915”(physical association)	0.000
IKBKG	NRARP	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (3): NRARP (Two-hybrid), NRARP (Positive Genetic), NRARP (Reconstituted Complex)

ESM2 similar proteins: A0MQH0, A4II29, A4IIX9, E9PTA2, O94826, P24786, Q0VC93, Q13507, Q16288, Q17QS6, Q25BN1, Q3ULA2, Q502M6, Q59H18, Q5GIG6, Q5IFJ9, Q5IS37, Q5IS82, Q5U5A6, Q5ZLX4, Q6DFV5, Q6GPR5, Q6GQW0, Q6TUI4, Q75Q39, Q7T3X9, Q7T3Y0, Q7TQP6, Q7Z6K4, Q7Z713, Q862Z2, Q8BPU7, Q8K4Q0, Q8N122, Q8VBX0, Q8WWX0, Q8WXK3, Q91987, Q91YD4, Q91ZA8

Diamond homologs: A2AQH4, A2AS55, A4II29, A5WVX9, A6QR20, B4E2M5, D3Z7P3, E9PTT0, G5EGA3, O83515, O94925, P13264, Q01317, Q15653, Q21920, Q3SX45, Q3U0L2, Q499M5, Q4FE45, Q4JHE0, Q502K3, Q54HW1, Q5H9F3, Q5U5A6, Q6NSI1, Q6NY19, Q6P6B7, Q7T3Y0, Q7Z6K4, Q80TN5, Q8IUH5, Q91ZA8, Q9BQI6, Q9CQ31, Q9VUW9, Q9XZC0, Q9Z2F6, A0A0R4IQZ2, C7B178, G0LXV8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RBPJ/NOTCH	“up-regulates quantity by expression”	NRARP	“transcriptional regulation”
NRARP	down-regulates	RBPJ/NOTCH	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

108 predictions. Top by Δscore:

Variant	Effect	Δscore
9:137301583:A:AC	donor_gain	0.8400
9:137301607:T:TA	donor_gain	0.8400
9:137301715:TG:T	donor_gain	0.7800
9:137301604:A:AC	donor_gain	0.7500
9:137301605:C:CC	donor_gain	0.7500
9:137301609:G:A	donor_gain	0.6500
9:137301214:TTCAC:T	acceptor_loss	0.6200
9:137301217:ACC:A	acceptor_loss	0.6200
9:137301218:CCT:C	acceptor_loss	0.6200
9:137301220:T:A	acceptor_loss	0.6200
9:137301456:G:A	donor_gain	0.6200
9:137301607:TC:T	donor_gain	0.6200
9:137301636:T:TA	donor_gain	0.5900
9:137301227:GAAAA:G	acceptor_loss	0.5800
9:137301452:ACGCG:A	donor_gain	0.5600
9:137301453:CGCGC:C	donor_gain	0.5600
9:137301606:T:C	donor_gain	0.5600
9:137301461:ATTCG:A	donor_gain	0.5300
9:137301646:C:CT	donor_gain	0.5300
9:137301605:CTTCG:C	donor_gain	0.5200
9:137301645:C:CT	donor_gain	0.5200
9:137301433:G:T	donor_gain	0.5100
9:137301478:G:A	donor_gain	0.4900
9:137301225:GAGAA:G	acceptor_loss	0.4800
9:137301226:AGAAA:A	acceptor_loss	0.4800
9:137301450:G:T	donor_gain	0.4800
9:137301453:CGCG:C	donor_gain	0.4800
9:137301219:C:CC	acceptor_gain	0.4700
9:137301585:C:T	donor_gain	0.4700
9:137301215:TCACC:T	acceptor_gain	0.4600

AlphaMissense

741 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:137301621:A:G	L103P	0.998
9:137301657:G:T	A91D	0.996
9:137301720:A:G	L70P	0.995
9:137301765:A:G	L55P	0.992
9:137301658:C:G	A91P	0.990
9:137301753:A:T	V59D	0.990
9:137301756:G:C	S58W	0.989
9:137301757:A:G	S58P	0.989
9:137301744:C:A	G62V	0.987
9:137301657:G:A	A91V	0.986
9:137301723:A:G	L69P	0.986
9:137301868:C:G	A21P	0.986
9:137301686:G:C	N81K	0.985
9:137301686:G:T	N81K	0.985
9:137301655:C:G	A92P	0.984
9:137301621:A:T	L103H	0.983
9:137301706:C:G	A75P	0.982
9:137301840:A:G	L30P	0.982
9:137301754:C:A	V59F	0.978
9:137301765:A:T	L55Q	0.978
9:137301876:A:G	F18S	0.976
9:137301676:A:G	W85R	0.975
9:137301676:A:T	W85R	0.975
9:137301831:A:G	L33P	0.975
9:137301687:T:A	N81I	0.974
9:137301705:G:T	A75D	0.974
9:137301650:G:C	F93L	0.973
9:137301650:G:T	F93L	0.973
9:137301652:A:G	F93L	0.973
9:137301708:C:A	G74V	0.973

dbSNP variants (sampled 300 via entrez): RS1000036321 (9:137300819 G>A), RS1000410163 (9:137301090 G>A,C), RS1000513361 (9:137302949 G>A), RS1001066487 (9:137303616 T>C), RS1001229715 (9:137302523 G>A), RS1001682158 (9:137302695 G>C), RS1002111051 (9:137299398 G>A,C), RS1002904521 (9:137301977 G>A), RS1003183667 (9:137300270 T>C), RS1004013207 (9:137301019 C>A), RS1004065560 (9:137301303 G>A), RS1005792545 (9:137300193 GA>G,GAA), RS1005886683 (9:137304201 C>G,T), RS1006301453 (9:137303778 A>T), RS1006563173 (9:137300546 T>C)

Disease associations

OMIM: gene MIM:619987 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006976_132	Macular thickness	3.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	3
sodium arsenite	affects expression, decreases expression	2
Calcitriol	decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Cadmium Chloride	increases expression	2
oxybenzone	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
arsenite	increases methylation	1
butyraldehyde	increases expression	1
ferrous chloride	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
licochalcone B	increases expression	1
jinfukang	decreases expression, affects cotreatment	1
prothioconazole	decreases expression	1
(+)-JQ1 compound	increases expression	1
PCI 5002	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Cannabidiol	decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Formaldehyde	increases expression	1

Clinical trials (associated diseases)

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