RNASE6

Summary

RNASE6 (ribonuclease A family member 6, HGNC:10048) is a protein-coding gene on chromosome 14q11.2, encoding Ribonuclease K6 (Q93091). Ribonuclease which shows a preference for the pyrimidines uridine and cytosine.

The protein encoded by this gene is a member of the ribonuclease A superfamily and functions in the urinary tract. The protein has broad-spectrum antimicrobial activity against pathogenic bacteria.

Source: NCBI Gene 6039 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_005615

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10048
Approved symbol	RNASE6
Name	ribonuclease A family member 6
Location	14q11.2
Locus type	gene with protein product
Status	Approved
Aliases	RAD1, RNaseK6
Ensembl gene	ENSG00000169413
Ensembl biotype	protein_coding
OMIM	601981
Entrez	6039

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000304677, ENST00000905521, ENST00000916164

RefSeq mRNA: 1 — MANE Select: NM_005615 NM_005615

CCDS: CCDS9558

Canonical transcript exons

ENST00000304677 — 2 exons

Exon	Start	End
ENSE00001124227	20781695	20782467
ENSE00001137183	20781268	20781338

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 98.36.

FANTOM5 (CAGE): breadth broad, TPM avg 19.1079 / max 764.3216, expressed in 496 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
138470	13.5432	476
138472	3.5519	347
138471	0.8692	211
138467	0.4389	149
138473	0.2383	102
138474	0.2006	96
138468	0.1168	75
138469	0.1121	68
138475	0.0368	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.36	gold quality
leukocyte	CL:0000738	98.23	gold quality
mononuclear cell	CL:0000842	98.21	gold quality
granulocyte	CL:0000094	97.82	gold quality
spleen	UBERON:0002106	94.55	gold quality
blood	UBERON:0000178	94.42	gold quality
gall bladder	UBERON:0002110	93.95	gold quality
lymph node	UBERON:0000029	92.91	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.72	gold quality
vermiform appendix	UBERON:0001154	92.38	gold quality
right coronary artery	UBERON:0001625	91.95	gold quality
rectum	UBERON:0001052	91.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.84	gold quality
right lung	UBERON:0002167	89.02	gold quality
descending thoracic aorta	UBERON:0002345	88.84	gold quality
right adrenal gland cortex	UBERON:0035827	87.63	gold quality
bone marrow	UBERON:0002371	86.56	gold quality
left coronary artery	UBERON:0001626	86.49	gold quality
omental fat pad	UBERON:0010414	86.16	gold quality
peritoneum	UBERON:0002358	86.07	gold quality
cauda epididymis	UBERON:0004360	85.85	gold quality
right adrenal gland	UBERON:0001233	85.74	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.70	gold quality
small intestine	UBERON:0002108	85.69	gold quality
corpus epididymis	UBERON:0004359	85.68	gold quality
upper lobe of left lung	UBERON:0008952	85.62	gold quality
adipose tissue of abdominal region	UBERON:0007808	85.37	gold quality
bone marrow cell	CL:0002092	85.29	gold quality
thoracic aorta	UBERON:0001515	85.20	gold quality
upper lobe of lung	UBERON:0008948	85.12	gold quality

Single-cell (SCXA)

Detected in 22 experiment(s), a significant marker in 22.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	357.60
E-HCAD-1	yes	97.85
E-MTAB-6701	yes	75.80
E-HCAD-4	yes	61.51
E-HCAD-10	yes	60.20
E-HCAD-6	yes	56.44
E-MTAB-8410	yes	48.68
E-CURD-46	yes	41.71
E-MTAB-10553	yes	38.71
E-GEOD-134144	yes	32.95
E-MTAB-10287	yes	28.05
E-HCAD-9	yes	26.41
E-CURD-112	yes	25.96
E-ANND-3	yes	23.07
E-MTAB-9067	yes	17.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

13 targeting RNASE6, 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-3065-5P	99.97	71.56	3281
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-5088-3P	98.29	66.63	1310
HSA-MIR-495-5P	97.62	68.28	682
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-4453	95.61	65.84	436
HSA-MIR-4538	95.61	65.34	449
HSA-MIR-4681	89.50	61.59	122

Literature-anchored findings (GeneRIF, showing 5)

• Ribonucleases 6 is an antimicrobial peptide with activity against uropathogens and participates in the maintenance of urinary tract sterility. (PMID:25075772)
• These results indicate that RNase6, as previously reported for RNase3, is able to specifically agglutinate Gram-negative bacteria as a main trait of its antimicrobial activity. (PMID:27089320)
• An RNase6 dual catalytic and extended binding site arrangement facilitates the cleavage of polymeric substrates (PMID:30287244)
• RNASE6 is a novel modifier of APOE-epsilon4 effects on cognition. (PMID:35896049)
• Human Ribonuclease 6 Has a Protective Role during Experimental Urinary Tract Infection. (PMID:37980892)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rnase6	ENSMUSG00000021880
rattus_norvegicus	Rnase6	ENSRNOG00000025597

Paralogs (12): RNASE1 (ENSG00000129538), RNASE7 (ENSG00000165799), RNASE2 (ENSG00000169385), RNASE3 (ENSG00000169397), RNASE8 (ENSG00000173431), RNASE11 (ENSG00000173464), RNASE10 (ENSG00000182545), RNASE9 (ENSG00000188655), RNASE13 (ENSG00000206150), ANG (ENSG00000214274), RNASE12 (ENSG00000258436), RNASE4 (ENSG00000258818)

Protein

Protein identifiers

Ribonuclease K6 — Q93091 (reviewed: Q93091)

All UniProt accessions (2): Q93091, Q6IB39

UniProt curated annotations — full annotation on UniProt →

Function. Ribonuclease which shows a preference for the pyrimidines uridine and cytosine. Has potent antibacterial activity against a range of Gram-positive and Gram-negative bacteria, including P.aeruginosa, A.baumanii, M.luteus, S.aureus, E.faecalis, E.faecium, S.saprophyticus and E.coli. Causes loss of bacterial membrane integrity, and also promotes agglutination of Gram-negative bacteria. Probably contributes to urinary tract sterility. Bactericidal activity is independent of RNase activity.

Subunit / interactions. Interacts (via N-terminus) with bacterial lipopolysaccharide (LPS).

Subcellular location. Secreted. Lysosome. Cytoplasmic granule.

Tissue specificity. Highly expressed in spleen (at protein level). Has little or no expression in healthy kidneys (at protein level). Detected in interstitial leukocytes in infected kidneys (at protein level). Expressed in ureter where it localizes to urothelial and submucosal leukocytes (at protein level). Strong expression in lung and thymus, and lower expression in heart, placenta, pancreas, liver, brain and skeletal muscle. Also expressed in monocytes and neutrophils.

Induction. Up-regulated in CD14+ monocytes in response to the uropathogenic E.coli strain CFT073.

Similarity. Belongs to the pancreatic ribonuclease family.

RefSeq proteins (1): NP_005606* (*=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 (30 total): strand 5, site 4, disulfide bond 4, mutagenesis site 4, helix 3, binding site 3, glycosylation site 2, active site 2, signal peptide 1, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
6ENP	X-RAY DIFFRACTION	1.04
5OAB	X-RAY DIFFRACTION	1.11
6MV6	X-RAY DIFFRACTION	1.5
4X09	X-RAY DIFFRACTION	1.72
6MV7	X-RAY DIFFRACTION	2.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q93091-F1	90.61	0.82

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 (6): 61 (critical for catalytic activity); 38 (proton acceptor); 145 (proton donor); 24 (important for bactericidal activity, bacterial agglutination activity and binding to bacterial lipopolysaccharide (lps)); 36 (important for bactericidal activity, bacterial agglutination activity and binding to bacterial lipopolysaccharide (lps)); 59 (facilitates cleavage of polynucleotide substrates)

Ligand- & substrate-binding residues (3): 61–65; 86; 105

Disulfide bonds (4): 46–104, 60–114, 78–129, 85–92

Glycosylation sites (2): 55, 100

Mutagenesis-validated functional residues (4):

Position	Phenotype
24	moderately impairs bactericidal activity, bacterial agglutination activity and binding to bacterial lipopolysaccharide (
36	strongly impairs bactericidal activity, bacterial agglutination activity and binding to bacterial lipopolysaccharide (lp
38	significantly reduced activity towards dinucleotides upa and cpa. slightly reduced activity towards polymeric substrates
59	no significant effect on activity towards dinucleotides upa and cpa. reduced activity towards polymeric substrates poly(

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6803157	Antimicrobial peptides
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 487 (showing top): PID_FANCONI_PATHWAY, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, DAVIES_MULTIPLE_MYELOMA_VS_MGUS_DN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, WALLACE_PROSTATE_CANCER_RACE_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, MCLACHLAN_DENTAL_CARIES_UP, PID_TELOMERASE_PATHWAY, GOBP_REGULATION_OF_NUCLEAR_DIVISION

GO Biological Process (9): RNA catabolic process (GO:0006401), defense response (GO:0006952), antibacterial humoral response (GO:0019731), innate immune response (GO:0045087), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), defense response to virus (GO:0051607), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), defense response to bacterium (GO:0042742)

GO Molecular Function (5): nucleic acid binding (GO:0003676), endonuclease activity (GO:0004519), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), nuclease activity (GO:0004518)

GO Cellular Component (4): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), lysosome (GO:0005764), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Innate Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
defense response to bacterium	3
antimicrobial humoral response	2
defense response	2
nuclease activity	2
RNA metabolic process	1
nucleic acid catabolic process	1
response to stress	1
immune response	1
defense response to symbiont	1
response to virus	1
response to bacterium	1
binding	1
catalytic activity, acting on RNA	1
catalytic activity	1
catalytic activity, acting on a nucleic acid	1
cellular anatomical structure	1
lytic vacuole	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

814 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASE6	RNASET2	O00584	871
RNASE6	RNASEL	Q05823	580
RNASE6	RNASE11	Q8TAA1	507
RNASE6	ANG	P03950	476
RNASE6	EPX	P11678	445
RNASE6	FCER1G	P30273	398
RNASE6	CTSK	P43235	382
RNASE6	RNASE12	Q5GAN4	370
RNASE6	IL9	P15248	353
RNASE6	MS4A2	Q01362	353
RNASE6	FCER1A	P12319	353
RNASE6	IL4R	P24394	353
RNASE6	IL3	P08700	300
RNASE6	MPO	P05164	286
RNASE6	CCDC169	A6NNP5	284

IntAct

2 interactions, top by confidence:

A	B	Type	Score
ARR3	RNASE6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (1): RNASE6 (Two-hybrid)

ESM2 similar proteins: A1YLB9, O46525, O46526, O46527, O46528, O46529, O46530, O46531, O46532, O46533, O46534, P00683, P00684, P08904, P39873, P61823, P81649, Q8SPN3, Q8SPN4, Q8SPZ4, Q8SPZ5, Q8SPZ6, Q8SPZ7, Q8SPZ8, Q8SQ04, Q8SQ05, Q8SQ06, Q8SQ08, Q8SQ11, Q8SQ12, Q8TDE3, Q8VD84, Q8VD87, Q8VD89, Q8VD93, Q93091, Q9D244, Q9H1E1, Q9QYX2, Q9QYX3

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

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	20
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1554 predictions. Top by Δscore:

Variant	Effect	Δscore
5:34908763:A:AC	donor_gain	1.0000
5:34908764:C:CC	donor_gain	1.0000
5:34908766:CAAG:C	donor_gain	1.0000
5:34908767:A:AC	donor_gain	1.0000
5:34908767:AAGA:A	donor_gain	1.0000
5:34911552:ACCT:A	donor_loss	1.0000
5:34911553:CCT:C	donor_loss	1.0000
5:34911703:AGGTT:A	donor_gain	1.0000
5:34914736:CTG:C	donor_gain	1.0000
5:34914737:TGT:T	donor_gain	1.0000
5:34914822:A:C	donor_gain	1.0000
5:34915898:GTAG:G	donor_loss	1.0000
5:34918442:GACT:G	donor_gain	1.0000
14:20781692:C:G	acceptor_gain	0.9900
14:20781693:A:AG	acceptor_gain	0.9900
14:20781694:G:GG	acceptor_gain	0.9900
14:20781694:GAAAA:G	acceptor_gain	0.9900
5:34908768:A:C	donor_gain	0.9900
5:34908775:G:C	donor_gain	0.9900
5:34908949:C:CC	acceptor_gain	0.9900
5:34911596:T:TA	donor_gain	0.9900
5:34911596:TC:T	donor_gain	0.9900
5:34912300:T:C	acceptor_gain	0.9900
5:34912300:T:TC	acceptor_gain	0.9900
5:34912308:C:CT	acceptor_gain	0.9900
5:34914689:CCATA:C	donor_loss	0.9900
5:34914691:ATAC:A	donor_loss	0.9900
5:34914692:TAC:T	donor_loss	0.9900
5:34914693:ACCTG:A	donor_loss	0.9900
5:34914694:C:G	donor_loss	0.9900

AlphaMissense

997 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:20781895:T:C	F66L	0.967
14:20781897:T:A	F66L	0.967
14:20781897:T:G	F66L	0.967
14:20781799:T:C	F34L	0.959
14:20781801:T:A	F34L	0.959
14:20781801:T:G	F34L	0.959
14:20781982:A:C	S95R	0.942
14:20781984:C:A	S95R	0.942
14:20781984:C:G	S95R	0.942
14:20781896:T:G	F66C	0.936
14:20782072:T:C	F125L	0.933
14:20782074:C:A	F125L	0.933
14:20782074:C:G	F125L	0.933
14:20781800:T:G	F34C	0.917
14:20781882:G:C	K61N	0.909
14:20781882:G:T	K61N	0.909
14:20782039:T:A	C114S	0.886
14:20782040:G:C	C114S	0.886
14:20781877:T:A	C60S	0.880
14:20781878:G:C	C60S	0.880
14:20781896:T:C	F66S	0.880
14:20781931:T:A	C78S	0.872
14:20781932:G:C	C78S	0.872
14:20781910:T:C	F71L	0.858
14:20781912:C:A	F71L	0.858
14:20781912:C:G	F71L	0.858
14:20782079:T:A	V127D	0.857
14:20782009:T:A	C104S	0.854
14:20782010:G:C	C104S	0.854
14:20781976:C:G	H93D	0.853

dbSNP variants (sampled 300 via entrez): RS1000970376 (14:20780067 A>G), RS1001974069 (14:20781581 T>G), RS1002404188 (14:20781227 T>C), RS1002960717 (14:20782780 C>A,T), RS1003287689 (14:20780396 G>A), RS1004589072 (14:20782453 C>A,T), RS1004914525 (14:20779280 T>C), RS1005621933 (14:20781443 C>A,T), RS1005872500 (14:20780764 A>G), RS1005924755 (14:20780424 T>C), RS1006872845 (14:20782238 C>A,G,T), RS1008171674 (14:20779658 T>C), RS1008556718 (14:20779495 G>A), RS1009546948 (14:20782090 C>A,T), RS1010143794 (14:20780103 A>G)

Disease associations

OMIM: gene MIM:601981 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006585_1102	Blood protein levels	4.000000e-164

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Cadmium	increases expression, decreases expression, increases abundance	2
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
arsenite	affects expression	1
sodium bichromate	decreases expression	1
nickel sulfate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Aspirin	increases expression	1
Cisplatin	increases expression	1
Diuron	decreases expression	1
Dust	decreases expression	1
Nickel	increases expression	1
Perfume	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Vincristine	decreases expression	1
Cyclosporine	decreases expression	1
Aflatoxin B1	increases methylation	1
Sodium Selenite	increases expression	1
Antirheumatic Agents	decreases expression	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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