ARNT2

Summary

ARNT2 (aryl hydrocarbon receptor nuclear translocator 2, HGNC:16876) is a protein-coding gene on chromosome 15q25.1, encoding Aryl hydrocarbon receptor nuclear translocator 2 (Q9HBZ2). Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function.

This gene encodes a member of the basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. The encoded protein acts as a partner for several sensor proteins of the bHLH-PAS family, forming heterodimers with the sensor proteins that bind regulatory DNA sequences in genes responsive to developmental and environmental stimuli. Under hypoxic conditions, the encoded protein complexes with hypoxia-inducible factor 1alpha in the nucleus and this complex binds to hypoxia-responsive elements in enhancers and promoters of oxygen-responsive genes. A highly similar protein in mouse forms functional complexes with both aryl hydrocarbon receptors and Single-minded proteins, suggesting additional roles for the encoded protein in the metabolism of xenobiotic compounds and the regulation of neurogenesis, respectively.

Source: NCBI Gene 9915 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Webb-Dattani syndrome (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 12
• Clinical variants (ClinVar): 281 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 56
• MANE Select transcript: NM_014862

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16876
Approved symbol	ARNT2
Name	aryl hydrocarbon receptor nuclear translocator 2
Location	15q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0307, bHLHe1
Ensembl gene	ENSG00000172379
Ensembl biotype	protein_coding
OMIM	606036
Entrez	9915

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 7 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000303329, ENST00000525103, ENST00000525505, ENST00000527771, ENST00000529181, ENST00000531595, ENST00000533983, ENST00000558849, ENST00000869655, ENST00000869656, ENST00000869657

RefSeq mRNA: 1 — MANE Select: NM_014862 NM_014862

CCDS: CCDS32307

Canonical transcript exons

ENST00000303329 — 19 exons

Exon	Start	End
ENSE00002170549	80404382	80404546
ENSE00002200555	80593600	80597933
ENSE00002442698	80513911	80513976
ENSE00002478564	80514320	80514405
ENSE00002482370	80574148	80574220
ENSE00002490988	80591568	80591704
ENSE00002530115	80581239	80581404
ENSE00002530720	80551199	80551275
ENSE00003465976	80508156	80508258
ENSE00003480525	80552640	80552774
ENSE00003528652	80555065	80555139
ENSE00003573495	80574987	80575110
ENSE00003577123	80457929	80457976
ENSE00003608537	80563088	80563239
ENSE00003615155	80475010	80475223
ENSE00003634137	80470218	80470431
ENSE00003639819	80450880	80450994
ENSE00003648686	80576866	80576965
ENSE00003671071	80580411	80580549

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 98.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1627 / max 379.7770, expressed in 998 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
148000	3.7754	765
148007	2.0313	73
148005	1.7904	92
147999	1.0001	429
147996	0.5078	247
147998	0.3988	231
148016	0.3973	169
148002	0.3686	113
148001	0.2691	98
147997	0.1215	61

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	98.66	gold quality
middle temporal gyrus	UBERON:0002771	98.60	gold quality
frontal pole	UBERON:0002795	98.28	gold quality
middle frontal gyrus	UBERON:0002702	98.16	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.14	gold quality
entorhinal cortex	UBERON:0002728	97.99	gold quality
cranial nerve II	UBERON:0000941	97.90	gold quality
superior vestibular nucleus	UBERON:0007227	97.80	gold quality
parietal lobe	UBERON:0001872	97.73	gold quality
ventral tegmental area	UBERON:0002691	97.71	gold quality
superior frontal gyrus	UBERON:0002661	97.67	gold quality
postcentral gyrus	UBERON:0002581	97.54	gold quality
orbitofrontal cortex	UBERON:0004167	97.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.51	gold quality
temporal lobe	UBERON:0001871	97.38	gold quality
corpus callosum	UBERON:0002336	97.35	gold quality
prefrontal cortex	UBERON:0000451	97.30	gold quality
caudate nucleus	UBERON:0001873	97.28	gold quality
frontal cortex	UBERON:0001870	97.25	gold quality
nucleus accumbens	UBERON:0001882	97.20	gold quality
CA1 field of hippocampus	UBERON:0003881	97.19	gold quality
medulla oblongata	UBERON:0001896	97.09	gold quality
telencephalon	UBERON:0001893	97.00	gold quality
Brodmann (1909) area 46	UBERON:0006483	97.00	gold quality
subthalamic nucleus	UBERON:0001906	96.98	gold quality
neocortex	UBERON:0001950	96.97	gold quality
putamen	UBERON:0001874	96.96	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.94	gold quality
cerebral cortex	UBERON:0000956	96.92	gold quality
amygdala	UBERON:0001876	96.88	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-84465	yes	23.54
E-ANND-3	yes	6.55

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

3 targets.

Target	Regulation
ARNT2
CYP1A1
SIM1

JASPAR motifs

Motif	Name	Family
MA1464.1	ARNT2	PAS domain factors
MA1464.2	ARNT2	PAS domain factors

JASPAR matrix evidence (PMIDs): PMID:25215497

Upstream regulators (CollecTRI, top): ARNT2, GATA3, HIF1A, NPAS1, NR1I2, SIM1

miRNA regulators (miRDB)

186 targeting ARNT2, 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-4262	100.00	73.26	3931
HSA-MIR-3925-3P	100.00	69.95	1237
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-10401-5P	99.99	65.79	948
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-548AN	99.97	70.91	2817
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-590-3P	99.96	74.34	6478
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-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-345-3P	99.89	70.23	1421

Literature-anchored findings (GeneRIF, showing 16)

• There is no association of ARNT2 gene with cleft palate only (n = 45) and cleft lip/palate (n = 37). (PMID:12210012)
• We thus propose that NDN regulates neuronal function and hypoxic response by regulating the activities of the ARNT2:SIM1 and ARNT2:HIF1alpha dimers, respectively. (PMID:17826745)
• a possible use of ARNT2 and GST A1 as prognostic breast cancer biomarkers. (PMID:17899366)
• promotes differentiation of IL-22-producing CD4(+) T-cells (PMID:20706985)
• In white males, rs4072568 in ARNT2 was also associated with BMI (P = 9 x 10(-4)) and % body fat (P = 0.001). (PMID:21512513)
• ARNT2 might play an important role in the modulation of HIF-1-regulated signaling and metabolism. (PMID:21945317)
• mutation of ARNT2 results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. (PMID:24022475)
• These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation. (PMID:24465693)
• nominal associations were found between autism spectrum disorder scores and single-nucleotide polymorphisms in OXT, ARNT2 and CD38 (PMID:24635660)
• Data suggest that selected human SIM1 (single-minded homolog 1) variants exhibit poor dimerization with ARNT2 and anomalous intracellular localization; these data were used to predict ‘hot-spot’ in SIM1/SIM2 (residues 290-326) critical for function. (PMID:24814368)
• Attenuated ARNT2 expression in HCC827 cells greatly promoted tumor growth. (PMID:25613063)
• Immunohistochemistry confirmed ARNT2 expression in cell sub-populations within proliferative zones of patients’ glioblastoma. Decreased ARNT2 expression was consistently observed in non-tumorigenic glioblastoma cells, compared to tumorigenic cells. Moreover, ARNT2 expression correlated with a tumorigenic molecular signature at both the tissue level within the tumor core and at the single cell level in the patients’ tumors (PMID:29149419)
• The single nucleotide polymorphisms rs4778599 in the gene encoding aryl hydrocarbon receptor nuclear translocator 2 (ARNT2), showed an association that survived correction for multiple testing with emotion recognition of audio-visual stimuli in women (PMID:29194499)
• Low expression of ARNT2 is associated with gastric cancer. (PMID:29948506)
• The meta-analysis of both populations showed that carriers of the ARNT2 rs1374213G, CX3CR1 rs7631529A, and CX3CR1 rs9823718G alleles (where the RefSeq identifier appears as a subscript) had a significantly increased risk of developing invasive aspergillosis according to a log-additive model. (PMID:31964743)
• Structures of NPAS4-ARNT and NPAS4-ARNT2 heterodimers reveal new dimerization modalities in the bHLH-PAS transcription factor family. (PMID:36343253)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	arnt2	ENSDARG00000103697
mus_musculus	Arnt2	ENSMUSG00000015709
rattus_norvegicus	Arnt2	ENSRNOG00000013017
drosophila_melanogaster	Met	FBGN0002723
drosophila_melanogaster	Clk	FBGN0023076
drosophila_melanogaster	gce	FBGN0261703
drosophila_melanogaster	tgo	FBGN0264075
caenorhabditis_elegans	aha-1	WBGENE00000095

Paralogs (6): BMAL2 (ENSG00000029153), BMAL1 (ENSG00000133794), CLOCK (ENSG00000134852), ARNT (ENSG00000143437), PASD1 (ENSG00000166049), NPAS2 (ENSG00000170485)

Protein

Protein identifiers

Aryl hydrocarbon receptor nuclear translocator 2 — Q9HBZ2 (reviewed: Q9HBZ2)

Alternative names: Class E basic helix-loop-helix protein 1

All UniProt accessions (3): Q9HBZ2, H0YKW1, X5DQN9

UniProt curated annotations — full annotation on UniProt →

Function. Transcription factor that plays a role in the development of the hypothalamo-pituitary axis, postnatal brain growth, and visual and renal function. Specifically recognizes the xenobiotic response element (XRE).

Subunit / interactions. Efficient DNA binding requires dimerization with another bHLH protein. Heterodimer with NPAS4. Heterodimer with SIM1. Heterodimer with the aryl hydrocarbon receptor (AHR) or the SIM1 protein. Interacts with TACC3.

Subcellular location. Nucleus.

Disease relevance. Webb-Dattani syndrome (WEDAS) [MIM:615926] A disorder characterized by postnatal microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, global developmental delay, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HBZ2-1	1	yes
Q9HBZ2-2	2

RefSeq proteins (1): NP_055677* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000014	PAS	Domain
IPR001067	Nuc_translocat	Family
IPR001610	PAC	Repeat
IPR011598	bHLH_dom	Domain
IPR013767	PAS_fold	Domain
IPR035965	PAS-like_dom_sf	Homologous_superfamily
IPR036638	HLH_DNA-bd_sf	Homologous_superfamily
IPR050933	Circadian_TF	Family

Pfam: PF00010, PF00989, PF14598

UniProt features (24 total): compositionally biased region 6, sequence variant 5, domain 4, sequence conflict 3, region of interest 3, chain 1, modified residue 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HBZ2-F1	59.49	0.22

Functional residue map

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

Post-translational modifications (1): 42

Function

Pathways and Gene Ontology

Reactome pathways

15 pathways

ID	Pathway
R-HSA-1989781	PPARA activates gene expression
R-HSA-211945	Phase I - Functionalization of compounds
R-HSA-211976	Endogenous sterols
R-HSA-211981	Xenobiotics
R-HSA-8937144	Aryl hydrocarbon receptor signalling
R-HSA-9768919	NPAS4 regulates expression of target genes
R-HSA-1430728	Metabolism
R-HSA-211859	Biological oxidations
R-HSA-211897	Cytochrome P450 - arranged by substrate type
R-HSA-212436	Generic Transcription Pathway
R-HSA-400206	Regulation of lipid metabolism by PPARalpha
R-HSA-556833	Metabolism of lipids
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-9634815	Transcriptional Regulation by NPAS4

MSigDB gene sets: 324 (showing top): GCM_MAP4K4, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BROWNE_HCMV_INFECTION_6HR_DN, REACTOME_BIOLOGICAL_OXIDATIONS, GOBP_RESPONSE_TO_ESTRADIOL, MODULE_493, REACTOME_ENDOGENOUS_STEROLS, SMID_BREAST_CANCER_RELAPSE_IN_LIVER_DN, MODULE_66, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, KEGG_PATHWAYS_IN_CANCER, SMID_BREAST_CANCER_LUMINAL_B_UP, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_DN, GOBP_RESPONSE_TO_OXYGEN_LEVELS, KEGG_RENAL_CELL_CARCINOMA

GO Biological Process (11): response to hypoxia (GO:0001666), in utero embryonic development (GO:0001701), regulation of DNA-templated transcription (GO:0006355), regulation of transcription by RNA polymerase II (GO:0006357), central nervous system development (GO:0007417), brain development (GO:0007420), positive regulation of cell population proliferation (GO:0008284), response to estradiol (GO:0032355), negative regulation of apoptotic process (GO:0043066), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase II (GO:0045944)

GO Molecular Function (11): RNA polymerase II cis-regulatory region sequence-specific DNA binding (GO:0000978), DNA-binding transcription factor activity, RNA polymerase II-specific (GO:0000981), DNA-binding transcription activator activity, RNA polymerase II-specific (GO:0001228), DNA-binding transcription factor activity (GO:0003700), aryl hydrocarbon receptor binding (GO:0017162), protein-containing complex binding (GO:0044877), protein heterodimerization activity (GO:0046982), sequence-specific double-stranded DNA binding (GO:1990837), DNA binding (GO:0003677), protein binding (GO:0005515), protein dimerization activity (GO:0046983)

GO Cellular Component (6): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), aryl hydrocarbon receptor complex (GO:0034751)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Cytochrome P450 - arranged by substrate type	2
Phase I - Functionalization of compounds	2
Metabolism	2
Regulation of lipid metabolism by PPARalpha	1
Biological oxidations	1
Transcriptional Regulation by NPAS4	1
RNA Polymerase II Transcription	1
Metabolism of lipids	1
Gene expression (Transcription)	1
Generic Transcription Pathway	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
regulation of DNA-templated transcription	3
RNA polymerase II transcription regulatory region sequence-specific DNA binding	3
cellular anatomical structure	3
DNA-templated transcription	2
transcription by RNA polymerase II	2
regulation of transcription by RNA polymerase II	2
binding	2
response to stress	1
response to decreased oxygen levels	1
chordate embryonic development	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
nervous system development	1
system development	1
central nervous system development	1
animal organ development	1
head development	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to lipid	1
response to oxygen-containing compound	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
positive regulation of RNA biosynthetic process	1
positive regulation of DNA-templated transcription	1
cis-regulatory region sequence-specific DNA binding	1
chromatin	1
DNA-binding transcription factor activity	1
DNA-binding transcription factor activity, RNA polymerase II-specific	1
DNA-binding transcription activator activity	1
positive regulation of transcription by RNA polymerase II	1
transcription cis-regulatory region binding	1
transcription regulator activity	1
signaling receptor binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
protein dimerization activity	1
double-stranded DNA binding	1
sequence-specific DNA binding	1

Protein interactions and networks

STRING

1076 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARNT2	HIF1A	Q16665	984
ARNT2	HIF3A	Q9Y2N7	958
ARNT2	EPAS1	Q99814	953
ARNT2	SIM1	P81133	928
ARNT2	NPAS4	Q8IUM7	807
ARNT2	EP300	Q09472	779
ARNT2	ARNT	P27540	690
ARNT2	EGLN1	Q9GZT9	645
ARNT2	OTP	Q5XKR4	619
ARNT2	EGLN3	Q9H6Z9	603
ARNT2	ELOC	Q15369	564
ARNT2	ELOB	Q15370	533
ARNT2	THRB	P10828	532
ARNT2	CUL2	Q13617	529
ARNT2	VAV3	Q9UKW4	526

IntAct

111 interactions, top by confidence:

A	B	Type	Score
ARNT2	DTX2	psi-mi:“MI:0915”(physical association)	0.670
ARNT2	CAPN7	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	STK16	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	AP3M1	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	LMO2	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	OSGIN1	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	PSMB1	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	LMO4	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	SIM1	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	FAAP20	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	AP1M1	psi-mi:“MI:0915”(physical association)	0.560
ARNT2	HIF1A	psi-mi:“MI:0915”(physical association)	0.550
ARNT2	TRAF4	psi-mi:“MI:0915”(physical association)	0.550
NPAS3	ARNT2	psi-mi:“MI:0915”(physical association)	0.550
ARNT2	S100A2	psi-mi:“MI:0915”(physical association)	0.400
ARNT2	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	CCDC33	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	CDR2	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	CEP57L1	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	CEP63	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	CTBP1	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	DYDC1	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	GOLGA2	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	IKZF3	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	KIFC3	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	LZTS2	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	MAGEA4	psi-mi:“MI:0915”(physical association)	0.370
ARNT2	MEIS2	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (107): ARNT2 (Reconstituted Complex), ARNT2 (Affinity Capture-MS), TRAF4 (Affinity Capture-MS), SIM2 (Affinity Capture-MS), HIF1A (Affinity Capture-MS), CLPP (Affinity Capture-MS), FNTA (Affinity Capture-MS), FNTB (Affinity Capture-MS), ARNT2 (Affinity Capture-MS), ARNT2 (Affinity Capture-Western), ARNT2 (FRET), ARNT2 (FRET), ARNT2 (Reconstituted Complex), ARNT2 (Reconstituted Complex), ARNT2 (Affinity Capture-Western)

ESM2 similar proteins: A0A0J9VT58, A0A0J9VYS2, A0A0J9W3S9, A0A0J9W9G2, A0A0J9WAS0, A0A0J9WVC0, A0A364LYQ6, A1C602, A1DG01, A2QFG8, A3LQV7, A5DF43, A5DRJ2, A8N767, B0D0T8, B0XVV1, B2AR36, B2W978, C4QV17, C4R1K8, C4Y4V1, C5DX31, C5E1J9, C5E2K7, C7YM38, D8Q8R5, O02748, O59746, P19541, P27540, P87233, Q00858, Q01371, Q03571, Q09750, Q0CHR0, Q0U7C8, Q2GSA4, Q2UMM2, Q4PD88

Diamond homologs: A0MLS5, A6NFD8, O00327, O02219, O02748, O08785, O15516, O15945, O61734, O88529, P27540, P41739, P53762, P79832, P90953, P97460, Q2NL18, Q2VPD4, Q5R4T2, Q5RAK8, Q5ZQU2, Q61324, Q6YGZ4, Q6YGZ5, Q78E60, Q7TS99, Q8BGD7, Q8IUM7, Q8QGQ6, Q8QGQ7, Q8WYA1, Q91YA8, Q91YA9, Q91YB0, Q91YB2, Q99743, Q9BE97, Q9DBX7, Q9DG12, Q9EPW1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	131
Likely benign	97
Benign	22

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
1946819	NM_014862.4(ARNT2):c.475C>T (p.Arg159Ter)	Pathogenic
2425994	NC_000015.9:g.(?80869187)(80869326_?)del	Pathogenic
3679939	NM_014862.4(ARNT2):c.835del (p.Val279fs)	Pathogenic
4277846	NM_014862.4(ARNT2):c.1780C>T (p.Gln594Ter)	Pathogenic
4715492	NM_014862.4(ARNT2):c.908_911dup (p.Gln305fs)	Pathogenic
4717833	NM_014862.4(ARNT2):c.523C>T (p.Gln175Ter)	Pathogenic
4777072	NM_014862.4(ARNT2):c.1204C>T (p.Arg402Ter)	Pathogenic
805850	NM_014862.4(ARNT2):c.1372_1373dup (p.Tyr459fs)	Pathogenic
4082495	NM_014862.4(ARNT2):c.1330C>T (p.Gln444Ter)	Likely pathogenic
4278465	NM_014862.4(ARNT2):c.147-1G>A	Likely pathogenic
801400	NM_014862.4(ARNT2):c.791+5G>A	Likely pathogenic

SpliceAI

4317 predictions. Top by Δscore:

Variant	Effect	Δscore
15:80404545:GG:G	donor_gain	1.0000
15:80404546:GG:G	donor_gain	1.0000
15:80450870:T:A	acceptor_gain	1.0000
15:80458069:A:AG	acceptor_gain	1.0000
15:80470196:T:TA	acceptor_gain	1.0000
15:80470202:C:A	acceptor_gain	1.0000
15:80470204:T:TA	acceptor_gain	1.0000
15:80470211:T:TA	acceptor_gain	1.0000
15:80470212:G:A	acceptor_gain	1.0000
15:80475008:A:AG	acceptor_gain	1.0000
15:80475009:G:GG	acceptor_gain	1.0000
15:80475009:GGA:G	acceptor_gain	1.0000
15:80475220:ACAGG:A	donor_loss	1.0000
15:80475221:CAGG:C	donor_loss	1.0000
15:80475222:AGGT:A	donor_loss	1.0000
15:80475223:GGTC:G	donor_loss	1.0000
15:80475224:G:GC	donor_loss	1.0000
15:80475225:T:A	donor_loss	1.0000
15:80508150:TCTTA:T	acceptor_loss	1.0000
15:80508151:CTTA:C	acceptor_loss	1.0000
15:80508152:TTA:T	acceptor_loss	1.0000
15:80508153:TAGG:T	acceptor_loss	1.0000
15:80508154:A:AG	acceptor_gain	1.0000
15:80508154:AGGCC:A	acceptor_gain	1.0000
15:80508155:G:GA	acceptor_gain	1.0000
15:80508155:GGCC:G	acceptor_gain	1.0000
15:80508155:GGCCG:G	acceptor_gain	1.0000
15:80508217:G:GT	donor_gain	1.0000
15:80508253:GA:G	donor_gain	1.0000
15:80514402:GCAG:G	donor_gain	1.0000

AlphaMissense

4736 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:80470225:C:A	H68N	1.000
15:80470225:C:G	H68D	1.000
15:80470226:A:G	H68R	1.000
15:80470226:A:T	H68L	1.000
15:80470227:T:A	H68Q	1.000
15:80470227:T:G	H68Q	1.000
15:80470235:T:A	I71N	1.000
15:80470235:T:G	I71S	1.000
15:80470237:G:A	E72K	1.000
15:80470238:A:C	E72A	1.000
15:80470238:A:G	E72G	1.000
15:80470238:A:T	E72V	1.000
15:80470239:A:C	E72D	1.000
15:80470239:A:T	E72D	1.000
15:80470240:A:T	R73W	1.000
15:80470241:G:C	R73T	1.000
15:80470241:G:T	R73M	1.000
15:80470242:G:C	R73S	1.000
15:80470242:G:T	R73S	1.000
15:80470243:C:A	R74S	1.000
15:80470243:C:G	R74G	1.000
15:80470244:G:C	R74P	1.000
15:80470246:A:G	R75G	1.000
15:80470247:G:C	R75T	1.000
15:80470247:G:T	R75I	1.000
15:80470248:A:C	R75S	1.000
15:80470248:A:T	R75S	1.000
15:80470249:C:G	R76G	1.000
15:80470249:C:T	R76W	1.000
15:80470250:G:A	R76Q	1.000

dbSNP variants (sampled 300 via entrez): RS1000014841 (15:80577417 C>T), RS1000025663 (15:80538035 A>G), RS1000044569 (15:80433371 T>G), RS1000075798 (15:80433562 G>T), RS1000076744 (15:80595655 T>A), RS1000084074 (15:80512654 A>G), RS1000113923 (15:80434115 T>A), RS1000122301 (15:80448542 C>T), RS1000124503 (15:80592829 G>T), RS1000151304 (15:80513614 C>T), RS1000175835 (15:80555499 G>A), RS1000184208 (15:80416464 A>G), RS1000193164 (15:80450439 G>A), RS1000222166 (15:80512059 C>G,T), RS1000223336 (15:80497690 G>A)

Disease associations

OMIM: gene MIM:606036 | disease phenotypes: MIM:615926, MIM:617173

GenCC curated gene-disease

Disease	Classification	Inheritance
Webb-Dattani syndrome	Strong	Autosomal recessive
septooptic dysplasia	Supportive	Autosomal dominant

Mondo (4): Webb-Dattani syndrome (MONDO:0014404), pulmonary disease, chronic obstructive, susceptibility to (MONDO:0100167), gnb5-related intellectual disability-cardiac arrhythmia syndrome (MONDO:0014953), septooptic dysplasia (MONDO:0008428)

Orphanet (2): GNB5-related intellectual disability-cardiac arrhythmia syndrome (Orphanet:542306), Hypothalamic insufficiency-secondary microcephaly-visual impairment-urinary anomalies syndrome (Orphanet:370006)

HPO phenotypes

56 total (30 of 56 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000028	Cryptorchidism
HP:0000076	Vesicoureteral reflux
HP:0000126	Hydronephrosis
HP:0000175	Cleft palate
HP:0000278	Retrognathia
HP:0000407	Sensorineural hearing impairment
HP:0000458	Anosmia
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000505	Visual impairment
HP:0000609	Optic nerve hypoplasia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000717	Autism
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000864	Abnormality of the hypothalamus-pituitary axis
HP:0000873	Diabetes insipidus
HP:0000958	Dry skin
HP:0000966	Hypohidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001331	Absent septum pellucidum
HP:0001513	Obesity
HP:0001959	Polydipsia
HP:0002002	Deep philtrum

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003262_602	Post bronchodilator FEV1	1.000000e-06
GCST003264_136	Post bronchodilator FEV1/FVC ratio	2.000000e-06
GCST005951_10	Body mass index	2.000000e-08
GCST006061_223	Atrial fibrillation	2.000000e-14
GCST006061_224	Atrial fibrillation	2.000000e-13
GCST006414_115	Atrial fibrillation	9.000000e-09
GCST006414_28	Atrial fibrillation	4.000000e-16
GCST006865_19	Bipolar disorder	6.000000e-06
GCST009368_55	HDL cholesterol levels x long total sleep time interaction (2df test)	4.000000e-10
GCST009368_84	HDL cholesterol levels x long total sleep time interaction (2df test)	2.000000e-09
GCST012597_1	Attention deficit hyperactivity disorder	9.000000e-08
GCST90007006_2	Gut microbiota relative abundance (unclassified genus belonging to family Erysipelotrichaceae)	3.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0007874	gut microbiome measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D025962	Septo-Optic Dysplasia	C10.292.562.700.375.875; C10.500.034.937; C10.500.760.500; C11.590.436.400.875; C16.131.666.034.937; C16.131.666.763.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, affects cotreatment, decreases expression	7
bisphenol A	affects expression, affects methylation, affects cotreatment, decreases expression, decreases reaction	4
trichostatin A	affects cotreatment, decreases expression	3
Ethinyl Estradiol	affects expression, decreases expression	3
entinostat	decreases expression, affects cotreatment	2
Vorinostat	affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Tetrachlorodibenzodioxin	decreases reaction, increases expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Esketamine	increases expression	1
o,p’-DDT	decreases expression, decreases reaction	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
afimoxifene	increases expression	1
sodium arsenite	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
zinc chromate	increases abundance, decreases expression	1
butylbenzyl phthalate	decreases expression, decreases reaction	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
belinostat	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
1,3-bis(4-hydroxyphenyl)-4-methyl-5-(4-(2-piperidinylethoxy)phenol)-1H-pyrazole	decreases expression, decreases reaction	1
licochalcone B	decreases expression	1
bisphenol S	decreases methylation	1

Cellosaurus cell lines

5 cell lines: 3 embryonic stem cell, 2 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0C7	SEES3-1V human ARNT2, clone1	Embryonic stem cell	Male
CVCL_A0C8	SEES3-1V human ARNT2, clone2	Embryonic stem cell	Male
CVCL_A0C9	SEES3-1V human ARNT2, clone3	Embryonic stem cell	Male
CVCL_A0KG	CUIMCi003-A	Induced pluripotent stem cell	Female
CVCL_C1SY	CUIMCi003-A-1	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00140413	PHASE4	COMPLETED	Endocrine Dysfunction and Growth Hormone Deficiency in Children With Optic Nerve Hypoplasia
NCT06760546	PHASE3	RECRUITING	A Trial of Setmelanotide in Patients With Congenital Hypothalamic Obesity (Sub-study of NCT05774756)
NCT05717855	Not specified	COMPLETED	Screening of Septo-optic Dysplasia During a Fetal Examination at 16-20 Weeks of Gestation
NCT06262152	Not specified	UNKNOWN	Sleep Profile of Patients With Septo-optic Dysplasia