ANG

Summary

ANG (angiogenin, HGNC:483) is a protein-coding gene on chromosome 14q11.2, encoding Angiogenin (P03950). Secreted ribonuclease that can either promote or restrict cell proliferation of target cells, depending on the context.

The protein encoded by this gene is a member of the RNase A superfamily though it has relatively weak ribonucleolytic activity. This protein is a potent mediator of new blood vessel formation and thus, in addition to the name RNase5, is commonly called angiogenin. This protein induces angiogenesis after binding to actin on the surface of endothelial cells. This protein also accumulates at the nucleolus where it stimulates ribosomal transcription. Under stress conditions this protein translocates to the cytosol where it hydrolyzes cellular tRNAs and influences protein synthesis. A signal peptide is cleaved from the precursor protein to produce a mature protein which contains a nuclear localization signal, a cell binding motif, and a catalytic domain. This protein has been shown to be both neurotrophic and neuroprotective and the mature protein has antimicrobial activity against some bacteria and fungi, including S. pneumoniae and C. albicans. Due to its effect on rRNA production and angiogenesis this gene plays important roles in cell growth and tumor progression. Mutations in this gene are associated with progression of amyotrophic lateral sclerosis (ALS). This gene and the neighboring RNase4 gene share promoters and 5’ exons though each gene then splices to a distinct 3’ exon containing the complete coding region of each gene. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 283 — RefSeq curated summary.

At a glance

• Gene–disease (curated): amyotrophic lateral sclerosis type 9 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 105 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 49
• Druggable target: yes
• MANE Select transcript: NM_001097577

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:483
Approved symbol	ANG
Name	angiogenin
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RNASE5, RAA1, HEL168
Ensembl gene	ENSG00000214274
Ensembl biotype	protein_coding
OMIM	105850
Entrez	283

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 19 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000336811, ENST00000397990, ENST00000554073, ENST00000885598, ENST00000885600, ENST00000885601, ENST00000885603, ENST00000885605, ENST00000885606, ENST00000885607, ENST00000885608, ENST00000885609, ENST00000885610, ENST00000885611, ENST00000885612, ENST00000885613, ENST00000885614, ENST00000885615, ENST00000885616, ENST00000885617

RefSeq mRNA: 6 — MANE Select: NM_001097577 NM_001097577, NM_001145, NM_001385271, NM_001385272, NM_001385273, NM_001385274

CCDS: CCDS9554

Canonical transcript exons

ENST00000397990 — 2 exons

Exon	Start	End
ENSE00003579216	20688764	20688874
ENSE00003900731	20693547	20694183

Expression profiles

Bgee: expression breadth ubiquitous, 238 present calls, max score 99.68.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.3203 / max 1531.9740, expressed in 1619 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138454	26.3203	1619
138455	4.6713	21
138453	1.3171	696

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.68	gold quality
liver	UBERON:0002107	99.04	gold quality
left ovary	UBERON:0002119	95.04	gold quality
right ovary	UBERON:0002118	94.23	gold quality
rectum	UBERON:0001052	94.07	gold quality
body of stomach	UBERON:0001161	94.03	gold quality
endocervix	UBERON:0000458	93.21	gold quality
mucosa of stomach	UBERON:0001199	92.58	gold quality
descending thoracic aorta	UBERON:0002345	92.55	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.54	gold quality
right lung	UBERON:0002167	92.37	gold quality
minor salivary gland	UBERON:0001830	92.21	gold quality
mucosa of transverse colon	UBERON:0004991	91.94	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.92	gold quality
stomach	UBERON:0000945	91.65	gold quality
omental fat pad	UBERON:0010414	91.60	gold quality
ascending aorta	UBERON:0001496	91.54	gold quality
peritoneum	UBERON:0002358	91.53	gold quality
thoracic aorta	UBERON:0001515	91.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	91.42	gold quality
saliva-secreting gland	UBERON:0001044	91.19	gold quality
aorta	UBERON:0000947	91.09	gold quality
transverse colon	UBERON:0001157	91.08	gold quality
gall bladder	UBERON:0002110	91.08	gold quality
popliteal artery	UBERON:0002250	91.00	gold quality
tibial artery	UBERON:0007610	90.98	gold quality
left coronary artery	UBERON:0001626	90.83	gold quality
colonic mucosa	UBERON:0000317	90.77	gold quality
ectocervix	UBERON:0012249	90.65	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.52	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-9	yes	67.01
E-MTAB-10553	yes	36.21
E-MTAB-10287	yes	33.90
E-GEOD-81608	yes	14.75
E-GEOD-36552	no	9.77
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CREB1, CTCF, ETS1, FOXO1, FOXO3, HIF1A, HNF4A, NR0B2, PPARA, PPARD, SP3

miRNA regulators (miRDB)

12 targeting ANG, 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-4715-3P	99.98	66.03	670
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6809-5P	99.13	68.45	1223
HSA-MIR-6755-3P	98.61	66.90	834
HSA-MIR-6776-5P	98.54	67.43	1304
HSA-MIR-6783-5P	97.67	67.21	1528
HSA-MIR-144-5P	97.66	69.90	531
HSA-MIR-6773-5P	97.04	64.30	595
HSA-MIR-212-5P	96.83	67.43	950
HSA-MIR-6724-5P	96.41	63.11	507
HSA-MIR-550B-3P	95.43	67.73	599

Literature-anchored findings (GeneRIF, showing 40)

• nucleolar localization; nucleolar signal peptide (PMID:11374889)
• Here we report that chANG, an antiangiogenin peptide, binds to the actin-binding site of angiogenin (PMID:11782452)
• Blood levels are elevated in myelodysplastic syndromes and in acute myeloid leukemia. (PMID:11847008)
• role of C-terminal fragment in defining enzymatic potency (PMID:11851402)
• Expression and localization of angiogenin in placenta; enhanced levels at term over first trimester villi (PMID:11984825)
• Distribution of angiogenin and its gene message in colorectal cancer patients has clinical relevance. (PMID:12168899)
• Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia. (PMID:12209593)
• An angiogenin-binding DNA sequence (CTCTCTCTCTCTCTCTCCCTC) has been identified from the nontranscribed region of rRNA gene and characterized as possessing angiogenin-dependent promoter activity that directs the expression of a luciferase reporter gene. (PMID:12515546)
• Human angiogenin has antimicrobial activity against C. albicans and S. pneumoniae. (PMID:12548285)
• High serum angiogenin levels were associated with choriocarcinoma (PMID:12705339)
• in umbilical cord plasma, a developmental increase was evident in concentrations of vascular endothelial growth factor(VEGF) and angiogenin during the last trimester of gestation, and VEGF level was lower in term fetuses born to mothers with diabetes (PMID:14593238)
• Compared with controls, patients with multiple myeloma show elevated serum levels. (PMID:14671622)
• The specific localization of angiogenin in peritubular myoid cells suggests that angiogenin plays physiologic roles in the human testis. (PMID:15064314)
• Finb functions as a sequence-specific transcriptional repressor of the hANG gene (PMID:15067362)
• elevated blood levels of angiogenin feature chronic myeloid malignancies, suggesting a role of angiogenin in the pathogenesis of these diseases (PMID:15128420)
• The distribution of ANG was studied in term placenta and by its expression in cultured trophoblastic cells. (PMID:15166501)
• serum angiogenin levels although not increased in comparison with healthy controls, may predict clinical outcome of patients with early chronic lymphocytic leukemia and help to refine Rai’s stratification (PMID:15182336)
• The inflammation associated with endometriosis, through increasing levels of peritoneal fluid angiogenin, might promote angiogenesis for progression of the disease and correlate with the extent of the disorder. (PMID:15236995)
• In Irish amyotrophic lateral sclerosis patients, there was a significant allelic association with the rs11701 SNP & a new mutation (K40I) that potentially inhibits angiogenin function. (PMID:15557516)
• Angiogenin-stimulated rRNA transcription in endothelial cells serves as a crossroad in the process of angiogenesis induced by various angiogenic factors. (PMID:15558023)
• The present study demonstrates for the first time, differential expression of mRNA and secretion for angiogenin and VCAM-1 from placental explants and trophoblasts in culture subjected to hypoxia (PMID:15979542)
• Elevated expression of angiogenin is associated with prostate cancer (PMID:16322296)
• Under hypoxic conditions, the ANG and VEGF secreted by renal proximal tubular epithelial cells may modulate angiogenesis and vascular remodeling in the renal interstitium via an increase in the production of HIF-1 (PMID:16490744)
• ANG is one of the neovascularization factors of gastric carcinoma and may work in coordination with VEGF, and promote the proliferation of gastric carcinoma cells (PMID:16937522)
• Absence of angiogenic genes not modification in Italian ALS patients. (PMID:17113198)
• in conclusion, we did not detect the association with rs11701-G or with any other newly detected variation in the ANG regulatory region with amyotropic lateral sclerosis (PMID:17462671)
• Our finding supports the evidence that the ANG gene is involved in ALS. (PMID:17703939)
• ANG mutations, identified in ALS patients, are associated with functional loss of ANG activity. Strong ANG expression, in normal spinal cord neurons and endothelial cells confirms plausibility of ANG dysfunction being relevant to pathogenesis of ALS. (PMID:17886298)
• Human ANG variants implicated in amyotrophic lateral sclerosis are characterized. (PMID:17900154)
• identified seven different mutations, five of which are novel, in nine patients but not in 515 healthy controls. Three mutations are located in the signal peptide region, three in the coding sequence, and one in the 3’ untranslated region. (PMID:18087731)
• In three continental population groups (Asia, Europe, Africa), the angiogenin and RNase 2 genes appear to exhibit markedly less genetic heterogeneity with regard to T195C and A238G (ANG) and C425A (RNASE2) SNPs. (PMID:18636464)
• Results describe significant differences between controls and patients with renal cell carcinoma both pre-operatively and post-operatively in angiogenin, PDGF and MCP-1 serum levels. (PMID:18808740)
• Overall, our findings support the implication of ANG gene mutations as a rare but widespread cause of ALS. (PMID:18852347)
• Angiogenin is expressed in human dermal papilla cells, where it might contribute to hair growth directly, by stimulating dermal papilla cells to proliferate, or indirectly, by inducing local vascularization. (PMID:18936943)
• angiogenin expression is decreased in the eutopic endometrium from women with advanced stage en (PMID:18955785)
• The results suggest that by increasing infected endothelial cell 45S rRNA synthesis, proliferation, migration, and angiogenesis, Kaposi Sarcoma Associated Herpesvirus-induced angiogenin could be playing a pivotal role in the pathogenesis of infection. (PMID:19158252)
• Angiogenin was significantly higher in Chronic heart failure patients compared to controls;Angiogenin is related to worsening heart failure severity (NYHA classification) (PMID:19160530)
• proteases contribute indirectly to the defense function of the stratum corneum by releasing the RNase inhibitor mediated inhibition of RNase 5 and RNase 7. (PMID:19262607)
• endogenous bFGF affects the expression of angiogenin in HeLa cells. (PMID:19287993)
• Angiogenin is required for stress-induced production of tiRNAs. (PMID:19332886)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
mus_musculus	Ang2	ENSMUSG00000047894
mus_musculus	Ang5	ENSMUSG00000053961
mus_musculus	Ang4	ENSMUSG00000060615
mus_musculus	Ang	ENSMUSG00000072115
mus_musculus	Ang6	ENSMUSG00000072598
rattus_norvegicus	Ang2	ENSRNOG00000025562

Paralogs (12): RNASE1 (ENSG00000129538), RNASE7 (ENSG00000165799), RNASE2 (ENSG00000169385), RNASE3 (ENSG00000169397), RNASE6 (ENSG00000169413), RNASE8 (ENSG00000173431), RNASE11 (ENSG00000173464), RNASE10 (ENSG00000182545), RNASE9 (ENSG00000188655), RNASE13 (ENSG00000206150), RNASE12 (ENSG00000258436), RNASE4 (ENSG00000258818)

Protein

Protein identifiers

Angiogenin — P03950 (reviewed: P03950)

Alternative names: Ribonuclease 5

All UniProt accessions (2): P03950, W0UV28

UniProt curated annotations — full annotation on UniProt →

Function. Secreted ribonuclease that can either promote or restrict cell proliferation of target cells, depending on the context. Endocytosed in target cells via its receptor PLXNB2 and translocates to the cytoplasm or nucleus. Under stress conditions, localizes to the cytoplasm and promotes the assembly of stress granules (SGs): specifically cleaves a subset of tRNAs within anticodon loops to produce tRNA-derived stress-induced fragments (tiRNAs), resulting in translation repression and inhibition of cell proliferation. tiRNas also prevent formation of apoptosome, thereby promoting cell survival. Preferentially cleaves RNAs between a pyrimidine and an adenosine residue, suggesting that it cleaves the anticodon loop of tRNA(Ala) (32-UUAGCAU-38) after positions 33 and 36. Cleaves a subset of tRNAs, including tRNA(Ala), tRNA(Glu), tRNA(Gly), tRNA(Lys), tRNA(Val), tRNA(His), tRNA(Asp) and tRNA(Sec). Under growth conditions and in differentiated cells, translocates to the nucleus and stimulates ribosomal RNA (rRNA) transcription, including that containing the initiation site sequences of 45S rRNA, thereby promoting cell growth and proliferation. Angiogenin induces vascularization of normal and malignant tissues via its ability to promote rRNA transcription. Involved in hematopoietic stem and progenitor cell (HSPC) growth and survival by promoting rRNA transcription in growth conditions and inhibiting translation in response to stress, respectively. Mediates the crosstalk between myeloid and intestinal epithelial cells to protect the intestinal epithelial barrier integrity: secreted by myeloid cells and promotes intestinal epithelial cells proliferation and survival. Also mediates osteoclast-endothelial cell crosstalk in growing bone: produced by osteoclasts and protects the neighboring vascular cells against senescence by promoting rRNA transcription.

Subunit / interactions. Homodimer. Interacts with RNH1; inhibiting ANG ribonuclease activity. Interacts with PCNA.

Subcellular location. Secreted. Nucleus. Nucleolus. Cytoplasm. Stress granule.

Tissue specificity. Expressed predominantly in the liver. Also detected in endothelial cells and spinal cord neurons.

Disease relevance. Amyotrophic lateral sclerosis 9 (ALS9) [MIM:611895] A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Activity regulation. Has weak tRNA ribonuclease activity by itself due to partial autoinhibition by its C-terminus (residues 140-147), which folds into a short alpha-helix that partially occludes the substrate-binding site. In absence of stress, the ribonuclease activity is inhibited by RNH1 in the cytoplasm. In response to stress, dissociates from RNH1 in the cytoplasm and associates with cytoplasmic ribosomes with vacant A-sites: ribosomes directly activate the tRNA ribonuclease activity of ANG by refolding the C-terminal alpha-helix. In response to stress, the angiogenic activity of ANG is inhibited by RNH1 in the nucleus.

Similarity. Belongs to the pancreatic ribonuclease family.

RefSeq proteins (6): NP_001091046, NP_001136, NP_001372200, NP_001372201, NP_001372202, NP_001372203 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001427	RNaseA	Family
IPR023411	RNaseA_AS	Active_site
IPR023412	RNaseA_domain	Domain
IPR036816	RNaseA-like_dom_sf	Homologous_superfamily

Pfam: PF00074

UniProt features (79 total): sequence variant 32, mutagenesis site 18, strand 8, helix 5, binding site 4, disulfide bond 3, turn 3, active site 2, signal peptide 1, chain 1, short sequence motif 1, modified residue 1

Structure

Experimental structures (PDB)

56 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
4AOH	X-RAY DIFFRACTION	1.04
5EOP	X-RAY DIFFRACTION	1.35
5M9Q	X-RAY DIFFRACTION	1.35
5M9R	X-RAY DIFFRACTION	1.44
7PNR	X-RAY DIFFRACTION	1.6
5M9M	X-RAY DIFFRACTION	1.65
1UN3	X-RAY DIFFRACTION	1.7
5M9V	X-RAY DIFFRACTION	1.7
4B36	X-RAY DIFFRACTION	1.76
8OO3	X-RAY DIFFRACTION	1.76
1B1I	X-RAY DIFFRACTION	1.8
1K59	X-RAY DIFFRACTION	1.8
1K5B	X-RAY DIFFRACTION	1.8
5M9P	X-RAY DIFFRACTION	1.8
7PNP	X-RAY DIFFRACTION	1.8
5EPZ	X-RAY DIFFRACTION	1.85
5M9S	X-RAY DIFFRACTION	1.85
7NPM	X-RAY DIFFRACTION	1.86
5M9J	X-RAY DIFFRACTION	1.9
5M9A	X-RAY DIFFRACTION	1.95
4AHM	X-RAY DIFFRACTION	1.96
4AHK	X-RAY DIFFRACTION	1.97
8OO4	X-RAY DIFFRACTION	1.99
1A4Y	X-RAY DIFFRACTION	2
1B1E	X-RAY DIFFRACTION	2
1B1J	X-RAY DIFFRACTION	2
1H0D	X-RAY DIFFRACTION	2
1H52	X-RAY DIFFRACTION	2
1H53	X-RAY DIFFRACTION	2
1HBY	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P03950-F1	90.50	0.81

Antibody-complex structures (SAbDab): 1 — 1H0D

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 (2): 37 (proton acceptor); 138 (proton donor)

Ligand- & substrate-binding residues (4): 45; 46; 105; 127

Post-translational modifications (1): 25

Disulfide bonds (3): 50–105, 63–116, 81–131

Mutagenesis-validated functional residues (18):

Position	Phenotype
29	affects substrate preference. significantly decreases binding affinity for rnh1.
32	significantly decreases binding affinity for rnh1.
36	slightly decreases binding affinity for rnh1.
37	abolished ribonuclease activity. does not affect binding to plxnb2 receptor.
59	homodimerization is similar to wild-type; causes mislocalization in the cytoplasm; strongly reduces ribonucleolytic acti
64	significantly decreases binding affinity for rnh1.
68	decreased ribonuclease activity.
90	abolished binding to plxnb2 receptor.
92	slightly decreases binding affinity for rnh1.
92	abolished binding to plxnb2 receptor.
104	increased ribonuclease activity.
104	slightly increased ribonuclease activity.
109–110	significantly decreases binding affinity for rnh1.
132	slightly decreases binding affinity for rnh1.
140–141	slightly increased ribonuclease activity.
140	strongly increased ribonuclease activity.
141	strongly increased ribonuclease activity.
143–144	increased ribonuclease activity.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-418990	Adherens junctions interactions
R-HSA-9708296	tRNA-derived small RNA (tsRNA or tRNA-related fragment, tRF) biogenesis
R-HSA-1500931	Cell-Cell communication
R-HSA-211000	Gene Silencing by RNA
R-HSA-421270	Cell-cell junction organization
R-HSA-446728	Cell junction organization
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 427 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_REGULATION_OF_TRANSLATION_IN_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GNF2_GSTM1, GOMF_NUCLEASE_ACTIVITY, BECKER_TAMOXIFEN_RESISTANCE_UP, GNF2_HPN, GOBP_TRNA_METABOLIC_PROCESS, MENSE_HYPOXIA_UP, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_OOGENESIS, GOBP_MACROMOLECULE_CATABOLIC_PROCESS

GO Biological Process (32): angiogenesis (GO:0001525), ovarian follicle development (GO:0001541), oocyte maturation (GO:0001556), response to hypoxia (GO:0001666), placenta development (GO:0001890), positive regulation of endothelial cell proliferation (GO:0001938), cell communication (GO:0007154), signal transduction (GO:0007165), rRNA transcription (GO:0009303), response to hormone (GO:0009725), tRNA decay (GO:0016078), cell migration (GO:0016477), antibacterial humoral response (GO:0019731), signaling (GO:0023052), actin filament polymerization (GO:0030041), negative regulation of translation in response to stress (GO:0032055), stress granule assembly (GO:0034063), positive regulation of phosphorylation (GO:0042327), homeostatic process (GO:0042592), negative regulation of apoptotic process (GO:0043066), innate immune response (GO:0045087), negative regulation of smooth muscle cell proliferation (GO:0048662), positive regulation of protein secretion (GO:0050714), defense response to Gram-positive bacterium (GO:0050830), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), hematopoietic stem cell proliferation (GO:0071425), cytoplasmic translation (GO:0002181), receptor-mediated endocytosis (GO:0006898), negative regulation of translation (GO:0017148), cell differentiation (GO:0030154), cellular response to stress (GO:0033554), tRNA stabilization (GO:0036416)

GO Molecular Function (18): DNA binding (GO:0003677), actin binding (GO:0003779), endonuclease activity (GO:0004519), RNA endonuclease activity (GO:0004521), RNA nuclease activity (GO:0004540), tRNA-specific ribonuclease activity (GO:0004549), signaling receptor binding (GO:0005102), copper ion binding (GO:0005507), heparin binding (GO:0008201), hydrolase activity (GO:0016787), rRNA binding (GO:0019843), peptide binding (GO:0042277), protein homodimerization activity (GO:0042803), ribosome binding (GO:0043022), receptor ligand activity (GO:0048018), nucleic acid binding (GO:0003676), nuclease activity (GO:0004518), protein binding (GO:0005515)

GO Cellular Component (14): extracellular region (GO:0005576), basement membrane (GO:0005604), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), chromosome (GO:0005694), nucleolus (GO:0005730), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), actin cytoskeleton (GO:0015629), endocytic vesicle (GO:0030139), growth cone (GO:0030426), angiogenin-PRI complex (GO:0032311), neuronal cell body (GO:0043025)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Cell-cell junction organization	1
Gene Silencing by RNA	1
Gene expression (Transcription)	1
Cell junction organization	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
cellular process	2
nuclease activity	2
RNA nuclease activity	2
intracellular membraneless organelle	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
female gonad development	1
anatomical structure development	1
developmental process involved in reproduction	1
cell maturation	1
oocyte development	1
response to stress	1
response to decreased oxygen levels	1
animal organ development	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
DNA-templated transcription	1
rRNA metabolic process	1
response to endogenous stimulus	1
response to chemical	1
tRNA metabolic process	1
RNA catabolic process	1
cell motility	1
antimicrobial humoral response	1
defense response to bacterium	1
regulation of biological process	1
actin polymerization or depolymerization	1
protein polymerization	1
translation	1
negative regulation of translation	1
cellular response to stress	1
regulation of translation in response to stress	1
membraneless organelle assembly	1

Protein interactions and networks

STRING

794 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANG	RNH1	P13489	937
ANG	RNASE2	P10153	926
ANG	RNASE8	Q8TDE3	901
ANG	RNASE3	P12724	879
ANG	RNASET2	O00584	828
ANG	PLXNB2	O15031	802
ANG	CXCL8	P10145	767
ANG	RNASEL	Q05823	740
ANG	EIF2AK1	Q9BQI3	694
ANG	SETX	Q7Z333	674
ANG	FSTL3	O95633	653
ANG	EGF	P01133	641
ANG	ANGPT1	Q15389	640
ANG	TIMP1	P01033	635
ANG	IL6	P05231	633

IntAct

44 interactions, top by confidence:

A	B	Type	Score
ANG	RNH1	psi-mi:“MI:0915”(physical association)	0.750
RNH1	ANG	psi-mi:“MI:0407”(direct interaction)	0.750
ANG	RNH1	psi-mi:“MI:0407”(direct interaction)	0.750
ANG	RNH1	psi-mi:“MI:0914”(association)	0.750
ACTN2	ANG	psi-mi:“MI:0915”(physical association)	0.630
ANG	ACTN2	psi-mi:“MI:0915”(physical association)	0.630
ANG	ACTN2	psi-mi:“MI:0407”(direct interaction)	0.630
ANG	PLAUR	psi-mi:“MI:0915”(physical association)	0.570
ANG	PLAUR	psi-mi:“MI:2364”(proximity)	0.570
ANG	PLAUR	psi-mi:“MI:0403”(colocalization)	0.570
FST	ANG	psi-mi:“MI:0915”(physical association)	0.570
FST	ANG	psi-mi:“MI:0403”(colocalization)	0.570
FST	ANG	psi-mi:“MI:0407”(direct interaction)	0.570
ANG	PCNA	psi-mi:“MI:0915”(physical association)	0.540
ANG	PCNA	psi-mi:“MI:0403”(colocalization)	0.540
ANG	ANXA2	psi-mi:“MI:0914”(association)	0.480
S100A10	ANG	psi-mi:“MI:0914”(association)	0.480
ANXA2	ANG	psi-mi:“MI:0914”(association)	0.480
S100A10	ANG	psi-mi:“MI:2364”(proximity)	0.480
ANG	ANXA2	psi-mi:“MI:2364”(proximity)	0.480
ANG	S100A10	psi-mi:“MI:0403”(colocalization)	0.480
ANG	ANXA2	psi-mi:“MI:0403”(colocalization)	0.480
PLAU	ANG	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (14): RNH1 (Affinity Capture-MS), ANG (Affinity Capture-Western), ANG (Reconstituted Complex), ANG (Two-hybrid), ANG (Two-hybrid), ANG (Two-hybrid), ANG (Co-crystal Structure), PM20D2 (Affinity Capture-MS), RNH1 (Affinity Capture-MS), ANG (Affinity Capture-MS), TP53 (Affinity Capture-Western), ANG (Affinity Capture-Western), ANG (Affinity Capture-Western), ANG (Two-hybrid)

ESM2 similar proteins: O46525, O46527, O46530, O55004, P00679, P03950, P07998, P08904, P15467, P15468, P21570, P31346, P31347, P34096, P61821, P61822, P81649, Q3TMQ6, Q5NVS4, Q5VI84, Q64438, Q71MJ0, Q861Y1, Q861Y2, Q861Y3, Q861Y4, Q861Y5, Q8HZQ0, Q8SPN4, Q8SPN5, Q8SPZ4, Q8SPZ5, Q8SQ04, Q8SQ05, Q8SQ06, Q8SQ07, Q8SQ08, Q8SQ09, Q8SQ11, Q8SQ12

Diamond homologs: A1YLB9, B3EWJ0, O18937, O35290, O35291, O35292, O46525, O46526, O46527, O46528, O46529, O46530, O46531, O46532, O46533, O46534, O55004, P00657, P00680, P00682, P00685, P03950, P08904, P10153, P12724, P15466, P15467, P15468, P16414, P24717, P34096, P47778, P47779, P47780, P47781, P47782, P47783, P47784, P47785, P47786

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ANG	up-regulates	Angiogenesis

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	55
Likely benign	23
Benign	15

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
18077	NM_001097577.3(ANG):c.189C>G (p.Cys63Trp)	Pathogenic
18082	NM_001097577.3(ANG):c.409G>A (p.Val137Ile)	Pathogenic
57746	GRCh38/hg38 14q11.2(chr14:20475357-21613255)x1	Pathogenic
59933	GRCh38/hg38 14q11.2(chr14:20127290-21376436)x3	Pathogenic
18080	NM_001097577.3(ANG):c.155G>A (p.Ser52Asn)	Likely pathogenic
815630	GRCh37/hg19 14q11.2(chr14:21159605-22252320)x4	Likely pathogenic

SpliceAI

794 predictions. Top by Δscore:

Variant	Effect	Δscore
14:20684687:G:GT	donor_gain	0.9800
14:20684693:GCGG:G	donor_gain	0.9800
14:20684755:CGAGG:C	donor_loss	0.9800
14:20684758:GGTA:G	donor_loss	0.9800
14:20684760:T:A	donor_loss	0.9800
14:20690898:C:CA	acceptor_gain	0.9800
14:20693541:CCGCA:C	acceptor_loss	0.9800
14:20693542:CGCA:C	acceptor_loss	0.9800
14:20693543:GCA:G	acceptor_loss	0.9800
14:20693544:CA:C	acceptor_loss	0.9800
14:20697848:A:AG	acceptor_gain	0.9800
14:20697849:G:GG	acceptor_gain	0.9800
14:20697943:GTTG:G	donor_gain	0.9700
14:20684757:AGG:A	donor_loss	0.9600
14:20684759:GTAG:G	donor_loss	0.9600
14:20689359:G:GT	donor_gain	0.9600
14:20693852:C:T	donor_gain	0.9600
14:20697849:GT:G	acceptor_gain	0.9600
14:20684756:GAG:G	donor_gain	0.9500
14:20684760:T:G	donor_loss	0.9500
14:20693545:A:AG	acceptor_gain	0.9500
14:20693546:G:GG	acceptor_gain	0.9500
14:20693546:GGA:G	acceptor_gain	0.9500
14:20694024:TC:T	donor_gain	0.9500
14:20698221:A:AG	acceptor_gain	0.9500
14:20684759:G:GG	donor_gain	0.9400
14:20693845:GAA:G	donor_gain	0.9400
14:20698225:CCAAG:C	acceptor_gain	0.9400
14:20685043:G:T	donor_gain	0.9300
14:20697951:G:GG	donor_gain	0.9300

AlphaMissense

955 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20693769:T:C	F69L	0.989
14:20693771:T:A	F69L	0.989
14:20693771:T:G	F69L	0.989
14:20693770:T:G	F69C	0.983
14:20693662:T:G	F33C	0.980
14:20693661:T:C	F33L	0.977
14:20693663:C:A	F33L	0.977
14:20693663:C:G	F33L	0.977
14:20693877:T:A	C105S	0.973
14:20693878:G:C	C105S	0.973
14:20693770:T:C	F69S	0.971
14:20693850:A:C	S96R	0.969
14:20693852:C:A	S96R	0.969
14:20693852:C:G	S96R	0.969
14:20693805:T:A	C81S	0.959
14:20693806:G:C	C81S	0.959
14:20693712:T:A	C50S	0.957
14:20693713:G:C	C50S	0.957
14:20693751:T:A	C63S	0.955
14:20693752:G:C	C63S	0.955
14:20693756:A:C	K64N	0.955
14:20693756:A:T	K64N	0.955
14:20693806:G:A	C81Y	0.955
14:20693662:T:C	F33S	0.954
14:20693917:A:G	Y118C	0.952
14:20693955:T:A	C131S	0.944
14:20693956:G:C	C131S	0.944
14:20693878:G:A	C105Y	0.943
14:20693910:T:A	C116S	0.943
14:20693911:G:C	C116S	0.943

dbSNP variants (sampled 300 via entrez): RS1000155177 (14:20683375 T>C,G), RS1000244219 (14:20692883 T>A), RS1000282480 (14:20692995 C>A), RS1000393623 (14:20686166 G>A), RS1000425114 (14:20694375 C>T), RS1000484011 (14:20689774 A>G), RS1000568174 (14:20683199 G>A), RS1000761974 (14:20684073 A>C,G), RS1000870343 (14:20686442 T>C,G), RS1001110952 (14:20684099 G>A,C,T), RS1001485697 (14:20691861 A>G), RS1001768696 (14:20692318 G>A,C), RS1001965931 (14:20686125 T>C,G), RS1002166668 (14:20684828 C>A), RS1002204193 (14:20692587 A>G,T)

Disease associations

OMIM: gene MIM:105850 | disease phenotypes: MIM:611895, MIM:612069

GenCC curated gene-disease

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 9	Definitive	Autosomal dominant
amyotrophic lateral sclerosis	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
amyotrophic lateral sclerosis type 9	Limited	AD

Mondo (3): amyotrophic lateral sclerosis type 9 (MONDO:0012753), amyotrophic lateral sclerosis type 10 (MONDO:0012790), amyotrophic lateral sclerosis (MONDO:0004976)

Orphanet (2): Amyotrophic lateral sclerosis (Orphanet:803), Frontotemporal dementia with motor neuron disease (Orphanet:275872)

HPO phenotypes

49 total (30 of 49 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002460	Distal muscle weakness
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_40	Blood protein levels	9.000000e-111

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
C567429	Amyotrophic Lateral Sclerosis 10 (supp.)
C567499	Amyotrophic Lateral Sclerosis 9 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5829 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	9
Cyclosporine	affects expression, decreases expression, increases expression	5
Cisplatin	affects cotreatment, increases expression, affects expression	4
cobaltous chloride	affects expression, increases expression, increases secretion, decreases reaction	3
Acetaminophen	affects expression, decreases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression, increases expression	3
bisphenol A	affects expression, affects cotreatment, decreases methylation	2
trichostatin A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases cleavage, increases reaction	2
entinostat	increases expression, affects cotreatment	2
Air Pollutants	decreases expression, increases abundance	2
Benzo(a)pyrene	decreases expression	2
Nickel	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
afuresertib	increases expression	1
sotorasib	affects cotreatment, decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
bis(tri-n-butyltin)oxide	decreases expression	1
tributyltin	decreases expression	1
beta-lapachone	decreases expression	1
trimellitic anhydride	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
zinc chloride	increases expression, decreases reaction	1
tobacco tar	decreases expression, decreases reaction	1
ochratoxin A	decreases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
methylmercury II	decreases expression	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
CHEMBL2215697	Binding	Inhibition of ANG	Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 induced pluripotent stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E7JL	KOLF2.1J ANG K41I SNV/SNV	Induced pluripotent stem cell	Male
CVCL_E7JM	KOLF2.1J ANG K41I SNV/WT	Induced pluripotent stem cell	Male
CVCL_E7NB	KOLF2.1J ANG 0.5kbdel DEL/DEL	Induced pluripotent stem cell	Male
CVCL_SC49	HAP1 ANG (-) 1	Cancer cell line	Male
CVCL_SC50	HAP1 ANG (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS