NRG3

Summary

NRG3 (neuregulin 3, HGNC:7999) is a protein-coding gene on chromosome 10q23.1, encoding Pro-neuregulin-3, membrane-bound isoform (P56975). Direct ligand for the ERBB4 tyrosine kinase receptor.

This gene is a member of the neuregulin gene family. This gene family encodes ligands for the transmembrane tyrosine kinase receptors ERBB3 and ERBB4 - members of the epidermal growth factor receptor family. Ligand binding activates intracellular signaling cascades and the induction of cellular responses including proliferation, migration, differentiation, and survival or apoptosis. This gene encodes neuregulin 3 (NRG3). NRG3 has been shown to activate the tyrosine phosphorylation of its cognate receptor, ERBB4, and is thought to influence neuroblast proliferation, migration and differentiation by signalling through ERBB4. NRG3 also promotes mammary differentiation during embryogenesis. Linkage studies have implicated this gene as a susceptibility locus for schizophrenia and schizoaffective disorder. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but their biological validity has not been verified.

Source: NCBI Gene 10718 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 141 total
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001010848

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7999
Approved symbol	NRG3
Name	neuregulin 3
Location	10q23.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000185737
Ensembl biotype	protein_coding
OMIM	605533
Entrez	10718

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 7 protein_coding, 2 nonsense_mediated_decay

ENST00000372141, ENST00000372142, ENST00000404547, ENST00000404576, ENST00000537893, ENST00000545131, ENST00000555784, ENST00000556918, ENST00000602794

RefSeq mRNA: 6 — MANE Select: NM_001010848 NM_001010848, NM_001165972, NM_001165973, NM_001370081, NM_001370082, NM_001370084

CCDS: CCDS31233, CCDS53547, CCDS91287

Canonical transcript exons

ENST00000372141 — 9 exons

Exon	Start	End
ENSE00001456991	81875194	81876163
ENSE00002436347	82985098	82987178
ENSE00003485397	82358739	82358868
ENSE00003487142	82958949	82959075
ENSE00003509804	82973788	82973915
ENSE00003575523	82738577	82738650
ENSE00003580859	82978950	82979120
ENSE00003593142	82865411	82865437
ENSE00003648886	82951469	82951571

Expression profiles

Bgee: expression breadth ubiquitous, 161 present calls, max score 89.84.

FANTOM5 (CAGE): breadth broad, TPM avg 3.1360 / max 108.5483, expressed in 507 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
105899	1.1730	339
105898	0.8323	231
105900	0.3023	109
105905	0.2155	76
105897	0.2069	92
105904	0.1560	88
105901	0.0883	56
105902	0.0712	45
105903	0.0660	40
205927	0.0244	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	89.84	gold quality
middle temporal gyrus	UBERON:0002771	89.59	gold quality
cortical plate	UBERON:0005343	88.78	gold quality
Brodmann (1909) area 23	UBERON:0013554	87.92	gold quality
prefrontal cortex	UBERON:0000451	85.94	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	85.39	gold quality
Brodmann (1909) area 9	UBERON:0013540	84.58	gold quality
anterior cingulate cortex	UBERON:0009835	84.53	gold quality
neocortex	UBERON:0001950	84.04	gold quality
primary visual cortex	UBERON:0002436	84.00	gold quality
frontal cortex	UBERON:0001870	83.89	gold quality
cerebral cortex	UBERON:0000956	83.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.75	gold quality
right frontal lobe	UBERON:0002810	82.75	gold quality
superior frontal gyrus	UBERON:0002661	81.94	gold quality
entorhinal cortex	UBERON:0002728	81.66	gold quality
amygdala	UBERON:0001876	80.82	gold quality
temporal lobe	UBERON:0001871	80.81	gold quality
Brodmann (1909) area 46	UBERON:0006483	80.65	gold quality
Ammon’s horn	UBERON:0001954	79.94	gold quality
occipital lobe	UBERON:0002021	79.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.49	silver quality
ventricular zone	UBERON:0003053	79.31	gold quality
caudate nucleus	UBERON:0001873	79.17	gold quality
forebrain	UBERON:0001890	79.12	gold quality
hypothalamus	UBERON:0001898	79.11	gold quality
oviduct epithelium	UBERON:0004804	78.88	gold quality
postcentral gyrus	UBERON:0002581	77.52	gold quality
nucleus accumbens	UBERON:0001882	77.22	gold quality
brain	UBERON:0000955	76.40	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	7098.49
E-HCAD-35	yes	92.63
E-CURD-119	yes	26.39
E-ANND-3	yes	5.40

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

151 targeting NRG3, 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-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3163	100.00	77.23	8605
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-4425	100.00	67.59	1049
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-4753-3P	99.90	71.03	3786

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 25)

• The NRG3 protein is a new post-translationally regulated isoform of neuregulin 3 expressed in the developing human central nervous system with a role in oligodendrocyte survival. (PMID:16478787)
• In transgenic female mice, Nrg3 has a role in the initiation of mammary placodes along the body axis; alterations in morphogenesis and differentiation of other epidermal appendages are also observed, including the hair follicles. (PMID:17880691)
• NRG3 was expressed in 42% of breast cancers studied. It was preferentially expressed in breast tumors co-expressing EGFR/HER4. (PMID:17962208)
• The result of tis study supports that the NRG3 gene is a susceptibility gene for schizophrenia. (PMID:18708184)
• NRG3 is primarily expressed in the central nervous system and is one of three paralogs of NRG1, a gene strongly implicated in SZ. (PMID:19118813)
• Results suggest that NRG3 may be modulating early attentional processes for perceptual sensitivity and vigilance, with opposite effects in affected individuals and healthy controls. (PMID:20548296)
• Data show that NRG3 is a schizophrenia susceptibility gene, provide quantitative insight into NRG3 transcription traits in the brain, and reveal a probable mechanistic basis for disease association. (PMID:20713722)
• Data show that rs1649942, which is located in the intron region of NM_001165973.1. (NRG3 neuregulin 3), was associated with poorer overall survival in women with optimally debulked tumors. (PMID:21705454)
• NRG3 polymorphisms and haplotypes were similar between schizophrenia patients and healthy controls of Korean ethnicity (PMID:21762460)
• Our results suggest a role for NRG3 in HSCR etiology and provide insights into the relative contribution of structural variants in both syndromic and non-syndromic HSCR. (PMID:22589734)
• Neuregulin 3 rs6584400 genetic carriers are associated with psychotic symptoms and attention performance in schizophrenia. (PMID:22831755)
• no association of SNPs or haplotypes with risk of schizophrenia in Han Chinese population (PMID:22981155)
• NRG3 may be a susceptibility gene for Hirschsprung’s disease in a Chinese population. (PMID:23315268)
• these data suggest that Nrg3/ErbB4 signaling may be an important factor in nicotine dependence. (PMID:23999525)
• This study demonstrated that genetic variants in the NRG3 gene play a role in alzheimer disease and revealed that SNPs in the NRG3 genes were more strongly associated with onset age of Alzherimer disease. (PMID:24061483)
• An association between rs10748842 genotype in neuregulin 3 does not fit a simple inefficiency model of risk association in dorsolateral prefrontal cortex physiology. (PMID:24431462)
• Data show that Williams-Beuren syndrome transcription factor (WSTF) release was mediated by neuregulin-3 (NRG3) following KRASG12V expression in intestinal epithelial cells. (PMID:27449290)
• These observations encourage investigation of the neurobiology of NRG3 isoforms and highlight inhibition of NRG3 signaling as a potential target for psychiatric treatment development. (PMID:27771971)
• common variants of GABRG2, RELN and NRG3 and the GABRG2-RELN-PTCH1 interaction networks might confer altered susceptibility to Hirschsprung disease. (PMID:27889765)
• No genetic correlation was found between Hirschsprung disease and the three SNPs at NRG3 (rs10748842, rs10883866 and rs6584400) (PMID:28256518)
• The BRE rs7572644 and NRG3 rs1649942 genetic variants were validated in an independent cohort of EOC Portuguese patients. (PMID:30287910)
• NRG3 contributes to cognitive deficits in chronic patients with schizophrenia. (PMID:31753594)
• Neuregulin 3 rs10748842 polymorphism contributes to the effect of body mass index on cognitive impairment in patients with schizophrenia. (PMID:32066712)
• Association of NRG3 and ERBB4 gene polymorphism with nicotine dependence in Turkish population. (PMID:34247340)
• Transcytosis and trans-synaptic retention by postsynaptic ErbB4 underlie axonal accumulation of NRG3. (PMID:35579602)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	nrg3b	ENSDARG00000089766
mus_musculus	Nrg3	ENSMUSG00000041014
rattus_norvegicus	Nrg3	ENSRNOG00000063450

Paralogs (3): NRG1 (ENSG00000157168), NRG2 (ENSG00000158458), NRG4 (ENSG00000169752)

Protein

Protein identifiers

Pro-neuregulin-3, membrane-bound isoform — P56975 (reviewed: P56975)

All UniProt accessions (7): D9ZHP6, D9ZHQ3, D9ZHQ6, D9ZHQ7, D9ZHQ8, P56975, R4GNI6

UniProt curated annotations — full annotation on UniProt →

Function. Direct ligand for the ERBB4 tyrosine kinase receptor. Binding results in ligand-stimulated tyrosine phosphorylation and activation of the receptor. Does not bind to the EGF receptor, ERBB2 or ERBB3 receptors. May be a survival factor for oligodendrocytes.

Subunit / interactions. Interacts with ERBB4.

Subcellular location. Cell membrane Secreted Cell membrane.

Tissue specificity. Highly expressed in most regions of the brain with the exception of corpus callosum. Expressed at lower level in testis. Not detected in heart, placenta, lung, liver, skeletal muscle, kidney, pancreas, spleen, thymus, prostate, ovary, small intestine, colon and peripheral blood leukocytes.

Post-translational modifications. Proteolytic cleavage close to the plasma membrane on the external face leads to the release of the soluble growth factor form. Extensive glycosylation precedes the proteolytic cleavage. Isoform 3 is glycosylated.

Domain organisation. The cytoplasmic domain may be involved in the regulation of trafficking and proteolytic processing. Regulation of the proteolytic processing involves initial intracellular domain dimerization. ERBB receptor binding is elicited entirely by the EGF-like domain.

Similarity. Belongs to the neuregulin family.

Isoforms (4)

UniProt ID	Names	Canonical?
P56975-1	1	yes
P56975-2	2
P56975-3	3, FBNRG3
P56975-4	4

RefSeq proteins (6): NP_001010848, NP_001159444, NP_001159445, NP_001357010, NP_001357011, NP_001357013 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000742	EGF	Domain
IPR040180	Neuregulin	Family

UniProt features (24 total): compositionally biased region 5, splice variant 4, region of interest 4, disulfide bond 3, chain 2, topological domain 2, sequence variant 2, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P56975-F1	50.59	0.03

Functional residue map

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

Disulfide bonds (3): 290–304, 298–317, 319–328

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-1227986	Signaling by ERBB2
R-HSA-1236394	Signaling by ERBB4
R-HSA-1250196	SHC1 events in ERBB2 signaling
R-HSA-1250342	PI3K events in ERBB4 signaling
R-HSA-1250347	SHC1 events in ERBB4 signaling
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1963640	GRB2 events in ERBB2 signaling
R-HSA-1963642	PI3K events in ERBB2 signaling
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-5673001	RAF/MAP kinase cascade
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6811558	PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling
R-HSA-8847993	ERBB2 Activates PTK6 Signaling
R-HSA-8863795	Downregulation of ERBB2 signaling
R-HSA-9664565	Signaling by ERBB2 KD Mutants
R-HSA-9665686	Signaling by ERBB2 TMD/JMD mutants

MSigDB gene sets: 194 (showing top): GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_GLAND_MORPHOGENESIS, GOBP_SYNAPSE_ASSEMBLY, GOBP_GROWTH, GOBP_NEUROGENESIS, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_CELL_CELL_SIGNALING, GOBP_FOREBRAIN_CELL_MIGRATION, GOMF_KINASE_ACTIVATOR_ACTIVITY, GOBP_TAXIS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_CELL_JUNCTION_ORGANIZATION, KEGG_ERBB_SIGNALING_PATHWAY, GOBP_SUBSTRATE_INDEPENDENT_TELENCEPHALIC_TANGENTIAL_MIGRATION

GO Biological Process (14): regulation of cell growth (GO:0001558), pattern specification process (GO:0007389), synapse assembly (GO:0007416), chemorepulsion involved in interneuron migration from the subpallium to the cortex (GO:0021842), intracellular signal transduction (GO:0035556), ERBB4 signaling pathway (GO:0038130), ERBB4-ERBB4 signaling pathway (GO:0038138), animal organ development (GO:0048513), modulation of chemical synaptic transmission (GO:0050804), mammary placode formation (GO:0060596), negative regulation of neuron migration (GO:2001223), signal transduction (GO:0007165), nervous system development (GO:0007399), mammary gland development (GO:0030879)

GO Molecular Function (6): growth factor activity (GO:0008083), transmembrane receptor protein tyrosine kinase activator activity (GO:0030297), receptor tyrosine kinase binding (GO:0030971), chemorepellent activity (GO:0045499), receptor ligand activity (GO:0048018), signaling receptor binding (GO:0005102)

GO Cellular Component (6): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Signaling by ERBB2	6
Signaling by ERBB4	3
Signaling by Receptor Tyrosine Kinases	2
Signaling by ERBB2 in Cancer	2
Intracellular signaling by second messengers	1
PI3K/AKT Signaling in Cancer	1
MAPK1/MAPK3 signaling	1
Negative regulation of the PI3K/AKT network	1
Signaling by PTK6	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative chemotaxis	2
signal transduction	2
receptor ligand activity	2
signaling receptor activator activity	2
signaling receptor binding	2
cellular anatomical structure	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	1
multicellular organism development	1
multicellular organismal process	1
nervous system development	1
cell junction assembly	1
synapse organization	1
interneuron migration from the subpallium to the cortex	1
directional guidance of interneurons involved in migration from the subpallium to the cortex	1
intracellular anatomical structure	1
ERBB signaling pathway	1
ERBB4 signaling pathway	1
anatomical structure development	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
mammary gland formation	1
ectodermal placode formation	1
neuron migration	1
negative regulation of cell migration	1
regulation of neuron migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
system development	1
gland development	1
transmembrane receptor protein tyrosine kinase activity	1
protein tyrosine kinase activator activity	1
protein tyrosine kinase binding	1
protein binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

656 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NRG3	ERBB4	Q15303	998
NRG3	NRG4	Q8WWG1	945
NRG3	ERBB3	P21860	933
NRG3	CADPS2	Q86UW7	858
NRG3	AUTS2	Q8WXX7	825
NRG3	ERBB2	P04626	796
NRG3	EGFR	P00533	789
NRG3	EGF	P01133	775
NRG3	DYRK1A	Q13627	712
NRG3	AREG	P15514	669
NRG3	PVALB	P20472	599
NRG3	BTC	P35070	582
NRG3	EREG	O14944	570
NRG3	NRG2	O14511	566
NRG3	CTNND2	Q9UQB3	554

IntAct

2 interactions, top by confidence:

A	B	Type	Score
DISC1	NRG3	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (3): NRG3 (Affinity Capture-RNA), NRG3 (Affinity Capture-Western), NRG3 (Affinity Capture-RNA)

ESM2 similar proteins: A0JNG6, A2AKB4, A7YWL5, B0BN13, O35181, O43734, O70142, O70240, O88286, O88566, P0DPB3, P0DPB4, P56975, P70298, P86174, P97303, Q00IB7, Q1LY51, Q2M3C6, Q2T9L4, Q3TY60, Q498S6, Q4V7B1, Q568Z1, Q5HZN9, Q5JTD0, Q5SYB0, Q5U5E5, Q5VT97, Q69ZB8, Q6PG95, Q6UXB0, Q6ZU67, Q76N89, Q80YE4, Q86XD5, Q8BWU3, Q8BZB3, Q8CD60, Q8N365

Diamond homologs: A2AJ76, A2ASS6, D3YXG0, G4SLH0, O01761, O08775, O14511, O35136, O35181, O35569, O60469, O89026, O93383, P07522, P0DMY9, P0DMZ0, P12960, P13591, P14781, P22063, P28685, P35918, P43322, P56974, P56975, P57087, P86468, Q00968, Q02246, Q02297, Q05199, Q12860, Q5DTJ9, Q61330, Q62718, Q63198, Q6DR98, Q86TC9, Q8NDA2, Q8VHZ8

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NRG3	up-regulates	ERBB4	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	116
Likely benign	9
Benign	8

Top pathogenic / likely-pathogenic (0)

SpliceAI

5322 predictions. Top by Δscore:

Variant	Effect	Δscore
10:81899637:AAT:A	acceptor_gain	1.0000
10:82032827:GCC:G	donor_gain	1.0000
10:82358735:ACAG:A	acceptor_loss	1.0000
10:82358736:CAG:C	acceptor_loss	1.0000
10:82358737:AGA:A	acceptor_loss	1.0000
10:82358865:GTCG:G	donor_gain	1.0000
10:82358869:G:GG	donor_gain	1.0000
10:82452212:T:TA	acceptor_gain	1.0000
10:81876159:ATTTC:A	donor_gain	0.9900
10:81876160:TTTC:T	donor_gain	0.9900
10:81876164:G:GG	donor_gain	0.9900
10:81889518:A:G	donor_gain	0.9900
10:81899637:A:AG	acceptor_gain	0.9900
10:81899637:AATG:A	acceptor_gain	0.9900
10:81899637:AATGG:A	acceptor_gain	0.9900
10:81899639:T:TA	acceptor_gain	0.9900
10:81899640:G:A	acceptor_gain	0.9900
10:81899775:T:G	donor_gain	0.9900
10:82032826:GGCC:G	donor_gain	0.9900
10:82043567:G:A	acceptor_gain	0.9900
10:82184602:A:AG	acceptor_gain	0.9900
10:82184603:A:G	acceptor_gain	0.9900
10:82289199:T:A	acceptor_gain	0.9900
10:82358733:T:TA	acceptor_gain	0.9900
10:82358737:A:AG	acceptor_gain	0.9900
10:82358738:G:GC	acceptor_gain	0.9900
10:82358738:GA:G	acceptor_gain	0.9900
10:82358738:GAT:G	acceptor_gain	0.9900
10:82358738:GATAC:G	acceptor_gain	0.9900
10:82358821:C:T	donor_gain	0.9900

AlphaMissense

4503 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:81875552:C:A	P71H	1.000
10:81875552:C:G	P71R	1.000
10:81875563:G:C	G75R	1.000
10:81875564:G:A	G75D	1.000
10:81875572:G:C	G78R	1.000
10:81875573:G:A	G78D	1.000
10:81875576:T:C	L79P	1.000
10:81875578:G:A	G80R	1.000
10:81875578:G:C	G80R	1.000
10:81875579:G:A	G80E	1.000
10:81875584:A:C	S82R	1.000
10:81875586:C:A	S82R	1.000
10:81875586:C:G	S82R	1.000
10:81875594:T:C	L85P	1.000
10:81875597:T:C	L86P	1.000
10:82358783:T:A	C290S	1.000
10:82358783:T:C	C290R	1.000
10:82358784:G:A	C290Y	1.000
10:82358784:G:C	C290S	1.000
10:82358785:C:G	C290W	1.000
10:82358807:T:A	C298S	1.000
10:82358807:T:C	C298R	1.000
10:82358808:G:A	C298Y	1.000
10:82358808:G:C	C298S	1.000
10:82358809:T:G	C298W	1.000
10:82358825:T:A	C304S	1.000
10:82358825:T:C	C304R	1.000
10:82358826:G:C	C304S	1.000
10:82358827:C:G	C304W	1.000
10:82358864:T:A	C317S	1.000

dbSNP variants (sampled 300 via entrez): RS1000001725 (10:82161358 C>T), RS1000003079 (10:82356401 C>T), RS1000005643 (10:82036472 T>A), RS1000006371 (10:82663619 G>A,T), RS1000009909 (10:82971203 A>G), RS1000010316 (10:82728005 G>T), RS1000018124 (10:82285503 A>T), RS1000018474 (10:82980957 A>T), RS1000018884 (10:82848500 A>C), RS1000021321 (10:81909974 T>G), RS1000021653 (10:82155688 G>C), RS1000022055 (10:82076803 C>T), RS1000024450 (10:82810694 C>T), RS1000026156 (10:82604817 A>G), RS1000027686 (10:82271491 C>G)

Disease associations

OMIM: gene MIM:605533 | disease phenotypes: MIM:189800, MIM:142623

GenCC curated gene-disease

Mondo (2): preeclampsia (MONDO:0005081), Hirschsprung disease (MONDO:0018309)

Orphanet (2): Preeclampsia (Orphanet:275555), Hirschsprung disease (Orphanet:388)

HPO phenotypes

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

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000201_6	Response to iloperidone treatment (QT prolongation)	2.000000e-06
GCST000960_15	Cardiac hypertrophy	1.000000e-06
GCST001762_27	Obesity-related traits	7.000000e-06
GCST001854_7	Retinopathy in non-diabetics	8.000000e-06
GCST002248_14	Fasting insulin (dietary factor interaction)	5.000000e-08
GCST002253_11	Homeostasis model assessment of insulin resistance (dietary factor interaction)	4.000000e-08
GCST003124_10	Mild influenza (H1N1) infection	3.000000e-10
GCST003125_5	Influenza A (H1N1) infection	4.000000e-09
GCST003135_6	Bipolar disorder and eating disorder	3.000000e-06
GCST003249_1	Basal metabolic rate	8.000000e-07
GCST003341_8	antipsychotic drug dosage in schizophrenia or schizoaffective disorder	4.000000e-06
GCST003864_1	Kidney disease (early and late stages) in type 1 diabetes	7.000000e-06
GCST003992_46	Photic sneeze reflex	2.000000e-12
GCST004640_12	Western dietary pattern	4.000000e-06
GCST004735_18	Epstein-Barr virus copy number in lymphoblastoid cell lines	7.000000e-07
GCST008162_31	Hip circumference	4.000000e-06
GCST008471_8	Non-alcoholic fatty liver disease activity score in non-alcoholic fatty liver disease	2.000000e-06
GCST009391_1638	Metabolite levels	5.000000e-06
GCST010314_5	Serum omega-6 to omega-3 polyunsaturated fatty acid ratio in metabolic syndrome	4.000000e-06
GCST010396_290	Gut microbiota (bacterial taxa, hurdle binary method)	4.000000e-08
GCST011359_5	Venous thromboembolism	2.000000e-24

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0002503	cardiac hypertrophy
EFO:0005134	amino acid measurement
EFO:0008111	diet measurement
EFO:0004501	HOMA-IR
EFO:1001488	influenza A (H1N1)
EFO:0007777	base metabolic rate measurement
EFO:0007792	antipsychotic drug use measurement
EFO:0007887	autosomal dominant compelling helio-ophthalmic outburst syndrome
EFO:0008421	non-alcoholic fatty liver disease severity measurement
EFO:0007787	plasma betaine measurement
EFO:0010732	omega-6:omega-3 polyunsaturated fatty acid ratio
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D006627	Hirschsprung Disease	C06.198.439; C06.405.469.158.701.439; C16.131.314.439
D011225	Pre-Eclampsia	C12.050.703.395.249

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs4933824	Toxicity	3	iloperidone	Acquired Long QT Syndrome (aLQTS)

PharmGKB variants

3 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4933824	NRG3	3	0.00	1	iloperidone
rs1649942	NRG3		0.00	0
rs12253008	NRG3		0.00	0

CTD chemical–gene interactions

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
methylmercuric chloride	decreases expression	1
trichostatin A	increases expression	1
afimoxifene	decreases expression, decreases reaction	1
sodium arsenite	increases expression	1
coumarin	decreases phosphorylation	1
casticin	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	decreases methylation	1
Arsenic Trioxide	increases expression	1
Fulvestrant	increases methylation	1
Arsenic	affects expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Estrogens	decreases expression, decreases reaction	1
Lead	affects expression	1
Nickel	decreases expression	1
Triclosan	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00117546	PHASE4	UNKNOWN	Cardiovascular and Autonomic Reactivity in Women With a History of Pre-eclampsia
NCT00567957	PHASE4	UNKNOWN	Remifentanil for General Anesthesia in Preeclamptics
NCT01030627	PHASE4	COMPLETED	Treatment Approaches to Preeclampsia
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01361425	PHASE4	UNKNOWN	Anti-Hypertensive Treatment In Stable Pregnant Women With Severe Pre-Eclampsia (Metildopape)
NCT01729468	PHASE4	COMPLETED	Prevention of Pre-eclampsia and SGA by Low-Dose Aspirin in Nulliparous Women With Abnormal First-trimester Uterine Artery Dopplers
NCT01761916	PHASE4	COMPLETED	Clonidine Versus Captopril for Treatment of Postpartum Very High Blood Pressure
NCT01912677	PHASE4	COMPLETED	Oral Antihypertensive Regimens for Management of Hypertension in Pregnancy
NCT02025426	PHASE4	TERMINATED	Phenylephrine Versus Ephedrine in Pre-eclampsia
NCT02091401	PHASE4	COMPLETED	A Trial Comparing Treatment With the Springfusor Infusion Pump to the IV Magnesium Sulfate Regimen
NCT02163655	PHASE4	COMPLETED	Diuretics for Postpartum High Blood Pressure in Preeclampsia
NCT02338687	PHASE4	COMPLETED	Low Dose Calcium to Prevent Preeclampsia
NCT02396030	PHASE4	TERMINATED	Different Schemes of Magnesium Sulfate for Preeclampsia
NCT02531490	PHASE4	UNKNOWN	Early Vascular Adjustments During Hypertensive Pregnancy
NCT02699827	PHASE4	COMPLETED	Adding MgSO4 to Epidural Levobupivacaine in CS for Patients With Preeclampsia
NCT02835339	PHASE4	COMPLETED	Magnesium Sulfate in Obese Preeclamptics
NCT02891174	PHASE4	COMPLETED	The Effect of Ibuprofen on Post-partum Blood Pressure in Women With Hypertensive Disorders of Pregnancy
NCT02911701	PHASE4	COMPLETED	Effect of Acetaminophen on Postpartum Blood Pressure Control in Preeclampsia With Severe Features
NCT03171480	PHASE4	COMPLETED	Use of Nitrous Oxide Donor for Labor Induction in Women With PreEclampsia
NCT03233880	PHASE4	UNKNOWN	Impact of Antichlamydial Treatment on the Rate of Preeclampsia
NCT03237000	PHASE4	UNKNOWN	Effect of Administering Intravenous Magnesium Sulfate on Fetal Cardiotocography and Neonatal Outcome in Preeclamptic Patients
NCT03506724	PHASE4	COMPLETED	Response to Anti-hypertensives in Pregnant and Postpartum Patients
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT03735433	PHASE4	TERMINATED	The Effect of Two Aspirin Dosing Strategies for Obese Women at High Risk for Preeclampsia
NCT03824119	PHASE4	UNKNOWN	Postpartum NSAIDS and Maternal Hypertension
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT04077853	PHASE4	COMPLETED	Progesterone in Expectantly Managed Early-onset Preeclampsia
NCT04158830	PHASE4	WITHDRAWN	Aspirin (ASA) Therapy and Preeclampsia Prevention
NCT04424693	PHASE4	UNKNOWN	Comparing the Incidence of Preeclampsia Between Pregnant Women Receiving Tdap Vaccinations at Week 28 or at Week 36
NCT04631627	PHASE4	UNKNOWN	Early Prediction and Randomised Prevention of Preeclampsia With Low Dose Aspirin in Chinese Cohort
NCT04656665	PHASE4	UNKNOWN	The Effectiveness of Aspirin on Preventing Pre-eclampsia
NCT04797949	PHASE4	WITHDRAWN	Adherence to Universal Aspirin Compared to Screening Indicated Aspirin for Prevention of Preeclampsia
NCT04908982	PHASE4	UNKNOWN	Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension
NCT05221164	PHASE4	UNKNOWN	162 mg of Aspirin for Prevention of Preeclampsia
NCT05294952	PHASE4	UNKNOWN	co Ihibtory Receptor in Preeclampsia
NCT05514847	PHASE4	ACTIVE_NOT_RECRUITING	Low Dose Aspirin for Preterm Preeclampsia Preventionmg/day Dose in High-risk Patients
NCT05586373	PHASE4	COMPLETED	Ibuprofen vs Dipyrone After C-section in Preeclampsia
NCT06069102	PHASE4	COMPLETED	Optimal Blood Pressure Treatment Thresholds Postpartum
NCT06107335	PHASE4	NOT_YET_RECRUITING	Effect of Albumin Versus Routine Care on Hemodynamic Response and Stability in Patients With Preeclampsia Guided by a Non-invasive Hemodynamic Monitoring System During Cesarean Delivery With Spinal Anesthesia
NCT06281665	PHASE4	RECRUITING	Treatment With Aspirin After Preeclampsia: TAP Trial