ANGEL2

Summary

ANGEL2 (angel homolog 2, HGNC:30534) is a protein-coding gene on chromosome 1q32.3, encoding RNA 2’,3’-cyclic phosphatase ANGEL2 (Q5VTE6). RNA 2’,3’-cyclic phosphatase that catalyzes the hydrolysis of RNA molecules with a 2’,3’-cyclic phosphate at the 3’ end to produce RNA with a linear 3’-phosphate group.

Enables mRNA 3’-UTR binding activity. Involved in 3’-UTR-mediated mRNA stabilization and negative regulation of mitotic cell cycle. Located in Cajal body and cytoplasm. Is active in mitochondrial matrix.

Source: NCBI Gene 90806 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_144567

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30534
Approved symbol	ANGEL2
Name	angel homolog 2
Location	1q32.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0759L, FLJ12793, Ccr4d
Ensembl gene	ENSG00000174606
Ensembl biotype	protein_coding
OMIM	619001
Entrez	90806

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding, 5 protein_coding_CDS_not_defined

ENST00000360506, ENST00000366962, ENST00000460337, ENST00000473303, ENST00000476904, ENST00000481918, ENST00000498650, ENST00000535388, ENST00000917617, ENST00000917618, ENST00000917619

RefSeq mRNA: 5 — MANE Select: NM_144567 NM_001300753, NM_001300755, NM_001300757, NM_001300758, NM_144567

CCDS: CCDS1512, CCDS73027

Canonical transcript exons

ENST00000366962 — 9 exons

Exon	Start	End
ENSE00001068480	213000786	213000912
ENSE00001163005	213005033	213005454
ENSE00001443127	212992182	212995192
ENSE00003470160	213008210	213008466
ENSE00003501161	212997155	212997318
ENSE00003576088	213015613	213015867
ENSE00003638920	213013093	213013418
ENSE00003679411	213007129	213007198
ENSE00003747209	213000326	213000383

Expression profiles

Bgee: expression breadth ubiquitous, 286 present calls, max score 93.21.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 17.4125 / max 229.6578, expressed in 1806 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
17430	8.5825	1774
17432	4.1537	1322
17433	3.8543	1544
17431	0.8220	451

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	93.21	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.75	gold quality
monocyte	CL:0000576	90.38	gold quality
mononuclear cell	CL:0000842	90.32	gold quality
mucosa of stomach	UBERON:0001199	90.10	gold quality
visceral pleura	UBERON:0002401	90.08	gold quality
leukocyte	CL:0000738	90.02	gold quality
adrenal tissue	UBERON:0018303	89.93	gold quality
parietal pleura	UBERON:0002400	89.82	gold quality
tibial nerve	UBERON:0001323	89.75	gold quality
pleura	UBERON:0000977	89.72	gold quality
primary visual cortex	UBERON:0002436	89.37	gold quality
left ovary	UBERON:0002119	89.35	gold quality
endocervix	UBERON:0000458	89.26	gold quality
skin of hip	UBERON:0001554	89.25	gold quality
germinal epithelium of ovary	UBERON:0001304	89.08	gold quality
right ovary	UBERON:0002118	89.03	gold quality
middle temporal gyrus	UBERON:0002771	88.93	gold quality
corpus callosum	UBERON:0002336	88.86	gold quality
body of uterus	UBERON:0009853	88.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	88.74	gold quality
choroid plexus epithelium	UBERON:0003911	88.64	gold quality
right lung	UBERON:0002167	88.60	gold quality
tibia	UBERON:0000979	88.57	gold quality
skin of abdomen	UBERON:0001416	88.48	gold quality
ovary	UBERON:0000992	88.36	gold quality
body of pancreas	UBERON:0001150	88.33	gold quality
CA1 field of hippocampus	UBERON:0003881	88.26	gold quality
nucleus accumbens	UBERON:0001882	88.18	gold quality
endothelial cell	CL:0000115	88.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.14
E-GEOD-70580	no	846.78

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

165 targeting ANGEL2, 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-3163	100.00	77.23	8605
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489

Literature-anchored findings (GeneRIF, showing 1)

• ANGEL2 is a member of the CCR4 family of deadenylases with 2’,3’-cyclic phosphatase activity. (PMID:32732418)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	angel2	ENSDARG00000016743
mus_musculus	Angel2	ENSMUSG00000026634
rattus_norvegicus	Angel2	ENSRNOG00000003795
drosophila_melanogaster	angel	FBGN0016762
caenorhabditis_elegans		WBGENE00020955

Paralogs (5): ANGEL1 (ENSG00000013523), CNOT6 (ENSG00000113300), CNOT6L (ENSG00000138767), NOCT (ENSG00000151014), PDE12 (ENSG00000174840)

Protein

Protein identifiers

RNA 2’,3’-cyclic phosphatase ANGEL2 — Q5VTE6 (reviewed: Q5VTE6)

All UniProt accessions (1): Q5VTE6

UniProt curated annotations — full annotation on UniProt →

Function. RNA 2’,3’-cyclic phosphatase that catalyzes the hydrolysis of RNA molecules with a 2’,3’-cyclic phosphate at the 3’ end to produce RNA with a linear 3’-phosphate group. Essential for the maturation and processing of mitochondrial RNAs, particularly those generated via non-canonical pathways. Antagonizes pre-tRNA processing and XBP1 mRNA splicing during the unfolded protein response by limiting the availability of 2’,3’-cyclic phosphate substrates for the tRNA ligase complex. Promotes tRNA recycling by eliminating 2’,3’-cyclic phosphate groups from cleaved tRNAs, thereby enabling the tRNA nucleotidyltransferase TRNT1 to reattach the CCA tail essential for aminoacylation and subsequent translation.

Subcellular location. Mitochondrion matrix.

Similarity. Belongs to the CCR4/nocturin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q5VTE6-1	1	yes
Q5VTE6-2	2

RefSeq proteins (5): NP_001287682, NP_001287684, NP_001287686, NP_001287687, NP_653168* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005135	Endo/exonuclease/phosphatase	Domain
IPR036691	Endo/exonu/phosph_ase_sf	Homologous_superfamily
IPR045816	ANGEL2_N	Domain
IPR050410	CCR4/nocturin_mRNA_transcr	Family

Pfam: PF03372, PF19339

Catalyzed reactions (Rhea), 2 shown:

• a 3’-end 2’,3’-cyclophospho-ribonucleotide-RNA + 2 H2O = a 3’-end ribonucleotide-RNA + phosphate + H(+) (RHEA:85011)
• a 3’-end 2’-phospho-ribonucleotide-RNA + H2O = a 3’-end ribonucleotide-RNA + phosphate (RHEA:85191)

UniProt features (53 total): strand 23, helix 11, binding site 7, mutagenesis site 7, turn 2, chain 1, splice variant 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6RW0	X-RAY DIFFRACTION	1.45
6RVZ	X-RAY DIFFRACTION	2.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5VTE6-F1	74.12	0.59

Functional residue map

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

Ligand- & substrate-binding residues (7): 173; 220; 220; 310; 351; 353; 533

Mutagenesis-validated functional residues (7):

Position	Phenotype
173	reduced catalytic activity.
220	loss of catalytic activity.
310	no effect on catalytic activity.
351	loss of catalytic activity.
353	reduced catalytic activity.
532	loss of catalytic activity.
533	reduced catalytic activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 205 (showing top): YAGI_AML_WITH_INV_16_TRANSLOCATION, TGCGCANK_UNKNOWN, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS, GOBP_TRNA_METABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_RNA_SPLICING, GOBP_3_UTR_MEDIATED_MRNA_STABILIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, OSWALD_HEMATOPOIETIC_STEM_CELL_IN_COLLAGEN_GEL_UP, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_NEGATIVE_REGULATION_OF_CELL_CYCLE, GOBP_REGULATION_OF_CELL_CYCLE, GOBP_MRNA_3_END_PROCESSING, GOBP_MITOCHONDRIAL_RNA_PROCESSING

GO Biological Process (5): negative regulation of RNA splicing (GO:0033119), negative regulation of mitotic cell cycle (GO:0045930), 3’-UTR-mediated mRNA stabilization (GO:0070935), mitochondrial mRNA 3’-end processing (GO:0090616), negative regulation of tRNA processing (GO:2000236)

GO Molecular Function (5): magnesium ion binding (GO:0000287), mRNA 3’-UTR binding (GO:0003730), RNA 2’,3’-cyclic phosphatase activity (GO:0160272), RNA 2’-phosphatase activity (GO:0160273), catalytic activity (GO:0003824)

GO Cellular Component (4): cytoplasm (GO:0005737), mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), Cajal body (GO:0015030)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of gene expression	2
mitochondrion	2
phosphatase activity	2
catalytic activity, acting on RNA	2
RNA splicing	1
regulation of RNA splicing	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
negative regulation of cell cycle	1
mRNA stabilization	1
mitochondrial RNA 3’-end processing	1
mRNA 3’-end processing	1
mitochondrial mRNA processing	1
tRNA processing	1
negative regulation of tRNA metabolic process	1
regulation of tRNA processing	1
metal ion binding	1
mRNA binding	1
molecular_function	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
nuclear ribonucleoprotein granule	1

Protein interactions and networks

STRING

1064 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANGEL2	TOE1	Q96GM8	834
ANGEL2	CNOT8	Q9UFF9	624
ANGEL2	TATDN3	Q17R31	593
ANGEL2	BEND7	Q8N7W2	558
ANGEL2	CNOT7	Q9UIV1	545
ANGEL2	PARN	O95453	537
ANGEL2	OTOL1	A6NHN0	534
ANGEL2	LYPD6B	Q8NI32	498
ANGEL2	RPS6KC1	Q96S38	489
ANGEL2	ST8SIA5	O15466	487
ANGEL2	GPCPD1	Q9NPB8	470
ANGEL2	KATNAL2	Q8IYT4	467
ANGEL2	SHLD1	Q8IYI0	458
ANGEL2	LOXHD1	Q8IVV2	455
ANGEL2	CAAP1	Q9H8G2	441

IntAct

30 interactions, top by confidence:

A	B	Type	Score
FAM136A	RBFOX3	psi-mi:“MI:0914”(association)	0.640
RPS2	MPHOSPH10	psi-mi:“MI:0914”(association)	0.530
ZFC3H1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.530
CIRBP	PRMT5	psi-mi:“MI:0914”(association)	0.530
LRP8	TYK2	psi-mi:“MI:0914”(association)	0.350
PB1	ESYT2	psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
PB2	IPO5	psi-mi:“MI:0914”(association)	0.350
EEF1D	VWA8	psi-mi:“MI:0914”(association)	0.350
ILF3	GTPBP10	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
MAMDC4		psi-mi:“MI:0914”(association)	0.350
CAMK2A	SMCHD1	psi-mi:“MI:0914”(association)	0.350
KRTAP13-3	PFDN6	psi-mi:“MI:0914”(association)	0.350
KRTAP19-7	WDR46	psi-mi:“MI:0914”(association)	0.350
PRMT8	HNRNPR	psi-mi:“MI:0914”(association)	0.350
KRTAP13-2	HTRA2	psi-mi:“MI:0914”(association)	0.350
KRTAP6-1	HTRA2	psi-mi:“MI:0914”(association)	0.350
SYNCRIP	DUSP11	psi-mi:“MI:0914”(association)	0.350
NAA40	MACROH2A1	psi-mi:“MI:0914”(association)	0.350
AMPD2	ZMPSTE24	psi-mi:“MI:0914”(association)	0.350
ANGEL2	HNRNPF	psi-mi:“MI:0914”(association)	0.350
	VWA8	psi-mi:“MI:2364”(proximity)	0.270
MGST3	VWA8	psi-mi:“MI:2364”(proximity)	0.270
PDK1	VWA8	psi-mi:“MI:2364”(proximity)	0.270
TRMT61B	VWA8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (90): ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS), ANGEL2 (Affinity Capture-MS)

ESM2 similar proteins: A0JPH4, A6H7I3, A8MS41, A9JRL3, B2RYM0, E1C3P4, F1ND48, O35710, O81916, P55265, P55266, P57097, P79942, P97573, Q09M05, Q0WKY2, Q149N8, Q1RMU2, Q2TBA3, Q4U2V3, Q5E9N9, Q5R6Z9, Q5RED8, Q5RGT6, Q5VTE6, Q5XIX3, Q60805, Q66H62, Q6DD21, Q6P549, Q7TPQ3, Q80TQ2, Q8K1C0, Q8K2I9, Q8K4J0, Q8NFZ0, Q8VCU0, Q96MI9, Q99MU3, Q99MV5

Diamond homologs: A6H7I3, B2RYM0, C4V7I7, O35710, O74874, P79942, Q08DF7, Q24239, Q3TIU4, Q5RGT6, Q5VTE6, Q6AXQ5, Q6CEJ6, Q6L8Q7, Q8K1C0, Q8SU52, Q8VCU0, Q8VYU4, Q9ET55, Q9LS39, Q9UNK9, A8MS41, A2BHJ4, Q0WKY2, Q5BJ41, Q6AXU9, Q8K3P5, Q8VEG6, Q96LI5, Q9M2F8, Q9ULM6, A1CIJ6, A1CW67, A2Q9L0, B7XK66, P0CP22, P0CP23, P31384, Q0CT27, Q1EA11

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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.

GO biological processes:

GO term	Partners	Fold	FDR
RNA processing	5	33.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	71
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1876 predictions. Top by Δscore:

Variant	Effect	Δscore
1:212997149:CCTTA:C	donor_loss	1.0000
1:212997150:CTTA:C	donor_loss	1.0000
1:212997151:TTA:T	donor_loss	1.0000
1:212997152:TACCT:T	donor_loss	1.0000
1:212997153:A:AC	donor_gain	1.0000
1:212997153:ACCTG:A	donor_loss	1.0000
1:212997154:C:CC	donor_gain	1.0000
1:212997175:T:TA	donor_gain	1.0000
1:212997315:CAAT:C	acceptor_gain	1.0000
1:212997316:AAT:A	acceptor_gain	1.0000
1:212997319:C:CC	acceptor_gain	1.0000
1:212999660:C:CA	donor_gain	1.0000
1:213000324:A:AC	donor_gain	1.0000
1:213000325:C:CC	donor_gain	1.0000
1:213008310:T:TA	donor_gain	1.0000
1:213008346:A:AC	donor_gain	1.0000
1:213008347:C:CC	donor_gain	1.0000
1:213008369:A:AC	donor_gain	1.0000
1:213008370:C:CC	donor_gain	1.0000
1:213008370:CTGT:C	donor_gain	1.0000
1:213015647:T:TA	donor_gain	1.0000
1:212997314:ACAAT:A	acceptor_gain	0.9900
1:212997315:CAATC:C	acceptor_gain	0.9900
1:212997317:AT:A	acceptor_gain	0.9900
1:212999733:T:TA	donor_gain	0.9900
1:213000314:T:A	donor_gain	0.9900
1:213000317:AGAAC:A	donor_loss	0.9900
1:213000318:GAACT:G	donor_loss	0.9900
1:213000319:AAC:A	donor_loss	0.9900
1:213000320:ACTCA:A	donor_loss	0.9900

AlphaMissense

3563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:212995081:T:A	D532V	1.000
1:212995081:T:C	D532G	1.000
1:212995081:T:G	D532A	1.000
1:213005108:A:C	N353K	1.000
1:213005108:A:T	N353K	1.000
1:213005204:C:A	K321N	1.000
1:213005204:C:G	K321N	1.000
1:213005217:C:G	R317P	1.000
1:213008253:C:A	R200M	1.000
1:213008253:C:G	R200T	1.000
1:212995077:A:C	H533Q	0.999
1:212995077:A:T	H533Q	0.999
1:212995079:G:C	H533D	0.999
1:212995080:A:C	D532E	0.999
1:212995080:A:T	D532E	0.999
1:212995082:C:G	D532H	0.999
1:212995102:G:T	P525Q	0.999
1:212995103:G:A	P525S	0.999
1:212997202:T:A	D479V	0.999
1:212997202:T:G	D479A	0.999
1:212997203:C:G	D479H	0.999
1:212997235:G:A	T468I	0.999
1:213005110:T:C	N353D	0.999
1:213005114:G:C	D351E	0.999
1:213005114:G:T	D351E	0.999
1:213005115:T:A	D351V	0.999
1:213005115:T:C	D351G	0.999
1:213005115:T:G	D351A	0.999
1:213005118:C:A	G350V	0.999
1:213005118:C:T	G350D	0.999

dbSNP variants (sampled 300 via entrez): RS1000050349 (1:213006966 C>T), RS1000051498 (1:213003780 A>G), RS1000106157 (1:212994079 C>G,T), RS1000168899 (1:212998998 G>A), RS1000313010 (1:213004088 C>T), RS1000495272 (1:212998834 T>C), RS1000610043 (1:212997086 T>C), RS1000761676 (1:212999108 G>A,C), RS1000878050 (1:212992987 A>C), RS1001066005 (1:212992988 G>C,T), RS1001124832 (1:213016944 C>A), RS1001197239 (1:213002823 A>C,G), RS1001313240 (1:213002658 C>T), RS1001495533 (1:213013853 TG>T), RS1001989189 (1:212993839 A>T)

Disease associations

OMIM: gene MIM:619001 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	7
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	decreases expression	1
abrine	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Methotrexate	increases expression	1
Silicon Dioxide	decreases expression	1
Tretinoin	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1

Clinical trials (associated diseases)

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