RNASE2

Summary

RNASE2 (ribonuclease A family member 2, HGNC:10045) is a protein-coding gene on chromosome 14q11.2, encoding Non-secretory ribonuclease (P10153). This is a non-secretory ribonuclease.

The protein encoded by this gene is a non-secretory ribonuclease that belongs to the pancreatic ribonuclease family, a subset of the ribonuclease A superfamily. The protein antimicrobial activity against viruses.

Source: NCBI Gene 6036 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 20 total
• GTEx eGene: eQTL in 17 tissues, sQTL in 0 (q < 0.05)
• Constraint (gnomAD): pLI 0.29 (intermediate), LOEUF 1.89 (unconstrained)
• MANE Select transcript: NM_002934

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10045
Approved symbol	RNASE2
Name	ribonuclease A family member 2
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	EDN, RAF3
Ensembl gene	ENSG00000169385
Ensembl biotype	protein_coding
OMIM	131410
Entrez	6036

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

MANE Select: ENST00000304625

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 1

ENST00000304625, ENST00001133415

RefSeq mRNA: 1 — MANE Select: NM_002934 NM_002934

CCDS: CCDS9561

Canonical transcript exons

ENST00000304625 — 2 exons

Exon	Start	End
ENSE00001124161	20955767	20956436
ENSE00001285128	20955487	20955536

Expression profiles

Bgee: expression breadth ubiquitous, 184 present calls, max score 99.52.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.7787 / max 176.2572, expressed in 128 samples.

Highest expression (Bgee): trabecular bone tissue, bone marrow, bone marrow cell, monocyte, mononuclear cell.

Genetic regulation across tissues (GTEx eQTL / sQTL)

RNASE2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 17 tissues and its splicing (sQTL) in 0 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

17 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	5.8e-26	+0.25	14:20891649:C:A
Nerve Tibial	eqtl	9.3e-11	+0.19	14:20891649:C:A
Adipose Visceral Omentum	eqtl	7.7e-04	+0.13	14:20891649:C:A
Esophagus Gastroesophageal Junction	eqtl	1.0e-03	-0.19	14:20881241:AG:A
Brain Hippocampus	eqtl	1.3e-03	+0.21	14:20965232:C:T
Skin Sun Exposed Lower leg	eqtl	1.8e-03	+0.20	14:20972173:A:ATG
Brain Nucleus accumbens basal ganglia	eqtl	5.4e-03	+0.20	14:20965232:C:T
Spleen	eqtl	8.9e-03	+0.20	14:20891649:C:A
Colon Sigmoid	eqtl	1.3e-02	+0.28	14:20715864:C:T
Brain Hypothalamus	eqtl	1.8e-02	+0.17	14:20970796:C:T
Artery Aorta	eqtl	2.6e-02	+0.41	14:20538631:A:G
Heart Atrial Appendage	eqtl	3.6e-02	-0.13	14:20991181:T:G
Muscle Skeletal	eqtl	3.7e-02	+0.14	14:20892970:T:A
Adipose Subcutaneous	eqtl	3.9e-02	-0.55	14:20684098:T:A
Brain Caudate basal ganglia	eqtl	4.3e-02	-0.61	14:20508301:T:C
Thyroid	eqtl	4.5e-02	-0.13	14:20966212:C:T
Esophagus Mucosa	eqtl	4.6e-02	-0.46	14:21160598:G:A

FANTOM5 promoters

2 alternative TSS:

Promoter ID	TPM avg	Samples expressed
138487	0.7481	126
138486	0.0306	11

Top tissues by expression

showing 100 of 276 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.52	gold quality
bone marrow	UBERON:0002371	98.92	gold quality
bone marrow cell	CL:0002092	97.66	gold quality
monocyte	CL:0000576	97.08	gold quality
mononuclear cell	CL:0000842	96.92	gold quality
leukocyte	CL:0000738	96.86	gold quality
granulocyte	CL:0000094	94.47	gold quality
blood	UBERON:0000178	93.60	gold quality
olfactory bulb	UBERON:0002264	87.78	gold quality
type B pancreatic cell	CL:0000169	86.87	gold quality
right lung	UBERON:0002167	85.83	gold quality
spleen	UBERON:0002106	85.49	gold quality
germinal epithelium of ovary	UBERON:0001304	82.90	gold quality
right adrenal gland cortex	UBERON:0035827	79.25	gold quality
right coronary artery	UBERON:0001625	78.75	gold quality
upper lobe of left lung	UBERON:0008952	78.49	gold quality
upper lobe of lung	UBERON:0008948	78.14	gold quality
right adrenal gland	UBERON:0001233	77.66	gold quality
left adrenal gland cortex	UBERON:0035825	77.05	gold quality
left adrenal gland	UBERON:0001234	76.91	gold quality
adrenal cortex	UBERON:0001235	76.01	gold quality
descending thoracic aorta	UBERON:0002345	75.78	gold quality
lower lobe of lung	UBERON:0008949	75.53	silver quality
left uterine tube	UBERON:0001303	75.41	gold quality
hair follicle	UBERON:0002073	74.54	gold quality
amniotic fluid	UBERON:0000173	74.50	gold quality
endothelial cell	CL:0000115	74.43	gold quality
mucosa of stomach	UBERON:0001199	73.81	gold quality
epithelial cell of pancreas	CL:0000083	73.72	gold quality
left coronary artery	UBERON:0001626	73.63	gold quality
vermiform appendix	UBERON:0001154	73.41	gold quality
adrenal gland	UBERON:0002369	73.27	gold quality
coronary artery	UBERON:0001621	73.10	gold quality
heart right ventricle	UBERON:0002080	73.03	silver quality
thymus	UBERON:0002370	72.53	gold quality
lung	UBERON:0002048	71.79	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	71.61	gold quality
cervix squamous epithelium	UBERON:0006922	71.25	gold quality
caecum	UBERON:0001153	71.16	gold quality
thoracic aorta	UBERON:0001515	70.31	gold quality
spinal cord	UBERON:0002240	70.21	gold quality
omental fat pad	UBERON:0010414	69.91	gold quality
peritoneum	UBERON:0002358	69.87	gold quality
mucosa of urinary bladder	UBERON:0001259	69.70	silver quality
cranial nerve II	UBERON:0000941	69.55	gold quality
ascending aorta	UBERON:0001496	69.42	gold quality
right atrium auricular region	UBERON:0006631	68.97	gold quality
layer of synovial tissue	UBERON:0007616	68.96	silver quality
adipose tissue of abdominal region	UBERON:0007808	68.80	gold quality
gall bladder	UBERON:0002110	68.51	gold quality
cardiac atrium	UBERON:0002081	68.50	gold quality
parietal pleura	UBERON:0002400	67.89	gold quality
pleura	UBERON:0000977	67.86	silver quality
decidua	UBERON:0002450	67.85	silver quality
nasal cavity epithelium	UBERON:0005384	67.55	gold quality
right ovary	UBERON:0002118	67.42	gold quality
CA1 field of hippocampus	UBERON:0003881	67.42	silver quality
substantia nigra	UBERON:0002038	67.30	gold quality
tibial nerve	UBERON:0001323	66.82	gold quality
middle frontal gyrus	UBERON:0002702	66.67	silver quality
aorta	UBERON:0000947	66.54	gold quality
midbrain	UBERON:0001891	66.16	gold quality
visceral pleura	UBERON:0002401	66.01	silver quality
heart	UBERON:0000948	65.80	gold quality
epithelium of nasopharynx	UBERON:0001951	65.54	gold quality
mucosa of paranasal sinus	UBERON:0005030	64.93	gold quality
cardiac ventricle	UBERON:0002082	64.92	gold quality
heart left ventricle	UBERON:0002084	64.83	gold quality
endometrium epithelium	UBERON:0004811	64.62	gold quality
subcutaneous adipose tissue	UBERON:0002190	63.89	gold quality
tibial artery	UBERON:0007610	63.87	gold quality
popliteal artery	UBERON:0002250	63.82	gold quality
tendon of biceps brachii	UBERON:0008188	63.57	gold quality
upper arm skin	UBERON:0004263	63.51	gold quality
lymph node	UBERON:0000029	63.47	gold quality
endocervix	UBERON:0000458	63.31	gold quality
quadriceps femoris	UBERON:0001377	63.13	gold quality
vastus lateralis	UBERON:0001379	63.13	gold quality
myometrium	UBERON:0001296	62.98	gold quality
smooth muscle tissue	UBERON:0001135	62.74	gold quality
cardiac muscle of right atrium	UBERON:0003379	62.66	gold quality
palpebral conjunctiva	UBERON:0001812	62.64	silver quality
left ventricle myocardium	UBERON:0006566	62.62	gold quality
tongue squamous epithelium	UBERON:0006919	62.62	gold quality
pancreatic ductal cell	CL:0002079	62.11	silver quality
fundus of stomach	UBERON:0001160	62.09	gold quality
hypothalamus	UBERON:0001898	61.95	gold quality
uterine cervix	UBERON:0000002	61.92	gold quality
triceps brachii	UBERON:0001509	61.76	gold quality
cerebellar vermis	UBERON:0004720	61.70	gold quality
choroid plexus epithelium	UBERON:0003911	61.49	silver quality
transverse colon	UBERON:0001157	61.07	gold quality
pigmented layer of retina	UBERON:0001782	61.00	silver quality
gluteal muscle	UBERON:0002000	60.97	gold quality
superficial temporal artery	UBERON:0001614	60.87	gold quality
connective tissue	UBERON:0002384	60.85	gold quality
muscle layer of sigmoid colon	UBERON:0035805	60.74	gold quality
adipose tissue	UBERON:0001013	60.70	gold quality
fallopian tube	UBERON:0003889	60.68	gold quality
orbitofrontal cortex	UBERON:0004167	60.55	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-MTAB-9801	yes	7288.46
E-GEOD-89232	yes	1840.59
E-CURD-112	yes	925.20
E-HCAD-10	yes	713.17
E-ANND-5	yes	473.26
E-HCAD-6	yes	355.05
E-ANND-3	yes	29.32
E-MTAB-9067	yes	23.17
E-CURD-122	yes	13.44
E-MTAB-10042	yes	12.54

HPA expression

RNA tissue specificity: Tissue enriched

52 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	1614.8	medium
Thymus	tissue	13.8
Smooth muscle	tissue	9.0	not detected
Appendix	tissue	8.5	not detected
Choroid plexus	tissue	5.2
Urinary bladder	tissue	4.8	not detected
Liver	tissue	4.3	not detected
Adipose tissue	tissue	4.2	not detected
Adrenal gland	tissue	4.1	not detected
Spleen	tissue	4.0	low
Skin 1	tissue	2.8	not detected
Lung	tissue	2.8	not detected
Gallbladder	tissue	2.5	not detected
Locus coeruleus	tissue	2.3
Hippocampus	tissue	1.9	not detected
Lymph node	tissue	1.8	not detected
Salivary gland	tissue	1.8	not detected
Pituitary gland	tissue	1.7
Placenta	tissue	1.7	not detected
Retina	tissue	1.5
Vagina	tissue	1.4	not detected
Nucleus accumbens	tissue	1.2
Cervix	tissue	1.0	not detected
Small intestine	tissue	0.9	not detected
Colon	tissue	0.7	not detected
Fallopian tube	tissue	0.7	not detected
Testis	tissue	0.6	not detected
Stomach 1	tissue	0.6	not detected
Heart muscle	tissue	0.6	not detected
Rectum	tissue	0.6	not detected
Tonsil	tissue	0.6	not detected
Tongue	tissue	0.5
Breast	tissue	0.4	not detected
Parathyroid gland	tissue	0.4	not detected
Ovary	tissue	0.3	not detected
Epididymis	tissue	0.3	not detected
Putamen	tissue	0.3
Kidney	tissue	0.3	high
Prostate	tissue	0.3	not detected
Postcentral gyrus	tissue	0.3
Seminal vesicle	tissue	0.2	not detected
Esophagus	tissue	0.2	not detected
Endometrium 1	tissue	0.2	not detected
Thyroid gland	tissue	0.2	not detected
Duodenum	tissue	0.2	not detected
Pancreas	tissue	0.1	not detected
Basal ganglia	tissue	0.1	not detected
Amygdala	tissue	0.1
Hippocampal formation	tissue	0.1
Ventral pallidum	tissue	0.1
Periaqueductal gray	tissue	0.1
Septum	tissue	0.1

Brain sub-regions (HPA Brain Atlas): detected in 184; highest nTPM — Lateral funiculus (white matter) (8.7), Nucleus raphe pallidus (7.3), Dorsal funiculus (white matter) (6.5), Anterior funiculus (white matter) (6.0), Blood vessel (5.4).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, CEBPA, CEBPG, GATA1, GATA2, HNF4A, MAZ, SP1, SPI1, ZNF362

miRNA regulators (miRDB)

Targeting RNASE2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

28 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-320A-3P	99.77	69.73	2107
HSA-MIR-320B	99.77	69.73	2107
HSA-MIR-320C	99.77	69.73	2107
HSA-MIR-320D	99.77	69.73	2107
HSA-MIR-4429	99.77	69.62	2111
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-1224-5P	99.48	65.59	803
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-548L	99.06	70.90	2560
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-3179	98.22	65.90	1445
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-3936	97.64	64.47	732
HSA-MIR-4689	96.97	65.79	1209
HSA-MIR-3139	96.68	66.77	652
HSA-MIR-6858-5P	96.05	64.59	1020
HSA-MIR-4765	93.11	66.17	737

Functional genomics

gnomAD constraint: pLI 0.294, LOEUF 1.89, missense Z 0.847 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000304625 — one region, missense o/e 0.86.

Literature-anchored findings (GeneRIF, showing 37)

• atomic resolution structure (PMID:11876642)
• crystal structure of a post-translationally modified form of eosinophil-derived neurotoxin (EDN) with four extra residues on its N terminus ((-4)EDN) has been solved and refined at atomic resolution (1 A) (PMID:11916383)
• EDN and ECP are paralogs in human and Old World monkeys. (PMID:11959927)
• evidence for glycosylphosphatidylinositol (GPI)-anchored neurotoxin on granulocytes (PMID:12606041)
• data suggest that peripheral blood eosinophils from subjects with untreated asthma have increased inflammatory capacity, as reflected by greater intracellular concentrations of EDN (PMID:15356558)
• Results reveal the dendritic cell-activating activity of eosinophil-derived neurotoxin and suggest that it is a likely participant of inflammatory and immune responses–an endogenous multifunctional immune alarmin. (PMID:15528350)
• Results describe the crystal structure of placental ribonuclease inhibitor in complex with eosinophil-derived neurotoxin, and a mutational analysis based on this structure. (PMID:15755456)
• May possibly be associated with the development of tropical pulmonary eosinophilia. (PMID:16014847)
• Elevated glycosylated form of EDN in urine is associated with ovarian cancer (PMID:16428483)
• EGO is a novel ncRNA gene expressed during eosinophil development and is necessary for normal MBP and EDN transcript expression. (PMID:17351112)
• Data show that uEPX/c levels did not correlate with established markers of asthma severity and eosinophilic airway inflammation in atopic asthmatic children. (PMID:17641730)
• MAZ and Sp1 play important roles on the transcriptional activation of the human edn promoter through specific binding to a 34-nt segment present in representative primate eosinophil rnase promoters. (PMID:17927842)
• Urinary concentrations of eosinophil-derived neurotoxin in patients with atopic dermatitis show a significant positive correlation with disease severity. (PMID:17965582)
• EDN can activate myeloid DCs by triggering the Toll-like receptor (TLR)2-myeloid differentiation factor 88 signaling pathway (PMID:18195069)
• 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)
• No variation in genes encoding eosinophil-derived neurotoxin for Atopic dermatitis pathogenesis in this German cohort. (PMID:19014520)
• the roles of the six discrete segments in transcription regulation were investigated and the -350/-329 region (ednR2) was shown to be involved in the regulation of edn expression (PMID:19115260)
• ECP and EDN disrupt skin integrity and cause inflammation (PMID:19717523)
• Eosinophil protein X in urine from asymptomatic neonates is a biomarker significantly associated with later development of allergic sensitization, nasal eosinophilia, and eczema during the first 6 years of life (PMID:21680952)
• findings show substantial amounts of EPX/EDN localise in an extra-granular, low equilibrium density compartment of eosinophils (PMID:23053729)
• A higher level of serum EDN was found specifically in patients with ALS, indicating that EDN may participate in the pathophysiology of Amyotrophic lateral sclerosis. (PMID:23533305)
• mRNA levels of eosinophil granule proteins, rather than sputum eosinophil%, may reflect airway hyperresponsiveness and airflow limitation. (PMID:24814827)
• increased in feces after the ingestion of enterocolitis-causative foods (PMID:24890227)
• RNASE2 gene expression was differentially expressed in rheumatoid arthritis patients considering a sequence polymorphism. (PMID:25221852)
• Serum EDN level may be a useful marker for monitoring persistent airflow limitation in adult patients with asthma who had positive results for house-dust-specific IgE antibodies. (PMID:26534742)
• In healthy children, 95th Percentile values ranged from 1519 mg/kg at 0 months to 54.4 mg/kg at 144 months for fecal calprotectin (fCP) and from 9.9 mg/kg at 0 months to 0.2 mg/kg at 144 months for fecal eosinophil-derived neurotoxin (fEDN). There was a significant association between age and fCP concentrations and age and fEDN concentrations and a significant association between fEDN and fCP. (PMID:28169973)
• EDN serum level could be considered a candidate molecule as a clinical biomarker for evaluating atopic dermatitis activity and a predictor of relapse (PMID:28866306)
• the rs3827907 C-allele appeared to particularly influence inhaled corticosteroid treatment response in the presence of eosinophilic inflammation (PMID:30367910)
• Immune Sensing of Synthetic, Bacterial, and Protozoan RNA by Toll-like Receptor 8 Requires Coordinated Processing by RNase T2 and RNase 2. (PMID:32294405)
• Combined assessment of serum eosinophil-derived neurotoxin and YKL-40 may identify Asthma-COPD overlap. (PMID:32571644)
• Blood eosinophil cationic protein and eosinophil-derived neurotoxin are associated with different asthma expression and evolution in adults. (PMID:34615736)
• RNASE2 Mediates Age-Associated B Cell Expansion Through Monocyte Derived IL-10 in Patients With Systemic Lupus Erythematosus. (PMID:35265065)
• RNase2 is a possible trigger of acute-on-chronic inflammation leading to mRNA vaccine-associated cardiac complication. (PMID:37105176)
• The Role of Eosinophil-Derived Neurotoxin and Vascular Endothelial Growth Factor in the Pathogenesis of Eosinophilic Asthma. (PMID:37174726)
• Eosinophil-derived neurotoxin levels in early childhood and association with preschool asthma - A prospective observational study. (PMID:37795650)
• Addressing diagnostic dilemmas in eosinophilic esophagitis using esophageal epithelial eosinophil-derived neurotoxin. (PMID:38374551)
• The antimicrobial protein, RNase 2 exhibits antiviral against respiratory syncytial virus. (PMID:9826755)

Cross-species orthologs

13 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnase2a	ENSMUSG00000047222
mus_musculus	Ear14	ENSMUSG00000050766
mus_musculus	Rnase2b	ENSMUSG00000059606
mus_musculus	Ear6	ENSMUSG00000062148
mus_musculus	Ear2	ENSMUSG00000072596
mus_musculus	Ear1	ENSMUSG00000072601
mus_musculus	Ear10	ENSMUSG00000090166
rattus_norvegicus	Rnase2	ENSRNOG00000032133
rattus_norvegicus	Ear1	ENSRNOG00000062969
rattus_norvegicus	Rnase3	ENSRNOG00000063957
rattus_norvegicus	Ear1l1	ENSRNOG00000070444
rattus_norvegicus	Rnase17	ENSRNOG00000077288
rattus_norvegicus	LOC100361866	ENSRNOG00000085776

Paralogs (12): RNASE1 (ENSG00000129538), RNASE7 (ENSG00000165799), RNASE3 (ENSG00000169397), RNASE6 (ENSG00000169413), RNASE8 (ENSG00000173431), RNASE11 (ENSG00000173464), RNASE10 (ENSG00000182545), RNASE9 (ENSG00000188655), RNASE13 (ENSG00000206150), ANG (ENSG00000214274), RNASE12 (ENSG00000258436), RNASE4 (ENSG00000258818)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1890463) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 1 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal startle reflex	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Gorilla gorilla gorilla	P47782	99.4%	Diamond
Pan troglodytes	P47785	99.4%	Diamond
Macaca nemestrina	Q8SPY5	99.4%	Diamond
Papio hamadryas	Q8SPY7	99.4%	Diamond
Pongo pygmaeus	O46526	98.7%	Diamond
Macaca mulatta	O46533	98.7%	Diamond
Macaca fascicularis	P47783	98.1%	Diamond
Chlorocebus aethiops	O46534	98.0%	Diamond
Miopithecus talapoin	Q8SPZ7	97.4%	Diamond
Aotus trivirgatus	O46528	96.0%	Diamond
Saguinus oedipus	O46530	96.0%	Diamond
Nomascus leucogenys	Q8SPY8	95.0%	Diamond
Saimiri sciureus	O46529	94.0%	Diamond
Saguinus labiatus	Q8SPY3	91.1%	Diamond
Callithrix jacchus	Q8SPY2	88.6%	Diamond
Sus scrofa	P81649	74.8%	Diamond
Bos taurus	P08904	72.7%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
SLC39A2	protein-coding	29986
METTL17	protein-coding	64745
RNASE1	protein-coding	6035
RNASE3	protein-coding	6037
RNASE6	protein-coding	6039

Protein

Protein identifiers

Non-secretory ribonuclease — P10153 (reviewed: P10153)

Alternative names: Eosinophil-derived neurotoxin, RNase UpI-2, Ribonuclease 2, Ribonuclease US

All UniProt accessions (2): P10153, W0UV60

UniProt curated annotations — full annotation on UniProt →

Function. This is a non-secretory ribonuclease. It is a pyrimidine specific nuclease with a slight preference for U. Cytotoxin and helminthotoxin. Selectively chemotactic for dendritic cells. Possesses a wide variety of biological activities.

Subunit / interactions. Interacts with and forms a tight 1:1 complex with RNH1. Dimerization of two such complexes may occur.

Subcellular location. Lysosome. Cytoplasmic granule.

Tissue specificity. Liver, lung, spleen, leukocytes and body fluids.

Post-translational modifications. A particular signal processing and glycosylation pattern may differentiate the UpI2 RNase, found specifically in pregnant women urine, from other nonsecretory RNases.

Domain organisation. The N-terminal region is necessary for mediating chemotactic activity.

Similarity. Belongs to the pancreatic ribonuclease family.

RefSeq proteins (1): NP_002925* (*=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 (34 total): strand 7, glycosylation site 6, disulfide bond 4, sequence conflict 4, helix 4, sequence variant 2, active site 2, signal peptide 1, chain 1, turn 1, binding site 1, modified residue 1

Structure

Experimental structures (PDB)

27 structures by resolution:

PDB	Title	Method	Resolution (Å)
9R6D	Structural characterization of a trehalose-binding site in human RNase2	X-RAY DIFFRACTION	0.94
1GQV	Atomic Resolution (0.98A) Structure of Eosinophil-Derived Neurotoxin	X-RAY DIFFRACTION	0.98
2BZZ	Crystal Structures of Eosinophil-derived Neurotoxin in Complex with the Inhibitors …	X-RAY DIFFRACTION	0.98
1K2A	Modified Form of Eosinophil-derived Neurotoxin	X-RAY DIFFRACTION	1
9GQM	Structural characterization of glucose- and fucose-binding sites in human RNase2	X-RAY DIFFRACTION	1.01
9GQP	Structural characterization of a N-acetyl-beta-neuraminic acid-binding site in human …	X-RAY DIFFRACTION	1.01
9QR7	Structural characterization of a N-acetylmuramic acid-binding site in human RNase2	X-RAY DIFFRACTION	1.01
9QYO	Structural characterization of a mannose-binding site in human RNase2	X-RAY DIFFRACTION	1.02
9R6E	Structural characterization of a N-Acetyl-D-glucosamine-binding site in human RNase2	X-RAY DIFFRACTION	1.02
9RAN	Structural characterization of a galactose-binding site in human RNase2	X-RAY DIFFRACTION	1.02
9GO7	Structural characterization of sucrose-binding site in human RNase2	X-RAY DIFFRACTION	1.04
9GO8	Structural characterization of malonate-binding site in human RNase2	X-RAY DIFFRACTION	1.04
9GQ0	Structural characterization of fucose-binding site in human RNase2	X-RAY DIFFRACTION	1.04
9GO4	Structural characterization of citrate-binding site in human RNase2	X-RAY DIFFRACTION	1.17
8QEW	Eosinophil Derived Neurotoxin/RNase 2 in complex with Tartrate	X-RAY DIFFRACTION	1.2
6SSO	EDN mutant L45H	X-RAY DIFFRACTION	1.21
2C01	Crystal Structures of Eosinophil-derived Neurotoxin in Complex with the Inhibitors …	X-RAY DIFFRACTION	1.24
9GNT	Structural characterization of a glucose-binding site in human RNase2	X-RAY DIFFRACTION	1.31
5E13	Crystal structure of Eosinophil-derived neurotoxin in complex with the triazole …	X-RAY DIFFRACTION	1.34
1HI2	Eosinophil-derived Neurotoxin (EDN) - Sulphate Complex	X-RAY DIFFRACTION	1.6
8F5X	Crystal structure of human eosinophil-derived neurotoxin (EDN, ribonuclease 2) in complex …	X-RAY DIFFRACTION	1.7
1HI3	Eosinophil-derived Neurotoxin (EDN) - Adenosine 2’-5’-Diphosphate Complex	X-RAY DIFFRACTION	1.8
1HI4	Eosinophil-derived Neurotoxin (EDN) - Adenosien-3’-5’-Diphosphate Complex	X-RAY DIFFRACTION	1.8
1HI5	Eosinophil-derived Neurotoxin (EDN) - Adenosine-5’-Diphosphate Complex	X-RAY DIFFRACTION	1.8
2C05	Crystal Structures of Eosinophil-derived Neurotoxin in Complex with the Inhibitors …	X-RAY DIFFRACTION	1.86
2BEX	Crystal structure of Placental Ribonuclease Inhibitor in complex with Human Eosinophil …	X-RAY DIFFRACTION	1.99
2C02	Crystal Structures of Eosinophil-derived Neurotoxin in Complex with the Inhibitors …	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P10153-F1	91.67	0.84

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Lyases, Predicted secreted proteins, Plasma proteins

Protein evidence: Evidence at protein level

Antibody reliability (HPA): IH enhanced

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)

Position	Role
42	proton acceptor
156	proton donor

Ligand- & substrate-binding residues (1)

Position	Role
65–69	substrate

Post-translational modifications (1)

Type	Positions
3’-nitrotyrosine	60

Disulfide bonds (4)

Type	Positions
Disulfide bond	50–110, 64–123, 82–138, 89–98

Glycosylation sites (6)

Type	Positions
N-linked (glcnac…) asparagine	111, 119, 44, 86, 92
C-linked (man) tryptophan	34

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—

MSigDB gene sets: 190 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOCC_SECRETORY_GRANULE, GOMF_NUCLEASE_ACTIVITY, MODULE_45, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MODULE_511, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, MODULE_16

GO Biological Process (4): innate immune response in mucosa (GO:0002227), RNA catabolic process (GO:0006401), chemotaxis (GO:0006935), defense response to virus (GO:0051607)

GO Molecular Function (8): nucleic acid binding (GO:0003676), ribonuclease A activity (GO:0004522), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (4): extracellular region (GO:0005576), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), lysosome (GO:0005764)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

21 GO namespaces:

Category	Terms
binding	2
nuclease activity	2
catalytic activity	2
mucosal immune response	1
innate immune response	1
RNA metabolic process	1
nucleic acid catabolic process	1
response to chemical	1
taxis	1
defense response	1
response to virus	1
RNA endonuclease activity	1
phosphorus-oxygen lyase activity	1
catalytic activity, acting on RNA	1
catalytic activity, acting on a nucleic acid	1
cellular anatomical structure	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
lytic vacuole	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 17 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
chemotaxis	BP	direct assay
defense response to virus	BP	direct assay
extracellular exosome	CC	high-throughput assay
RNA nuclease activity	MF	direct assay

Protein interactions and networks

STRING

showing 16 of 1,038 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASE2	EPX	P11678	979
RNASE2	PRG2	P13727	939
RNASE2	ANG	P03950	920
RNASE2	RNASET2	O00584	811
RNASE2	RNASEL	Q05823	699
RNASE2	CD300A	Q9UGN4	682
RNASE2	IL5	P05113	675
RNASE2	LILRB3	O75022	638
RNASE2	CLC	Q05315	606
RNASE2	RNASE3	P12724	604
RNASE2	CCL11	P50877	570
RNASE2	IL5RA	Q01344	570
RNASE2	LILRB2	Q8N423	561
RNASE2	CD300C	Q08708	551
RNASE2	IL13	P35225	547
RNASE2	CCL26	Q9Y258	547

IntAct

Human interaction partners of RNASE2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

3 partners by confidence:

Partner	Interaction type	MIscore	Records
DLG2	physical association	0.560	3
RNH1	direct interaction	0.440	1
PCP2	physical association	0.400	1

BioGRID (5 interactions; top human partners by supporting records): DLG2 (Two-hybrid), GEMIN4 (Two-hybrid), PCP2 (Affinity Capture-MS), SPPL3 (Positive Genetic), YWHAQ (Reconstituted Complex)

SIGNOR signaling

1 signaling interactions:

A	Effect	B	Mechanism
EPX	“up-regulates activity”	RNASE2	“post translational modification”

Disease & clinical

Genetic variants

Variant evidence for RNASE2: 20 ClinVar records (0 pathogenic / likely pathogenic); 2 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	1
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 19 predictions of 99):

Position(s)	Effect	Δscore	Sites
14:20955537–20955538	donor_loss	0.9900	5
14:20955765–20955766	acceptor_loss	0.9400	6
14:20955764	acceptor_loss	0.9100
14:20955538	donor_loss	0.8100
14:20955939	donor_gain	0.6900
14:20956183	acceptor_gain	0.6900
14:20955941	donor_gain	0.6800
14:20955818	acceptor_gain	0.6600
14:20955819	acceptor_gain	0.6100
14:20955764	acceptor_loss	0.5400

AlphaMissense

345 missense substitutions predicted likely pathogenic (of 1,069 scored), across 79 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M54	9	0.857	0.967
F38	8	0.938	0.992
F70	8	0.936	0.992
N68	8	0.924	0.968
H42	8	0.896	0.950
D158	8	0.880	0.920
S101	8	0.872	0.977
H99	8	0.859	0.976
D146	8	0.854	0.928
H156	8	0.848	0.937
N97	8	0.837	0.966
C98	7	0.955	0.979
C110	7	0.955	0.984
C123	7	0.954	0.982
C138	7	0.952	0.977
C89	7	0.951	0.975
C82	7	0.949	0.975
C64	7	0.943	0.984
C50	7	0.915	0.968
N58	7	0.910	0.953

HPA cancer prognostics

RNA cancer specificity: Cancer enriched (Glioblastoma Multiforme)

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

2 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	2.1e-06
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	0.000559

Disease associations

OMIM: gene MIM:131410 | disease phenotypes:

GWAS associations

2 associations:

Study	Trait	p-value
GCST006585_1737	Blood protein levels	2e-26
GCST000705_7	Crohn’s disease	6e-8

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5120 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

2 measured of 13 human assays (13 total across all organisms); most potent 2 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
5’-phospho-2’-deoxyuridine 3-pyrophosphate (P’->5’) adenosine 3’-phosphate	KI	360000 nM
CHEMBL401150	KI	360000 nM

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.75	Ki	180	nM	CHEMBL401150
6.75	Ki	180	nM	CHEMBL455775

PubChem BioAssay actives

2 with measured affinity, of 13 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
[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [[(2R,3S,5R)-5-(2,4-dioxopyrimidin-1-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl] hydrogen phosphate	345853: Inhibition of human EDN	ki	0.1800	uM
[[(2R,3S,4R,5R)-5-(6-aminopurin-9-yl)-4-hydroxy-3-phosphonooxyoxolan-2-yl]methoxy-hydroxyphosphoryl] [(2R,3S,5R)-5-(2,4-dioxopyrimidin-1-yl)-2-(phosphonooxymethyl)oxolan-3-yl] hydrogen phosphate	718195: Inhibition of EDN	ki	0.1800	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects expression, increases abundance, increases expression, decreases expression	3
Acetaminophen	decreases expression	2
Ozone	affects expression, increases abundance, increases expression	2
Tretinoin	affects cotreatment, decreases expression, increases expression	2
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
CGP 52608	affects binding, increases reaction	1
Salmeterol Xinafoate	decreases expression	1
Arsenic Trioxide	affects cotreatment, decreases expression	1
Beclomethasone	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Cyclophosphamide	decreases expression	1
Cytarabine	increases expression	1
Fonofos	increases methylation	1
Parathion	increases methylation	1
Urethane	decreases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	increases methylation	1
Aflatoxin B1	increases methylation	1
Asbestos, Serpentine	decreases expression	1
Asbestos, Crocidolite	decreases expression	1
Antirheumatic Agents	decreases expression	1
Lactic Acid	increases expression	1
Particulate Matter	decreases expression, increases abundance	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
CHEMBL2215700	Binding	Inhibition of EDN	Triazole pyrimidine nucleosides as inhibitors of Ribonuclease A. Synthesis, biochemical, and structural evaluation. — *Bioorg Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.