ADAR

Summary

ADAR (adenosine deaminase RNA specific, HGNC:225) is a protein-coding gene on chromosome 1q21.3, encoding Double-stranded RNA-specific adenosine deaminase (P55265). Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. It is a selective cancer dependency (DepMap: 40.7% of cell lines).

This gene encodes the enzyme responsible for RNA editing by site-specific deamination of adenosines. This enzyme destabilizes double-stranded RNA through conversion of adenosine to inosine. Mutations in this gene have been associated with dyschromatosis symmetrica hereditaria. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 103 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ADAR-related type 1 interferonopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 1,719 total — 70 pathogenic, 31 likely-pathogenic
• Phenotypes (HPO): 122
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 40.7% of screened cell lines
• MANE Select transcript: NM_001111

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:225
Approved symbol	ADAR
Name	adenosine deaminase RNA specific
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	ADAR1, DRADA
Ensembl gene	ENSG00000160710
Ensembl biotype	protein_coding
OMIM	146920
Entrez	103

Gene structure

Transcript identifiers

Ensembl transcripts: 44 — 25 protein_coding, 10 retained_intron, 9 nonsense_mediated_decay

ENST00000368471, ENST00000368474, ENST00000463920, ENST00000471068, ENST00000492630, ENST00000494866, ENST00000526905, ENST00000529168, ENST00000534279, ENST00000647682, ENST00000648231, ENST00000648311, ENST00000648714, ENST00000648871, ENST00000649021, ENST00000649022, ENST00000649042, ENST00000649408, ENST00000649724, ENST00000649749, ENST00000679375, ENST00000679465, ENST00000679805, ENST00000679899, ENST00000680270, ENST00000680305, ENST00000680472, ENST00000681056, ENST00000681235, ENST00000681429, ENST00000681683, ENST00000681786, ENST00000681901, ENST00000713626, ENST00000713628, ENST00000713629, ENST00000713630, ENST00000713631, ENST00000713632, ENST00000713633, ENST00000713634, ENST00000713635, ENST00000921186, ENST00000970492

RefSeq mRNA: 10 — MANE Select: NM_001111 NM_001025107, NM_001111, NM_001193495, NM_001365045, NM_001365046, NM_001365047, NM_001365048, NM_001365049, NM_015840, NM_015841

CCDS: CCDS1071, CCDS30879, CCDS44231

Canonical transcript exons

ENST00000368474 — 15 exons

Exon	Start	End
ENSE00001053903	154598402	154598585
ENSE00001053906	154590184	154590409
ENSE00001053908	154589757	154589928
ENSE00001053911	154596805	154596995
ENSE00001053914	154597828	154597976
ENSE00001174669	154597123	154597267
ENSE00001174679	154585217	154585344
ENSE00001174682	154585753	154585865
ENSE00001174692	154588125	154588258
ENSE00001200522	154588551	154588673
ENSE00003507884	154601041	154602626
ENSE00003684197	154586181	154586363
ENSE00004020513	154582057	154585043
ENSE00004020517	154607992	154608186
ENSE00004020523	154589369	154589462

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.1418 / max 807.5337, expressed in 1823 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14825	32.6647	1802
14831	24.3078	1810
14824	3.1921	893
14830	0.6297	378
14828	0.3903	188
14826	0.2758	140
14823	0.2511	95
14827	0.1674	71
14822	0.1659	62
14829	0.0969	43

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.45	gold quality
middle temporal gyrus	UBERON:0002771	98.90	gold quality
visceral pleura	UBERON:0002401	98.56	gold quality
middle frontal gyrus	UBERON:0002702	98.56	gold quality
parietal pleura	UBERON:0002400	98.39	gold quality
pleura	UBERON:0000977	98.36	gold quality
cervix squamous epithelium	UBERON:0006922	98.36	silver quality
palpebral conjunctiva	UBERON:0001812	98.33	gold quality
thymus	UBERON:0002370	98.32	gold quality
paraflocculus	UBERON:0005351	98.23	gold quality
medial globus pallidus	UBERON:0002477	98.18	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.14	gold quality
parotid gland	UBERON:0001831	98.03	gold quality
frontal pole	UBERON:0002795	97.96	gold quality
globus pallidus	UBERON:0001875	97.95	gold quality
blood	UBERON:0000178	97.91	gold quality
pylorus	UBERON:0001166	97.87	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.86	gold quality
endometrium epithelium	UBERON:0004811	97.83	gold quality
tibia	UBERON:0000979	97.76	gold quality
caput epididymis	UBERON:0004358	97.75	gold quality
cerebellar vermis	UBERON:0004720	97.73	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.73	gold quality
cardia of stomach	UBERON:0001162	97.70	gold quality
oviduct epithelium	UBERON:0004804	97.65	gold quality
jejunal mucosa	UBERON:0000399	97.61	gold quality
pancreatic ductal cell	CL:0002079	97.60	gold quality
lateral globus pallidus	UBERON:0002476	97.60	gold quality
trigeminal ganglion	UBERON:0001675	97.57	gold quality
tendon of biceps brachii	UBERON:0008188	97.55	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.27
E-MTAB-6142	no	198.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SPI1, STAT1

miRNA regulators (miRDB)

134 targeting ADAR, 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-6870-5P	99.99	68.55	2115
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-1299	99.77	71.24	2389

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• crystallization and diffraction results when complexed with a chimeric oligonucleotide (PMID:11752786)
• overexpression inhibits HDV RNA replication and compromises virus viabiltiy (PMID:11907222)
• Up-regulation of type I interferon inducible 150kDa ADAR1 is associated with induction of A to G transcript mutations in systemic lupus erythematosus (SLE) T lymphocytes. (PMID:12243919)
• The IFN-inducible RNA-specific adenosine deaminase ADAR1 promoter possesses a KCS-like (KCS-l) element. (PMID:12396729)
• ADAR1 is primarily responsible for editing HDV RNA at the amber/W site during HDV infection. (PMID:12414985)
• Results identify regions in human adenosine deaminase that acts on RNA (ADAR1) that interfere with nuclear localization and mediate cytoplasmic accumulation. (PMID:12429827)
• ADAR1 has a role in protein translation independent of RNA editing (PMID:12453429)
• mutations involved in causing dyschromatosis symmetrica hereditaria have been identified in the gene that encodes double-stranded RNA-specific adenosine deaminase (DSRAD) as the disease gene (PMID:12916015)
• ADAR1 variants are differentially regulated during acute inflammation: the localization of these variants and of A-to-I RNA editing in the cytoplasm, nucleus, and nucleolus is intracellularly reorganized in response to inflammatory stimulation (PMID:12954622)
• the intracellular distribution of the various ADAR1 isoforms is determined by NLS-c, NES, NoLS, and a regulatory motif (PMID:14711814)
• This is the first report on DSRAD as the causative gene of dyschromatosis symmetrica hereditaria in the Chinese population. (PMID:15102079)
• data add new variants to the repertoire of ADAR mutations in Dyschromatosis symmetrica hereditaria (PMID:15146470)
• Atomic force microscopy imaging of the Zalpha domain of ADAR1 complexed with supercoiled plasmid Z-DNA. (PMID:15342791)
• R1155W missense mutation is a new mutation in exon 15 of DSRAD, the pathogenic gene of dyschromatosis symmetrica hereditaria (PMID:15659327)
• Frame-shift mutations in the DSRAD gene could cause dyschromatosis symmetrica hereditaria in the chinese population. (PMID:15724015)
• We report 16 novel mutations containing six missense substitutions, two splice site mutations, six frameshift mutations, and two nonsense mutations found in Japanese patients with dyschromatosis symmetrica hereditaria. (PMID:15955093)
• ADAR1 has the potential both to change information content through editing of mRNA and to regulate gene expression through interacting with NF90 (PMID:16055709)
• Identification of a deletion mutation in the ADAR gene of a Chinese family with Dyschromatosis symmetrica hereditaria is reported. (PMID:16133458)
• induction of ADAR1-L may at least partially cause the antiviral effect of IFN-alpha in natural immune response to HDV as well as in case of therapeutic administration of IFN (PMID:16475990)
• 10 novel mutations responsible for dyschromatosis symmetrica hereditaria: p.Q102fsX123, p.T369fsX374, p.S664fsX677, p.R892L, p.I913R, p.R916Q, p.P990fsX1016, p.C1081S, p.C1169F, and p.K1187X. (PMID:16917490)
• ADAR1-L induces mutations in the viral RNA which leads to a loss of viral protein function and reduced viral infectivity, and contributes to the innate antiviral immune response. (PMID:17020943)
• reports two novel mutations c.2116 G > A (E706K) and c.2848 C > T (Q950X) in the DSRAD gene identified in two Chinese pedigrees with DSH (PMID:17021765)
• Missense mutation of the double-stranded RNA-specific adenosine deaminase gene is associated with dyschromatosis symmetrica hereditaria (PMID:17033168)
• ADAR1 interacts with dsRNA-activated protein kinase PKR, inhibits its kinase activity, and suppresses the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha) phosphorylation, and thus increases host susceptibility to viral infection. (PMID:17079286)
• 5 families and 3 sporadic patients with dyschromatosis symmetrica hereditaria in a Chinese Han population were studied. By direct sequencing, 5 novel ADAR gene mutations and 3 mutations described previously were identified, all were heterozygous. (PMID:17225010)
• Novel deletion mutation of gene in a Chinese family with Dyschromatosis Symmetrica Hereditaria (PMID:17478391)
• G to A mutation at the position 3,125 in exon 12 of the DSRAD gene induces a R1042H change in the putative deaminase domain of DSRAD. This, among other DSRAD mutations, is characteristic to dyschromatosis symmetrica hereditaria (PMID:17569068)
• A deletion mutation (c.2447G > A) in the ADAR gene has been detected in this in a pedigree with dyschromatosis symmetrical hereditar, which is probably one of the molecular bases of the pathogenesis of the disease. (PMID:17680540)
• elevated levels of ADAR1, as found in astrocytomas, do indeed interfere with ADAR2 specific editing activity, and the endogenous ADAR1 can form heterodimers with ADAR2 in astrocytes (PMID:18178553)
• Six novel mutations of the ADAR1 gene are reported in Chinese patients with dyschromatosis symmetrica hereditaria. (PMID:18243666)
• suggests a regulatory pathway by a combination of ADAR1 A-to-I editing enzyme and RNA degradation presumably with the aid of hUpf1 (PMID:18362360)
• ADAR1 mRNA is expressed broadly in larynx carcinoma. (PMID:18422172)
• The mutation is a novel heterozygous nucleotide T–>C transition at position 3617 in exon 15 of the DSRAD gene, which induces a M1206T change in the putative deaminase domain of DSRAD. (PMID:18627385)
• histological findings in dyschromatosis symmetrica hereditaria mainly induced by the ADAR1 gene mutations. (PMID:18705826)
• These data suggested the role of ADAR in modulation of HIV-1 replication. (PMID:18753201)
• Four novel mutations of the ADAR1 gene have been reported in patients with dyschromatosis symmetrica hereditaria. (PMID:18799292)
• Overexpressed ADAR1 specifically edits a yet unknown cellular substrate, which in turn affects plasmid-based gene expression. (PMID:18835380)
• dsRBD3 in ADAR1 can mediate nuclear import, while interaction of all dsRBDs might control nuclear export. (PMID:19124606)
• two interferon-induced proteins, ADAR1 and PKR, have antagonistic functions on HIV production (PMID:19605474)
• The data support an active B-Z transition mechanism in which the Z alpha(ADAR1) protein first binds to B-DNA and then converts it to left-handed Z-DNA, a conformation that is then stabilized by the additional binding of a second Z alpha(ADAR1) molecule. (PMID:19637911)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	adar	ENSDARG00000012389
mus_musculus	Adar	ENSMUSG00000027951
rattus_norvegicus	Adar	ENSRNOG00000020744
drosophila_melanogaster	CG12493	FBGN0035571
drosophila_melanogaster	blanks	FBGN0035608
caenorhabditis_elegans		WBGENE00000080

Paralogs (14): STAU2 (ENSG00000040341), ZFR (ENSG00000056097), ADAT1 (ENSG00000065457), ZFR2 (ENSG00000105278), STAU1 (ENSG00000124214), ILF3 (ENSG00000129351), TARBP2 (ENSG00000139546), ADAD2 (ENSG00000140955), ILF2 (ENSG00000143621), ADAD1 (ENSG00000164113), STRBP (ENSG00000165209), PRKRA (ENSG00000180228), ADARB2 (ENSG00000185736), ADARB1 (ENSG00000197381)

Protein

Protein identifiers

Double-stranded RNA-specific adenosine deaminase — P55265 (reviewed: P55265)

Alternative names: 136 kDa double-stranded RNA-binding protein, Interferon-inducible protein 4, K88DSRBP

All UniProt accessions (20): P55265, A0A3B3IRQ9, A0A3B3ISU1, A0A3B3ISX1, A0A3B3ITG9, A0A7P0TA14, A0A7P0Z4F9, A0A7P0Z4K3, A0AAG2TPR9, A0AAG2TPY2, A0AAG2U5V6, A0AAG2U823, A0AAQ5BGH8, A0AAQ5BGJ0, A0AAQ5BGJ1, A0AAQ5BGJ3, A0AAQ5BGJ4, A0AAQ5BGK3, A0AAQ5BGL3, A2IBT1

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) referred to as A-to-I RNA editing. This may affect gene expression and function in a number of ways that include mRNA translation by changing codons and hence the amino acid sequence of proteins since the translational machinery read the inosine as a guanosine; pre-mRNA splicing by altering splice site recognition sequences; RNA stability by changing sequences involved in nuclease recognition; genetic stability in the case of RNA virus genomes by changing sequences during viral RNA replication; and RNA structure-dependent activities such as microRNA production or targeting or protein-RNA interactions. Can edit both viral and cellular RNAs and can edit RNAs at multiple sites (hyper-editing) or at specific sites (site-specific editing). Its cellular RNA substrates include: bladder cancer-associated protein (BLCAP), neurotransmitter receptors for glutamate (GRIA2) and serotonin (HTR2C) and GABA receptor (GABRA3). Site-specific RNA editing of transcripts encoding these proteins results in amino acid substitutions which consequently alters their functional activities. Exhibits low-level editing at the GRIA2 Q/R site, but edits efficiently at the R/G site and HOTSPOT1. Its viral RNA substrates include: hepatitis C virus (HCV), vesicular stomatitis virus (VSV), measles virus (MV), hepatitis delta virus (HDV), and human immunodeficiency virus type 1 (HIV-1). Exhibits either a proviral (HDV, MV, VSV and HIV-1) or an antiviral effect (HCV) and this can be editing-dependent (HDV and HCV), editing-independent (VSV and MV) or both (HIV-1). Impairs HCV replication via RNA editing at multiple sites. Enhances the replication of MV, VSV and HIV-1 through an editing-independent mechanism via suppression of EIF2AK2/PKR activation and function. Stimulates both the release and infectivity of HIV-1 viral particles by an editing-dependent mechanism where it associates with viral RNAs and edits adenosines in the 5’UTR and the Rev and Tat coding sequence. Can enhance viral replication of HDV via A-to-I editing at a site designated as amber/W, thereby changing an UAG amber stop codon to an UIG tryptophan (W) codon that permits synthesis of the large delta antigen (L-HDAg) which has a key role in the assembly of viral particles. However, high levels of ADAR1 inhibit HDV replication.

Subunit / interactions. Homodimer. Homodimerization is essential for its catalytic activity. Isoform 5 can form heterodimers with ADARB1/ADAR2. Isoform 1 interacts with ILF2/NF45 and ILF3/NF90. Binding to ILF3/NF90 up-regulates ILF3-mediated gene expression. Isoform 1 and isoform 5 (via DRBM 3 domain) interact with TNPO1. Isoform 5 (via DRBM domains) interacts with XPO5. Isoform 1 and isoform 5 can interact with EIF2AK2/PKR and UPF1.

Subcellular location. Cytoplasm. Nucleus Cytoplasm. Nucleus. Nucleolus.

Tissue specificity. Ubiquitously expressed, highest levels were found in brain and lung. Isoform 5 is expressed at higher levels in astrocytomas as compared to normal brain tissue and expression increases strikingly with the severity of the tumor, being higher in the most aggressive tumors.

Post-translational modifications. Sumoylation reduces RNA-editing activity.

Disease relevance. Dyschromatosis symmetrica hereditaria (DSH) [MIM:127400] An autosomal dominant pigmentary genodermatosis characterized by a mixture of hyperpigmented and hypopigmented macules distributed on the face and the dorsal parts of the hands and feet, that appear in infancy or early childhood. The disease is caused by variants affecting the gene represented in this entry. Aicardi-Goutieres syndrome 6 (AGS6) [MIM:615010] A form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The third dsRNA-binding domain (DRBM 3) contains an additional N-terminal alpha-helix that is part of a bi-partite nuclear localization signal, together with the sequence immediately C-terminal to DRBM 3. The presence of DRBM 3 is important to bring together the N-terminal and the C-terminal part of the bi-partite nuclear localization signal for import mediated by TNPO1. RNA binding interferes with nuclear import. The first Z-binding domain binds Z-DNA.

Induction. Isoform 1 is induced by interferon alpha. Isoform 5 is constitutively expressed.

Miscellaneous. Produced by alternative promoter usage. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1. Produced by alternative splicing of isoform 1. Produced by alternative promoter usage.

Isoforms (5)

UniProt ID	Names	Canonical?
P55265-1	1, ADAR-a, ADAR1L, p150	yes
P55265-2	2, ADAR-b
P55265-3	3, ADAR-c
P55265-4	4
P55265-5	5, ADAR1S, p110

RefSeq proteins (10): NP_001020278, NP_001102, NP_001180424, NP_001351974, NP_001351975, NP_001351976, NP_001351977, NP_001351978, NP_056655, NP_056656 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002466	A_deamin	Domain
IPR014720	dsRBD_dom	Domain
IPR036388	WH-like_DNA-bd_sf	Homologous_superfamily
IPR036390	WH_DNA-bd_sf	Homologous_superfamily
IPR042371	Z_dom	Domain
IPR044456	ADAR1_DSRM_1	Domain
IPR044457	ADAR1_DSRM_3	Domain

Pfam: PF00035, PF02137, PF02295

Enzyme classification (BRENDA):

• EC 3.5.4.37 — double-stranded RNA adenine deaminase (BRENDA: 11 organisms, 31 substrates, 15 inhibitors, 0 Km, 2 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
8-AZAADENINE IN DOUBLE-STRANDED RNA	—	0
ADENINE IN DOUBLE-STRANDED RNA	—	0

Catalyzed reactions (Rhea), 1 shown:

• adenosine in double-stranded RNA + H2O + H(+) = inosine in double-stranded RNA + NH4(+) (RHEA:10120)

UniProt features (102 total): sequence variant 16, mutagenesis site 14, helix 12, modified residue 12, strand 9, sequence conflict 7, cross-link 7, domain 6, region of interest 6, splice variant 4, binding site 3, compositionally biased region 2, turn 2, chain 1, active site 1

Structure

Experimental structures (PDB)

24 structures.

PDB	Method	Resolution (Å)
1XMK	X-RAY DIFFRACTION	0.97
7ZJ1	X-RAY DIFFRACTION	1.65
1QBJ	X-RAY DIFFRACTION	2.1
3F21	X-RAY DIFFRACTION	2.2
2GXB	X-RAY DIFFRACTION	2.25
7C0I	X-RAY DIFFRACTION	2.4
3F22	X-RAY DIFFRACTION	2.5
2ACJ	X-RAY DIFFRACTION	2.6
3IRR	X-RAY DIFFRACTION	2.65
3F23	X-RAY DIFFRACTION	2.7
7C0J	X-RAY DIFFRACTION	2.75
3IRQ	X-RAY DIFFRACTION	2.8
7ZLQ	X-RAY DIFFRACTION	2.8
5ZUP	X-RAY DIFFRACTION	2.9
5ZUO	X-RAY DIFFRACTION	2.9
5ZU1	X-RAY DIFFRACTION	3.01
9B83	ELECTRON MICROSCOPY	3.01
9B84	ELECTRON MICROSCOPY	3.2
9B89	ELECTRON MICROSCOPY	3.87
1QGP	SOLUTION NMR
2L54	SOLUTION NMR
2MDR	SOLUTION NMR
8GBC	SOLUTION NMR
8GBD	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P55265-F1	68.86	0.35

Functional residue map

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

Catalytic / active sites (1): 912 (proton donor)

Ligand- & substrate-binding residues (3): 910; 966; 1036

Post-translational modifications (19): 26, 285, 481, 601, 603, 614, 629, 636, 808, 814, 823, 825, 384, 408, 418, 418, 418, 580, 875

Mutagenesis-validated functional residues (14):

Position	Phenotype
418	abolishes sumoylation.
708–801	abolishes nuclear location.
708–710	decreased nuclear and partially cytoplasmic location.
712–715	no effect on nuclear location. no effect on rna binding.
716–724	disrupts the bi-partite nuclear localization signal and abolishes nuclear location.
716	disrupts the bi-partite nuclear localization signal and abolishes nuclear location; when associated with s-719 and n-723
718	no effect on nuclear location; when associated with a-721 and a-724.
719	disrupts the bi-partite nuclear localization signal and abolishes nuclear location; when associated with n-716 and n-723
721	no effect on nuclear location; when associated with a-721 and a-724.
723	disrupts the bi-partite nuclear localization signal and abolishes nuclear location; when associated with n-716 and s-719
724	no effect on nuclear location; when associated with a-718 and a-721.
725–801	disrupts nuclear localization signal. no effect on rna binding.
777–778	strongly impaired rna binding. no effect on nuclear location.
801	abolishes interaction with tnpo1, tnpo1-mediated nuclear import and nuclear location.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-75102	C6 deamination of adenosine
R-HSA-77042	Formation of editosomes by ADAR proteins
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9833482	PKR-mediated signaling

MSigDB gene sets: 661 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_HEMATOPOIETIC_PROGENITOR_CELL_DIFFERENTIATION, GOBP_CELLULAR_RESPONSE_TO_VIRUS, MORF_MBD4, GOBP_MYELOID_CELL_HOMEOSTASIS, MORF_RAB5A, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_ERYTHROCYTE_HOMEOSTASIS, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_UP, GOBP_RESPONSE_TO_TYPE_I_INTERFERON

GO Biological Process (31): osteoblast differentiation (GO:0001649), hematopoietic progenitor cell differentiation (GO:0002244), somatic diversification of immune receptors via somatic mutation (GO:0002566), adenosine to inosine editing (GO:0006382), RNA processing (GO:0006396), mRNA processing (GO:0006397), protein import into nucleus (GO:0006606), protein export from nucleus (GO:0006611), response to virus (GO:0009615), base conversion or substitution editing (GO:0016553), mRNA modification (GO:0016556), erythrocyte differentiation (GO:0030218), pre-miRNA processing (GO:0031054), response to interferon-alpha (GO:0035455), negative regulation of protein kinase activity by regulation of protein phosphorylation (GO:0044387), positive regulation of viral genome replication (GO:0045070), innate immune response (GO:0045087), defense response to virus (GO:0051607), definitive hemopoiesis (GO:0060216), negative regulation of type I interferon-mediated signaling pathway (GO:0060339), hematopoietic stem cell homeostasis (GO:0061484), RISC complex assembly (GO:0070922), hepatocyte apoptotic process (GO:0097284), cellular response to virus (GO:0098586), negative regulation of post-transcriptional gene silencing by regulatory ncRNA (GO:1900369), negative regulation of hepatocyte apoptotic process (GO:1903944), immune system process (GO:0002376), apoptotic process (GO:0006915), regulatory ncRNA-mediated gene silencing (GO:0031047), miRNA processing (GO:0035196), positive regulation of type I interferon-mediated signaling pathway (GO:0060340)

GO Molecular Function (9): DNA binding (GO:0003677), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), double-stranded RNA adenosine deaminase activity (GO:0003726), tRNA-specific adenosine deaminase activity (GO:0008251), metal ion binding (GO:0046872), adenosine deaminase activity (GO:0004000), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (9): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), membrane (GO:0016020), supraspliceosomal complex (GO:0044530), nuclear lumen (GO:0031981)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
mRNA Editing: A to I Conversion	2
Interferon Signaling	1
Antimicrobial mechanism of IFN-stimulated genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell differentiation	2
hemopoiesis	2
mRNA metabolic process	2
intracellular protein transport	2
RNA modification	2
nucleic acid binding	2
deaminase activity	2
intracellular membrane-bounded organelle	2
nuclear lumen	2
cytoplasm	2
ossification	1
somatic diversification of immune receptors	1
base conversion or substitution editing	1
gene expression	1
RNA biosynthetic process	1
primary metabolic process	1
RNA processing	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
nuclear export	1
response to other organism	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
miRNA processing	1
response to cytokine	1
negative regulation of protein kinase activity	1
viral genome replication	1
regulation of viral genome replication	1
positive regulation of viral process	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
negative regulation of cytokine-mediated signaling pathway	1
negative regulation of innate immune response	1
type I interferon-mediated signaling pathway	1
regulation of type I interferon-mediated signaling pathway	1
RNA binding	1

Protein interactions and networks

STRING

2598 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ADAR	AXIN1	O15169	993
ADAR	DICER1	Q9UPY3	991
ADAR	ADA	P00813	952
ADAR	GSK3B	P49841	895
ADAR	DHX9	Q08211	852
ADAR	IFIH1	Q9BYX4	800
ADAR	AGO2	Q9UKV8	775
ADAR	DVL1	O14640	757
ADAR	UPF1	Q92900	750
ADAR	RNASEH2A	O75792	742
ADAR	DVL2	O14641	739
ADAR	GRIA2	P42262	730
ADAR	RNASEH2B	Q5TBB1	724
ADAR	RNASEH2C	Q8TDP1	720
ADAR	SAMHD1	Q9Y3Z3	718

IntAct

180 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ADAR	NS	psi-mi:“MI:0403”(colocalization)	0.660
ADAR	NS	psi-mi:“MI:0915”(physical association)	0.660
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
ILF3	ADAR	psi-mi:“MI:0914”(association)	0.640
ADAR	TARDBP	psi-mi:“MI:0915”(physical association)	0.560
FOXP3	FOXP2	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
USP38	AHSG	psi-mi:“MI:0914”(association)	0.530
ILF2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
UPF1	ADAR	psi-mi:“MI:0915”(physical association)	0.520
ADAR		psi-mi:“MI:0915”(physical association)	0.510
CUL3	ACOT7	psi-mi:“MI:0914”(association)	0.500
FMR1	ACOT7	psi-mi:“MI:0914”(association)	0.500
ADAR		psi-mi:“MI:0915”(physical association)	0.490

BioGRID (388): ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS), ADAR (Co-fractionation), ADAR (Affinity Capture-RNA), ADAR (Affinity Capture-MS), ADAR (Affinity Capture-MS)

ESM2 similar proteins: A0JPP1, A0JPQ7, A2VDN6, E6ZGB4, O75151, O75376, O88974, P0CH95, P22682, P55265, P55266, Q14919, Q15047, Q15459, Q17R89, Q2YDP3, Q3UIA2, Q3YEC7, Q4KKX4, Q4V7W5, Q5F3B1, Q5R6Y9, Q5SFM8, Q5U3K5, Q60974, Q61909, Q68EM7, Q6P949, Q6ZM86, Q80TJ7, Q86XZ4, Q8CFK2, Q8K1N4, Q8K4S7, Q8K4Z5, Q8N5Y2, Q8R3Y5, Q8VHI6, Q8VI24, Q92625

Diamond homologs: A0A7H0DN38, A8EV88, P19525, P21081, P21605, P33863, P55265, P55266, Q32NG0, Q3KR54, Q5SUE7, Q63184, Q96M93, Q99MU3, Q9DHS8, A2RFW8, A8AWC2, B5XKB7, B8GAM6, C0MCR4, P0DF14, P0DF15, P51400, P66670, P66672, P78563, P97473, P97616, Q08E27, Q0IIG6, Q12906, Q15633, Q1J7V3, Q1JCZ9, Q1JI19, Q1JMX4, Q22618, Q3SWU0, Q48UR6, Q5BJ52

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
AKT	“down-regulates activity”	ADAR	phosphorylation
AKT3	“down-regulates activity”	ADAR	phosphorylation
AKT2	“down-regulates activity”	ADAR	phosphorylation
AKT1	“down-regulates activity”	ADAR	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transport of Mature Transcript to Cytoplasm	7	21.7×	1e-06
mRNA 3’-end processing	12	19.2×	1e-10
RNA Polymerase II Transcription Termination	9	16.1×	3e-07
Transport of Mature mRNA derived from an Intron-Containing Transcript	11	13.6×	4e-08
mRNA Polyadenylation	19	13.6×	7e-14
Processing of Capped Intron-Containing Pre-mRNA	19	12.7×	9e-14
SARS-CoV-1 modulates host translation machinery	5	12.6×	2e-03
Nonsense-Mediated Decay (NMD)	6	11.4×	6e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of mRNA splicing, via spliceosome	5	27.2×	1e-04
alternative mRNA splicing, via spliceosome	5	20.7×	4e-04
mRNA export from nucleus	10	18.1×	4e-08
activation of innate immune response	5	14.8×	2e-03
mRNA transport	7	11.3×	3e-04
negative regulation of translation	9	10.8×	3e-05
regulation of alternative mRNA splicing, via spliceosome	7	10.5×	4e-04
RNA splicing	19	10.3×	4e-11

Disease & clinical

Clinical variants and AI predictions

ClinVar

1719 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	70
Likely pathogenic	31
Uncertain significance	896
Likely benign	574
Benign	62

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073320	NM_001111.5(ADAR):c.2344C>T (p.Gln782Ter)	Pathogenic
1073687	NM_001111.5(ADAR):c.2929_2939dup (p.Met981fs)	Pathogenic
1184494	NM_001111.5(ADAR):c.3202+1G>A	Pathogenic
126560	NM_001111.5(ADAR):c.1630C>T (p.Arg544Ter)	Pathogenic
1322858	NM_001111.5(ADAR):c.2079+1G>C	Pathogenic
1356340	NM_001111.5(ADAR):c.85C>T (p.Gln29Ter)	Pathogenic
1437688	NM_001111.5(ADAR):c.2309del (p.Pro770fs)	Pathogenic
1451454	NM_001111.5(ADAR):c.763C>T (p.Gln255Ter)	Pathogenic
1452076	NM_001111.5(ADAR):c.2128_2131dup (p.Asn711fs)	Pathogenic
1454211	NM_001111.5(ADAR):c.344del (p.Gly115fs)	Pathogenic
1456115	NM_001111.5(ADAR):c.982C>T (p.Arg328Ter)	Pathogenic
1458191	NM_001111.5(ADAR):c.929dup (p.Ser311fs)	Pathogenic
14817	NM_001111.5(ADAR):c.1420C>T (p.Arg474Ter)	Pathogenic
14818	NM_001111.5(ADAR):c.2768T>C (p.Leu923Pro)	Pathogenic
14819	NM_001111.5(ADAR):c.2854A>T (p.Lys952Ter)	Pathogenic
14820	NM_001111.5(ADAR):c.3494T>C (p.Phe1165Ser)	Pathogenic
14821	NM_001111.5(ADAR):c.2077C>T (p.Gln693Ter)	Pathogenic
14822	NM_001111.5(ADAR):c.941_942del (p.Ser314fs)	Pathogenic
1675376	NM_001111.5(ADAR):c.1491dup (p.Glu498fs)	Pathogenic
1973592	NM_001111.5(ADAR):c.520C>T (p.Arg174Ter)	Pathogenic
1993678	NM_001111.5(ADAR):c.649dup (p.Ser217fs)	Pathogenic
1993820	NM_001111.5(ADAR):c.1000del (p.Val333_Leu334insTer)	Pathogenic
2016140	NM_001111.5(ADAR):c.133G>T (p.Glu45Ter)	Pathogenic
2019241	NM_001111.5(ADAR):c.2583del (p.Ser862fs)	Pathogenic
2023208	NM_001111.5(ADAR):c.3402T>A (p.Tyr1134Ter)	Pathogenic
2083083	NM_001111.5(ADAR):c.296dup (p.Arg100fs)	Pathogenic
2164267	NM_001111.5(ADAR):c.439del (p.Leu147fs)	Pathogenic
2202845	NM_001111.5(ADAR):c.3040G>T (p.Glu1014Ter)	Pathogenic
2202849	NM_001111.5(ADAR):c.1096_1097del (p.Lys366fs)	Pathogenic
2228217	NM_001111.5(ADAR):c.3255_3256del (p.Asp1087fs)	Pathogenic

SpliceAI

2024 predictions. Top by Δscore:

Variant	Effect	Δscore
1:154588121:TCA:T	donor_loss	1.0000
1:154588122:CACCG:C	donor_loss	1.0000
1:154588123:A:AC	donor_gain	1.0000
1:154588123:A:T	donor_loss	1.0000
1:154588123:AC:A	donor_gain	1.0000
1:154588124:C:CA	donor_gain	1.0000
1:154588124:C:T	donor_loss	1.0000
1:154588124:CC:C	donor_gain	1.0000
1:154588124:CCG:C	donor_gain	1.0000
1:154588124:CCGT:C	donor_gain	1.0000
1:154588124:CCGTT:C	donor_gain	1.0000
1:154588150:T:A	donor_gain	1.0000
1:154588254:CAGTG:C	acceptor_gain	1.0000
1:154588255:AGTG:A	acceptor_gain	1.0000
1:154588256:GTG:G	acceptor_gain	1.0000
1:154588257:TG:T	acceptor_gain	1.0000
1:154588257:TGC:T	acceptor_loss	1.0000
1:154588259:C:CC	acceptor_gain	1.0000
1:154588259:CTG:C	acceptor_loss	1.0000
1:154588260:T:G	acceptor_loss	1.0000
1:154589753:TCA:T	donor_loss	1.0000
1:154589754:CA:C	donor_loss	1.0000
1:154589755:A:AC	donor_gain	1.0000
1:154589756:C:CC	donor_gain	1.0000
1:154589924:GGGAG:G	acceptor_gain	1.0000
1:154589925:GGAG:G	acceptor_gain	1.0000
1:154589926:GAG:G	acceptor_gain	1.0000
1:154589926:GAGC:G	acceptor_loss	1.0000
1:154589927:AG:A	acceptor_gain	1.0000
1:154589928:GCT:G	acceptor_loss	1.0000

AlphaMissense

8074 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:154584856:A:G	W1211R	1.000
1:154584856:A:T	W1211R	1.000
1:154585244:A:G	L1139P	1.000
1:154585279:G:C	N1127K	1.000
1:154585279:G:T	N1127K	1.000
1:154585285:G:C	S1125R	1.000
1:154585285:G:T	S1125R	1.000
1:154585287:T:G	S1125R	1.000
1:154586256:A:G	W1043R	1.000
1:154586256:A:T	W1043R	1.000
1:154586267:T:A	K1039I	1.000
1:154586270:T:A	D1038V	1.000
1:154586271:C:G	D1038H	1.000
1:154586272:A:C	S1037R	1.000
1:154586272:A:T	S1037R	1.000
1:154586274:T:G	S1037R	1.000
1:154586275:A:C	C1036W	1.000
1:154586276:C:T	C1036Y	1.000
1:154586277:A:G	C1036R	1.000
1:154586279:G:A	S1035F	1.000
1:154586317:C:A	W1022C	1.000
1:154586317:C:G	W1022C	1.000
1:154586319:A:G	W1022R	1.000
1:154586319:A:T	W1022R	1.000
1:154586351:A:T	I1011N	1.000
1:154586358:C:G	G1009R	1.000
1:154586363:C:T	G1007E	1.000
1:154588135:C:A	K1003N	1.000
1:154588135:C:G	K1003N	1.000
1:154588137:T:C	K1003E	1.000

dbSNP variants (sampled 300 via entrez): RS1000007129 (1:154620416 A>C,G), RS1000122954 (1:154593209 G>A), RS1000177076 (1:154593485 A>G), RS1000268386 (1:154589487 T>C), RS1000279524 (1:154627560 T>A), RS1000403525 (1:154599582 G>A), RS1000456776 (1:154587436 T>C), RS1000457621 (1:154591758 C>T), RS1000465118 (1:154606767 A>G), RS1000625089 (1:154598306 T>C), RS1000691926 (1:154599910 C>T), RS1000796953 (1:154605369 T>C), RS1000902872 (1:154611132 A>G), RS1000929182 (1:154581662 C>A,T), RS1000956098 (1:154618471 T>C)

Disease associations

OMIM: gene MIM:146920 | disease phenotypes: MIM:127400, MIM:615010, MIM:225750, MIM:114500, MIM:600513, MIM:303350

GenCC curated gene-disease

Disease	Classification	Inheritance
dyschromatosis symmetrica hereditaria	Definitive	Autosomal dominant
Aicardi-Goutieres syndrome 6	Definitive	Autosomal recessive
familial infantile bilateral striatal necrosis	Supportive	Autosomal dominant
Aicardi-Goutieres syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (3)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Leigh syndrome	Limited	AR
ADAR-related type 1 interferonopathy	Definitive	AR
ADAR-related type 1 interferonopathy	Definitive	AD

Mondo (10): dyschromatosis symmetrica hereditaria (MONDO:0007483), Aicardi-Goutieres syndrome 6 (MONDO:0014007), Aicardi-Goutieres syndrome (MONDO:0018866), ADAR-related type 1 interferonopathy (MONDO:0700261), colorectal cancer (MONDO:0005575), familial sleep-related hypermotor epilepsy (MONDO:0000030), hereditary spastic paraplegia (MONDO:0019064), intellectual disability (MONDO:0001071), microcephaly (MONDO:0001149), familial infantile bilateral striatal necrosis (MONDO:0010080)

Orphanet (6): Dyschromatosis symmetrica hereditaria (Orphanet:41), Aicardi-Goutières syndrome (Orphanet:51), Sleep-related hypermotor epilepsy (Orphanet:98784), Hereditary spastic paraplegia (Orphanet:685), NON RARE IN EUROPE: Colorectal cancer (Orphanet:466667), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

122 total (30 of 122 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000054	Micropenis
HP:0000252	Microcephaly
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000496	Abnormality of eye movement
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000625	Eyelid coloboma
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000819	Diabetes mellitus
HP:0000821	Hypothyroidism
HP:0000958	Dry skin
HP:0000965	Cutis marmorata
HP:0001063	Acrocyanosis
HP:0001087	Developmental glaucoma
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001276	Hypertonia
HP:0001285	Spastic tetraparesis
HP:0001288	Gait disturbance

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001942_19	Prostate cancer	2.000000e-08
GCST002665_2	Cerebrospinal fluid levels of Alzheimer’s disease-related proteins	6.000000e-63
GCST003681_7	C-reactive protein levels or triglyceride levels (pleiotropy)	6.000000e-09
GCST004748_61	Lung cancer	5.000000e-07
GCST004750_91	Squamous cell lung carcinoma	6.000000e-06
GCST010241_15	Apolipoprotein A1 levels	3.000000e-18
GCST010796_1388	Electrocardiogram morphology (amplitude at temporal datapoints)	4.000000e-08
GCST010796_1389	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-08
GCST012198_2	Interleukin-6 levels	4.000000e-13

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004810	interleukin-6 measurement
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0004458	C-reactive protein measurement
EFO:0004530	triglyceride measurement
EFO:0004614	apolipoprotein A 1 measurement
EFO:0004327	electrocardiography

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C535607	Aicardi-Goutieres syndrome (supp.)
C579932	Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (supp.)
C535729	Dyschromatosis symmetrica hereditaria 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5465291 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.33	Kd	4.673	nM	CHEMBL3752910
8.33	ED50	4.673	nM	CHEMBL3752910
8.11	Kd	7.701	nM	CHEMBL5653589
8.11	ED50	7.701	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 7 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147804: Binding affinity to human ADAR incubated for 45 mins by Kinobead based pull down assay	kd	0.0047	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147804: Binding affinity to human ADAR incubated for 45 mins by Kinobead based pull down assay	kd	0.0077	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	4
CBLC137	increases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	increases expression	1
alpha-pinene	affects cotreatment, increases expression, increases oxidation, increases abundance	1
uranyl acetate	affects expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects localization	1
sodium arsenite	increases abundance, increases expression	1
tetrabromobisphenol A	decreases expression	1
perfluorooctanoic acid	decreases expression	1
methacrylaldehyde	affects cotreatment, increases expression, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
chromium hexavalent ion	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	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment, increases expression	1
Air Pollutants	affects cotreatment, increases abundance, increases expression, increases oxidation	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	affects methylation	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5382469	Binding	Binding affinity to ADAR in human MDA-MB-231 cells at 20 uM incubated for 2 to 5 hrs by pull down based LC-MS analysis	Cyclopropenone, Cyclopropeniminium Ion, and Cyclopropenethione as Novel Electrophilic Warheads for Potential Target Discovery of Triple-Negative Breast Cancer. — J Med Chem

Cellosaurus cell lines

15 cell lines: 10 cancer cell line, 3 induced pluripotent stem cell, 2 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2R5	Abcam HEK293T ADAR KO	Transformed cell line	Female
CVCL_B8AX	Abcam HCT 116 ADAR KO	Cancer cell line	Male
CVCL_B9CZ	Abcam A-549 ADAR KO	Cancer cell line	Male
CVCL_C1NX	CHOPi009-A	Induced pluripotent stem cell	Male
CVCL_C1NY	CHOPi010-A	Induced pluripotent stem cell	Female
CVCL_C1NZ	CHOPi011-A	Induced pluripotent stem cell	Male
CVCL_D2DQ	Abcam MCF-7 ADAR KO	Cancer cell line	Female
CVCL_D8H5	Ubigene HCT 116 ADAR KO	Cancer cell line	Male
CVCL_D8YR	Ubigene HEK293 ADAR KO	Transformed cell line	Female
CVCL_DX22	HAP1 ADAR (-) ADARB1 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00114829	PHASE4	UNKNOWN	Preoperative Assessment of Colon Tumor
NCT00114842	PHASE4	COMPLETED	Magnetic Resonance (MR) Colonography With Fecal Tagging
NCT00114946	PHASE4	TERMINATED	A Study to Compare Two Avastin-Based Treatment Regimens for the Treatment of Metastatic Colorectal Cancer
NCT00122720	PHASE4	COMPLETED	The Effect of Darbepoetin Upon Rehabilitation for Colorectal Cancer Surgery
NCT00129870	PHASE4	TERMINATED	CONCEPT: Comparison of Oxaliplatin vs Conventional Methods With Calcium/Magnesium in First-Line Metastatic Colorectal Cancer
NCT00138060	PHASE4	COMPLETED	Toxicity/Benefit Ratio Optimization of Chemotherapy in Colorectal Cancer (CRC) Patients by Determination of Individual Genotypic Determinants
NCT00216424	PHASE4	TERMINATED	Capecitabine (Xeloda) and Radiation for Patients With Rectosigmoid Carcinoma
NCT00327093	PHASE4	TERMINATED	Elaboration of a Model for Predicting Efficacy of Monoclonal Antibodies (Cetuximab and Bevacizumab) in Patients With Colorectal Cancer and Liver Metastases
NCT00332943	PHASE4	COMPLETED	MR Colonography With Fecal Tagging. Barium vs. BariumFerumoxsil
NCT00441311	PHASE4	COMPLETED	Dissemination of Colorectal Cancer Screening to Primary Care Physicians
NCT00460837	PHASE4	WITHDRAWN	Comparison of Bowel Preparation in Virtual Colonoscopy (VC) - Patient Experience
NCT00473980	PHASE4	COMPLETED	Preoperative Non-steroidal Anti-inflammatory Drugs(NSAID) to Colorectal Cancer Patients
NCT00488904	PHASE4	COMPLETED	Omega-3 Fatty Acids and Postoperative Complications After Colorectal Surgery
NCT00496678	PHASE4	COMPLETED	Trial of Patient Navigation-Activation
NCT00502671	PHASE4	COMPLETED	A Study of Xeloda (Capecitabine) as Adjuvant Monotherapy in Patients With Colon Cancer.
NCT00559676	PHASE4	COMPLETED	Study of Biomarkers in Patients Undergoing Chemotherapy for Metastatic Colorectal Cancer
NCT00577031	PHASE4	COMPLETED	OBELIX Study: A Study of Avastin (Bevacizumab) in Combination With XELOX in Patients With Metastatic Cancer of the Colon or Rectum.
NCT00626054	PHASE4	COMPLETED	Comparison of Two Methods of Administration of a PEG Solution
NCT00812864	PHASE4	COMPLETED	Pharmacokinetic Study of Capecitabine in Elderly Cancer Patient (≥ 75 Years)
NCT00868569	PHASE4	UNKNOWN	Transhepatic Arterial Chemotherapy (TAC) Versus Transcatheter Arterial Chemoembolization (TACE) Plus Folfox4 as the Treatment of Unresectable Liver Metastasis of Colorectal Cancer
NCT00868816	PHASE4	COMPLETED	Oxaliplatine Based Adjuvant Chemotherapy for Stage II/III Colorectal Cancer: 8 Cycles Versus 12 Cycles
NCT00874406	PHASE4	UNKNOWN	Preoperative Transhepatic Arterial Chemotherapy (TAC) in the Treatment of Liver Metastasis of Resectable Colorectal Cancer
NCT00928928	PHASE4	COMPLETED	Oxidative Stress Markers in Open and Laparoscopic Colectomy for Cancer
NCT00942461	PHASE4	COMPLETED	Inflammatory Response in Laparoscopic and Open Colectomy
NCT01023633	PHASE4	UNKNOWN	OPTIMOX1 in Chinese mCRC Patients
NCT01271582	PHASE4	UNKNOWN	Investigation of Association Between UGT1A1 Polymorphisms and Irinotecan Toxicity in Korean Patients
NCT01315990	PHASE4	UNKNOWN	FOLFIRI in Combination With Cetuximab in the First-line Treatment of Metastatic Colorectal Cancer Including a Regular Dermal Prophylaxis to Prevent Acneiforme Follicular Exanthema
NCT01493713	PHASE4	COMPLETED	Correlation Between RECIST, Morphologic Response by CT- Histopathologic Response in Hepatic Metastasis Secondary to Colorectal Cancer
NCT01609660	PHASE4	COMPLETED	Impact of Probiotics on the Intestinal Microbiota
NCT01641458	PHASE4	COMPLETED	Pharmacology-driven Dosing of Fluoropyrimidines in Cancer Patients
NCT01689792	PHASE4	COMPLETED	A Multi-centre Study Comparing the Polyp Detection Rate of Two Different Types of Bowel Preparation: a 2-litre Solution (MOVIPREP®) Versus a Hyperosmotic and Stimulant Combined Low Volume Bowel Preparation (Sodium Picosulfate and Magnesium Citrate)
NCT01695772	PHASE4	COMPLETED	A Study of Bevacizumab Plus 5-Flurouracil (5-FU) Based Doublet Chemotherapy as Neoadjuvant Therapy for Participants With Previously Untreated Unresectable Liver-Only Metastases From Colorectal Cancer
NCT01695863	PHASE4	COMPLETED	Efficacy and Patient Satisfaction of Miralax and Gatorade Versus Movi Prep
NCT01706822	PHASE4	TERMINATED	Radial Reload Laparoscopic LAR Case Series
NCT01740947	PHASE4	TERMINATED	Does Administration of Antibiotics in Patients Undergoing Surgery for Colorectal Cancer Result in Less Complications and Better Prognosis?
NCT01831310	PHASE4	COMPLETED	Nutrition for Colorectal Cancer Patients and Neutrophil Functions
NCT01841294	PHASE4	UNKNOWN	NK Activity Modulation Induced by Intravenous Lidocaine During Colorectal Laparoscopic Surgery
NCT01959061	PHASE4	UNKNOWN	Efficacy and Safety of Raltitrexed-based Transarterial Chemoembolisation(TACE)for Colorectal Cancer Liver Metastases
NCT02032953	PHASE4	UNKNOWN	Enhancing the Anabolic Effect of Perioperative Nutrition With Insulin While Maintaining Normoglycemia
NCT02567331	PHASE4	COMPLETED	A Study of Capecitabine (Xeloda) in Patients With Metastatic Colorectal Cancer