RNASET2

Summary

RNASET2 (ribonuclease T2, HGNC:21686) is a protein-coding gene on chromosome 6q27, encoding Ribonuclease T2 (O00584). Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8.

This ribonuclease gene is a novel member of the Rh/T2/S-glycoprotein class of extracellular ribonucleases. It is a single copy gene that maps to 6q27, a region associated with human malignancies and chromosomal rearrangement.

Source: NCBI Gene 8635 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cystic leukoencephalopathy without megalencephaly (Definitive, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 193 total — 9 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 21
• MANE Select transcript: NM_003730

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21686
Approved symbol	RNASET2
Name	ribonuclease T2
Location	6q27
Locus type	gene with protein product
Status	Approved
Aliases	RNASE6PL, FLJ10907, bA514O12.3
Ensembl gene	ENSG00000026297
Ensembl biotype	protein_coding
OMIM	612944
Entrez	8635

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 17 protein_coding, 8 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000028008, ENST00000358165, ENST00000366855, ENST00000421787, ENST00000467705, ENST00000476238, ENST00000478180, ENST00000496851, ENST00000499370, ENST00000508775, ENST00000509073, ENST00000510083, ENST00000611959, ENST00000620173, ENST00000682498, ENST00000682774, ENST00000683158, ENST00000683333, ENST00000683770, ENST00000683968, ENST00000684086, ENST00000684236, ENST00000870279, ENST00000870280, ENST00000870281, ENST00000870282, ENST00000870283, ENST00000870284, ENST00000870285, ENST00000926043, ENST00000951734, ENST00000951735

RefSeq mRNA: 1 — MANE Select: NM_003730 NM_003730

CCDS: CCDS5295

Canonical transcript exons

ENST00000508775 — 9 exons

Exon	Start	End
ENSE00000000172	166922113	166929791
ENSE00002073023	166956097	166956550
ENSE00003486328	166948570	166948625
ENSE00003526295	166934091	166934136
ENSE00003532324	166931044	166931118
ENSE00003588757	166946682	166946739
ENSE00003615824	166943019	166943089
ENSE00003666098	166952488	166952548
ENSE00003674256	166938895	166939008

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 47.7564 / max 1338.7329, expressed in 1805 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
76694	34.7602	1688
76695	12.2156	1765
76693	0.7805	309

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right uterine tube	UBERON:0001302	99.29	gold quality
granulocyte	CL:0000094	99.27	gold quality
blood	UBERON:0000178	99.23	gold quality
monocyte	CL:0000576	99.16	gold quality
leukocyte	CL:0000738	99.16	gold quality
mononuclear cell	CL:0000842	99.16	gold quality
spleen	UBERON:0002106	99.16	gold quality
parotid gland	UBERON:0001831	99.08	gold quality
seminal vesicle	UBERON:0000998	98.81	gold quality
olfactory bulb	UBERON:0002264	98.45	gold quality
lymph node	UBERON:0000029	98.06	gold quality
inferior vagus X ganglion	UBERON:0005363	97.96	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.89	gold quality
cauda epididymis	UBERON:0004360	97.74	gold quality
periodontal ligament	UBERON:0008266	97.74	gold quality
colonic mucosa	UBERON:0000317	97.60	gold quality
endometrium	UBERON:0001295	97.59	gold quality
caput epididymis	UBERON:0004358	97.59	gold quality
rectum	UBERON:0001052	97.55	gold quality
gall bladder	UBERON:0002110	97.49	gold quality
corpus epididymis	UBERON:0004359	97.37	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.34	gold quality
bone marrow	UBERON:0002371	97.22	gold quality
bone marrow cell	CL:0002092	97.21	gold quality
cardia of stomach	UBERON:0001162	97.20	gold quality
spinal cord	UBERON:0002240	97.18	gold quality
vermiform appendix	UBERON:0001154	97.14	gold quality
caecum	UBERON:0001153	97.07	gold quality
bone element	UBERON:0001474	97.05	gold quality
fallopian tube	UBERON:0003889	97.00	gold quality

Single-cell (SCXA)

Detected in 33 experiment(s), a significant marker in 31.

Experiment	Marker?	Max mean expression
E-MTAB-9435	yes	2751.03
E-MTAB-8495	yes	1730.31
E-MTAB-6701	yes	73.39
E-HCAD-4	yes	66.83
E-HCAD-10	yes	54.77
E-MTAB-10287	yes	53.06
E-HCAD-1	yes	50.74
E-GEOD-84465	yes	47.93
E-GEOD-135922	yes	43.19
E-MTAB-10553	yes	39.70
E-MTAB-8142	yes	36.75
E-CURD-122	yes	34.01
E-CURD-46	yes	32.54
E-HCAD-35	yes	30.62
E-GEOD-134144	yes	26.85

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 40)

• RNASET2 found to significantly decrease the metastatic potential of ovarian cancer cell line in vivo; tumor suppression by RNASET2 is suggested to not be mediated by its ribonuclease activity (PMID:15809705)
• The results presented herein represent a further advancement toward the molecular understanding of the tumour suppressive properties of the human RNASET2 protein. (PMID:16620762)
• Loss of RNASET2 is associated with melanoma (PMID:18543608)
• RNaseT2 is a cell growth regulator and it does not induce senescence in SV40 immortalized cell lines. (PMID:19382914)
• Study shows that loss-of-function mutations in the gene encoding the RNASET2 glycoprotein lead to cystic leukoencephalopathy, an autosomal recessive disorder with an indistinguishable clinical and neuroradiological phenotype. (PMID:19525954)
• Familial cystic leukoencephalopathy arising in RNASET2-deficient humans is a manifestation of an lysosomal storage disorders in which rRNA is the best candidate for the noxious storage material. (PMID:21199949)
• The expression of the human tumor suppressor protein RNASET2 was studied in baculovirus-insect cell and Pichia pastoris heterologous systems. (PMID:21446958)
• Molecular signature induced by RNASET2, a tumor antagonizing gene, in ovarian cancer cells. (PMID:21646684)
• Tax represses expression of RNase T2. (PMID:21994792)
• a possible involvement of RNASET2 in P-body formation in mammalian cells. (PMID:22188480)
• RNASET2–an autoantigen in anaplastic large cell lymphoma identified by protein array analysis. (PMID:22732457)
• The catalytic features of RNase T2 in presence of bivalent cations were analyzed and the structural consequences of known clinical mutations were investigated. (PMID:22735700)
• Higher expression of RNASET2 in the semen of asthenozoospermia individuals may contribute to sperm motility impairment. (PMID:23258633)
• Ribonuclease T2, an ancient and phylogenetically conserved RNase, has a role in development of ovarian neoplasms (PMID:23630276)
• Genotypes of single nucleotide polymorphisms (SNPs) in RNASET2 gene were determined. (PMID:24327149)
• RNASET2 contributes to vitiligo pathogenesis by inhibiting TRAF2 expression. (PMID:24457966)
• Results show that downregulation of RNASET2 and GGNBP2 in drug-resistant ovarian cancer tissues/cells contributes to the regulation of drug resistance in ovarian cancer. (PMID:24842157)
• RNASET2 has antitumorigenic and antiangiogenic activities; a truncated version of human RNASET2, starting at E50 (trT2-50) and devoid of ribonuclease activity, has actin binding and anticancer-related biological activities (PMID:25426551)
• describe a multi-step strategy that allows production of highly pure, catalytically competent recombinant RNASET2 in both wild-type and mutant forms (PMID:25663099)
• Biological features allow to put forward the hypothesis that the RNASET2 protein can act as a molecular barrier for limiting the damages and tissue remodeling events occurring during the earlier step of cell transformation. (PMID:25797262)
• RNASET2 tag SNP but not CCR6 polymorphisms is associated with autoimmune thyroid diseases in the Chinese Han population (PMID:25928629)
• RNASET2 may contribute to the development of vitiligo by inhibiting TNF Receptor-Associated Factor 2 expression and lead directly to apoptosis of melanocytes (PMID:26067323)
• inhibits melanocyte outgrowth through interacting with shootin1; this effect may be associated with vitiligo pathogenesis (PMID:26293343)
• RNASET2, an IBD susceptibility gene, is a component of TL1A-mediated pathways regulating cytokine production. (PMID:28400196)
• Studied association of and RNASET2, GPR174, and PTPN22 gene polymorphisms and liver damage(LD) due to Graves’ disease (GD) hyperthyroidism. Found GPR174 rs3827440, PTPN22 rs3789604, and RNASET2 rs9355610 were significantly associated with altered GD-derived LD risk. (PMID:28568286)
• RNASET2 is the enzyme that degrades the RNAs (PMID:28730546)
• High RNASET2 expression is associated with reduced sperm motility. (PMID:29581387)
• In poorly differentiated lung neuroendocrine carcinomas, RNASET2 expression may be upregulated as a consequence of the activation of the hypoxia-induced HIF-1alpha pathway, thus behaving as an alarmin-like molecule. (PMID:29763721)
• The human RNASET2 protein affects the polarization pattern of human macrophages in vitro. (PMID:30218741)
• Regulation of mitochondrion-associated cytosolic ribosomes by mammalian mitochondrial ribonuclease T2 (PMID:30385512)
• the lysosomal endoribonuclease RNase T2 is a non-redundant upstream component of TLR8-dependent RNA recognition. (PMID:31778653)
• Immune Sensing of Synthetic, Bacterial, and Protozoan RNA by Toll-like Receptor 8 Requires Coordinated Processing by RNase T2 and RNase 2. (PMID:32294405)
• Zebrafish disease model of human RNASET2-deficient cystic leukoencephalopathy displays abnormalities in early microglia. (PMID:32295832)
• FBXO6-mediated RNASET2 ubiquitination and degradation governs the development of ovarian cancer. (PMID:33767133)
• Hypoxia Enhances the Expression of RNASET2 in Human Monocyte-Derived Dendritic Cells: Role of PI3K/AKT Pathway. (PMID:34299186)
• Human RNASET2: A Highly Pleiotropic and Evolutionary Conserved Tumor Suppressor Gene Involved in the Control of Ovarian Cancer Pathogenesis. (PMID:36012339)
• Myelin oligodendrocyte glycoprotein-associated disease is associated with BANK1, RNASET2 and TNIP1 polymorphisms. (PMID:36054934)
• A potential role of human RNASET2 overexpression in the pathogenesis of Graves’ disease. (PMID:36180758)
• Diagnostic and therapeutic potential of RNASET2 in Crohn’s disease: Disease-risk polymorphism modulates allelic-imbalance in expression and circulating protein levels and recombinant-RNASET2 attenuates pro-inflammatory cytokine secretion. (PMID:36466822)
• HIF2alpha-induced upregulation of RNASET2 promotes triglyceride synthesis and enhances cell migration in clear cell renal cell carcinoma. (PMID:36728187)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rnaset2	ENSDARG00000036282
mus_musculus	Rnaset2b	ENSMUSG00000094724
mus_musculus	Rnaset2a	ENSMUSG00000095687
rattus_norvegicus	Rnaset2	ENSRNOG00000013190
drosophila_melanogaster	RNaseX25	FBGN0010406
caenorhabditis_elegans		WBGENE00019624

Protein

Protein identifiers

Ribonuclease T2 — O00584 (reviewed: O00584)

Alternative names: Ribonuclease 6

All UniProt accessions (9): A0A087WWI1, A0A087WZM2, A0A804HJ89, A0A804HJZ7, A0A804HKZ2, D6REQ6, D6RHI9, O00584, J3QQ64

UniProt curated annotations — full annotation on UniProt →

Function. Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8. Cleaves preferentially single-stranded RNA molecules between purine and uridine residues, which critically contributes to the supply of catabolic uridine and the generation of purine-2’,3’-cyclophosphate-terminated oligoribonucleotides. In turn, RNase T2 degradation products promote the RNA-dependent activation of TLR8. In plasmacytoid dendritic cells, it cooperates with PLD3 or PLD4 5’->3’ exonucleases to process RNA fragments and release 2’,3’-cyclic guanosine monophosphate (2’,3’-cGMP), a potent stimulatory ligand for TLR7. Also plays a key role in degradation of mitochondrial RNA and processing of non-coding RNA imported from the cytosol into mitochondria. Participates as well in degradation of mitochondrion-associated cytosolic rRNAs.

Subcellular location. Secreted. Lysosome lumen. Endoplasmic reticulum lumen. Mitochondrion intermembrane space.

Tissue specificity. Ubiquitous. Higher expression levels observed in the temporal lobe and fetal brain.

Disease relevance. Leukoencephalopathy, cystic, without megalencephaly (LCWM) [MIM:612951] An infantile-onset syndrome of cerebral leukoencephalopathy. Affected newborns develop microcephaly and neurologic abnormalities including psychomotor impairment, seizures and sensorineural hearing impairment. The brain shows multifocal white matter lesions, anterior temporal lobe subcortical cysts, pericystic abnormal myelination, ventriculomegaly and intracranial calcifications. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by Zn(2+) and Cu(2+).

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the RNase T2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O00584-1	1	yes
O00584-2	2

RefSeq proteins (1): NP_003721* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001568	RNase_T2-like	Family
IPR018188	RNase_T2_His_AS_1	Active_site
IPR033130	RNase_T2_His_AS_2	Active_site
IPR033697	Ribonuclease_T2_eukaryotic	Family
IPR036430	RNase_T2-like_sf	Homologous_superfamily

Pfam: PF00445

Enzyme classification (BRENDA):

• EC 4.6.1.19 — ribonuclease T2 (BRENDA: 54 organisms, 147 substrates, 64 inhibitors, 73 Km, 16 kcat entries)

Substrate kinetics (BRENDA)

30 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CPU	0.076–20	11
APG	0.003–1.14	4
APA	0.005–0.065	3
APC	0.025–0.13	3
APU	0.03–0.078	3
CPG	0.11–2.15	3
GPA	0.02–0.072	3
GPC	0.107–0.11	3
GPG	0.044–0.71	3
GPU	0.075–0.12	3
UPA	0.05–0.144	3
UPG	0.06–0.69	3
UPU	0.113–0.22	3
2’,3’-CCMP	0.16–0.4	2
2’,3’-CUMP	0.43–6.1	2

Catalyzed reactions (Rhea), 3 shown:

• a ribonucleotidyl-ribonucleotide-RNA + H2O = a 3’-end 3’-phospho-ribonucleotide-RNA + a 5’-end dephospho-ribonucleoside-RNA + H(+) (RHEA:68052)
• a guanylyl-uridine-RNA = a 3’-end 2’,3’-cyclophospho-GMP-RNA + a 5’-end dephospho-uridine-RNA (RHEA:81323)
• an adenylyl-uridine-RNA = a 3’-end 2’,3’-cyclophospho-AMP-RNA + a 5’-end dephospho-uridine-RNA (RHEA:81383)

UniProt features (35 total): helix 10, strand 6, disulfide bond 4, active site 3, glycosylation site 3, splice variant 2, sequence variant 2, mutagenesis site 2, signal peptide 1, chain 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3T0O	X-RAY DIFFRACTION	1.59

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00584-F1	87.25	0.71

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 (3): 65; 114; 118

Disulfide bonds (4): 184–241, 202–213, 48–55, 75–121

Glycosylation sites (3): 76, 106, 212

Mutagenesis-validated functional residues (2):

Position	Phenotype
65	abolishes the effect on degradation of mitochondrion-associated cytosolic rrnas.
118	abolishes the effect on degradation of mitochondrion-associated cytosolic rrnas.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

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

MSigDB gene sets: 248 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, GOMF_NUCLEASE_ACTIVITY, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, SCIBETTA_KDM5B_TARGETS_UP, GNF2_LYN, WIELAND_UP_BY_HBV_INFECTION, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, FOSTER_TOLERANT_MACROPHAGE_DN, KIM_RESPONSE_TO_TSA_AND_DECITABINE_UP, GOMF_RNA_ENDONUCLEASE_ACTIVITY

GO Biological Process (3): RNA catabolic process (GO:0006401), innate immune response (GO:0045087), immune system process (GO:0002376)

GO Molecular Function (8): RNA binding (GO:0003723), RNA endonuclease activity (GO:0004521), RNA nuclease activity (GO:0004540), hydrolase activity (GO:0016787), ribonuclease T2 activity (GO:0033897), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), lyase activity (GO:0016829)

GO Cellular Component (10): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), mitochondrial intermembrane space (GO:0005758), lysosome (GO:0005764), endoplasmic reticulum lumen (GO:0005788), azurophil granule lumen (GO:0035578), lysosomal lumen (GO:0043202), extracellular exosome (GO:0070062), mitochondrion (GO:0005739), endoplasmic reticulum (GO:0005783)

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
nuclease activity	2
catalytic activity	2
vacuolar lumen	2
cytoplasm	2
intracellular membrane-bounded organelle	2
RNA metabolic process	1
nucleic acid catabolic process	1
immune response	1
defense response to symbiont	1
biological_process	1
nucleic acid binding	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity, acting on RNA	1
RNA endonuclease activity	1
phosphorus-oxygen lyase activity	1
catalytic activity, acting on a nucleic acid	1
cellular anatomical structure	1
mitochondrial envelope	1
organelle envelope lumen	1
lytic vacuole	1
endoplasmic reticulum	1
intracellular organelle lumen	1
secretory granule lumen	1
azurophil granule	1
lysosome	1
extracellular vesicle	1
endomembrane system	1

Protein interactions and networks

STRING

1024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RNASET2	CEP43	O95684	886
RNASET2	RNASE6	Q93091	871
RNASET2	ANG	P03950	828
RNASET2	RNASE2	P10153	815
RNASET2	RNASE1	P07998	773
RNASET2	RNASEL	Q05823	669
RNASET2	RNASE3	P12724	654
RNASET2	CCR6	P51684	614
RNASET2	CCRL2	O00421	608
RNASET2	FOXP1	Q9H334	566
RNASET2	A0A3B3IT14	A0A3B3IT14	515
RNASET2	LMOD1	P29536	498
RNASET2	HLA-DQA2	P01906	494
RNASET2	TLR8	Q9NR97	478
RNASET2	GYG1	P46976	473

IntAct

13 interactions, top by confidence:

A	B	Type	Score
RNASET2	PDIA5	psi-mi:“MI:0914”(association)	0.530
	RNASET2	psi-mi:“MI:0915”(physical association)	0.370
DYRK1A	TEX13D	psi-mi:“MI:0914”(association)	0.350
IGF2R	MANBA	psi-mi:“MI:0914”(association)	0.350
SKP1	RNASET2	psi-mi:“MI:0914”(association)	0.350
RNASET2		psi-mi:“MI:0915”(physical association)	0.000
	RNASET2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (24): TRAF2 (Affinity Capture-Western), PDIA5 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), RNASET2 (Co-fractionation), PDIA5 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), RNASET2 (Affinity Capture-RNA), RNASET2 (Affinity Capture-MS), RNASET2 (Affinity Capture-MS), RNASET2 (Affinity Capture-MS), PDIA5 (Affinity Capture-MS), FBXO2 (Affinity Capture-MS), RNASET2 (Affinity Capture-MS), FBXO6 (Affinity Capture-Western), RNASET2 (Affinity Capture-Western)

ESM2 similar proteins: A0S864, A2VDN0, A6QLI0, C0HKG5, C0HKG6, O00584, O09051, O43278, O95897, P08571, P12958, P13506, P15262, P17561, P28770, P28771, P28772, P32187, P32188, P38528, P86729, P86734, Q06AV4, Q16661, Q4R540, Q568Y7, Q5F259, Q5NVC3, Q5PQL7, Q5SC59, Q5SC60, Q5XII0, Q62190, Q6AYE5, Q6GPK2, Q6PVW7, Q71SY6, Q86UD1, Q8IUK5, Q8QZR4

Diamond homologs: B8XY56, C0HKG5, C0HKG6, O00584, P04007, P10281, P42813, P42815, P80022, P80196, Q40379, Q5B3K6, Q7M329, Q7M438, Q7M456, O61887, P19791, P23540, P24657, P81477, Q02933, Q7SID5, P81296, P08056, Q4WXZ5, Q5AK94, Q5AKB1, Q6BHB1, Q6CAV7, Q6FP42, Q75BW5, P42814, Q6CRT6, O80324, P83618, O80322, O80325, P93460, Q01796, Q38716

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	3
Uncertain significance	72
Likely benign	55
Benign	16

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1071170	NC_000006.11:g.(?167356507)(167369670_?)del	Pathogenic
2148852	NM_003730.6(RNASET2):c.291G>A (p.Trp97Ter)	Pathogenic
2576615	NM_003730.6(RNASET2):c.332+1G>T	Pathogenic
412	NM_003730.6(RNASET2):c.550T>C (p.Cys184Arg)	Pathogenic
413	NM_003730.6(RNASET2):c.87-1341_147+1181del	Pathogenic
414	NM_003730.6(RNASET2):c.262-2A>G	Pathogenic
415	NM_003730.6(RNASET2):c.332+1del	Pathogenic
416	NM_003730.6(RNASET2):c.50_64del (p.Ala17_Leu21del)	Pathogenic
872952	NM_003730.6(RNASET2):c.233C>A (p.Ser78Ter)	Pathogenic
1098640	NM_003730.6(RNASET2):c.148-1G>T	Likely pathogenic
3391303	NM_003730.6(RNASET2):c.195_198del (p.Gly66fs)	Likely pathogenic
547106	GRCh37/hg19 6q27(chr6:167360170-167362113)x0	Likely pathogenic

SpliceAI

1944 predictions. Top by Δscore:

Variant	Effect	Δscore
6:166929685:T:TA	donor_gain	1.0000
6:166940029:AGAG:A	donor_gain	1.0000
6:166929643:CTCAG:C	donor_gain	0.9900
6:166929788:CATC:C	acceptor_gain	0.9900
6:166929790:TC:T	acceptor_gain	0.9900
6:166929791:CC:C	acceptor_gain	0.9900
6:166931034:A:C	donor_gain	0.9900
6:166934135:CA:C	acceptor_gain	0.9900
6:166938891:CCAC:C	donor_loss	0.9900
6:166938892:CA:C	donor_loss	0.9900
6:166938892:CACCT:C	donor_loss	0.9900
6:166938893:A:T	donor_loss	0.9900
6:166938893:ACC:A	donor_loss	0.9900
6:166938894:C:A	donor_loss	0.9900
6:166939005:CTTC:C	acceptor_gain	0.9900
6:166939008:CCTG:C	acceptor_loss	0.9900
6:166939008:CCTGT:C	acceptor_loss	0.9900
6:166939009:C:CA	acceptor_loss	0.9900
6:166939010:T:A	acceptor_loss	0.9900
6:166939010:T:C	acceptor_loss	0.9900
6:166946754:T:C	acceptor_gain	0.9900
6:166948500:C:CT	donor_gain	0.9900
6:166952547:CA:C	acceptor_gain	0.9900
6:166952549:C:CC	acceptor_gain	0.9900
6:166956091:ACT:A	donor_loss	0.9900
6:166956095:A:AC	donor_gain	0.9900
6:166956096:C:CC	donor_gain	0.9900
6:166956096:CCG:C	donor_gain	0.9900
6:166929686:C:A	donor_gain	0.9800
6:166929790:TCCTA:T	acceptor_loss	0.9800

AlphaMissense

1688 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:166938996:C:A	W115C	0.999
6:166938996:C:G	W115C	0.999
6:166948587:C:A	W62C	0.998
6:166948587:C:G	W62C	0.998
6:166938999:C:A	E114D	0.997
6:166938999:C:G	E114D	0.997
6:166938998:A:G	W115R	0.996
6:166938998:A:T	W115R	0.996
6:166939008:C:A	W111C	0.996
6:166939008:C:G	W111C	0.996
6:166952533:C:A	W34C	0.996
6:166952533:C:G	W34C	0.996
6:166948589:A:G	W62R	0.995
6:166948589:A:T	W62R	0.995
6:166952506:C:A	W43C	0.995
6:166952506:C:G	W43C	0.995
6:166938936:A:C	F135L	0.994
6:166938936:A:T	F135L	0.994
6:166938937:A:C	F135C	0.994
6:166938938:A:G	F135L	0.994
6:166931060:C:G	C184S	0.993
6:166931061:A:T	C184S	0.993
6:166938940:T:C	Y134C	0.993
6:166938986:C:A	G119W	0.993
6:166938997:C:G	W115S	0.993
6:166946739:C:A	W68C	0.993
6:166946739:C:G	W68C	0.993
6:166938937:A:G	F135S	0.992
6:166943060:C:A	W97C	0.992
6:166943060:C:G	W97C	0.992

dbSNP variants (sampled 300 via entrez): RS1000087986 (6:166945146 C>G,T), RS1000092991 (6:166932363 T>C), RS1000158695 (6:166940747 T>C), RS1000268197 (6:166947590 C>T), RS1000302904 (6:166942925 T>C), RS1000355570 (6:166942647 T>C), RS1000356368 (6:166956813 A>G,T), RS1000454654 (6:166945937 C>A,T), RS1000656498 (6:166944016 A>G), RS1000687677 (6:166943876 C>T), RS1000896286 (6:166928002 A>G), RS1000943224 (6:166937966 G>A), RS1000994514 (6:166955751 G>C), RS1001003299 (6:166932032 T>C), RS1001045109 (6:166944712 C>G)

Disease associations

OMIM: gene MIM:612944 | disease phenotypes: MIM:612951

GenCC curated gene-disease

Disease	Classification	Inheritance
cystic leukoencephalopathy without megalencephaly	Definitive	Autosomal recessive

Mondo (1): cystic leukoencephalopathy without megalencephaly (MONDO:0013058)

Orphanet (1): Cystic leukoencephalopathy without megalencephaly (Orphanet:85136)

HPO phenotypes

21 total (21 of 21 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000295	Doll-like facies
HP:0000407	Sensorineural hearing impairment
HP:0000639	Nystagmus
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001332	Dystonia
HP:0002119	Ventriculomegaly
HP:0002305	Athetosis
HP:0002352	Leukoencephalopathy
HP:0002465	Poor speech
HP:0002514	Cerebral calcification
HP:0003593	Infantile onset
HP:0003677	Slowly progressive
HP:0007042	Focal white matter lesions
HP:0011344	Severe global developmental delay
HP:0011400	Abnormal CNS myelination

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000692_2	Vitiligo	1.000000e-16
GCST001200_9	Graves’ disease	7.000000e-10
GCST001725_92	Inflammatory bowel disease	7.000000e-21
GCST002094_6	Crohn’s disease	8.000000e-12
GCST002218_7	Endometrial cancer	8.000000e-06
GCST002361_2	Smooth-surface caries	7.000000e-06
GCST002751_1	Spontaneous preterm birth (preterm birth)	1.000000e-09
GCST004131_51	Inflammatory bowel disease	9.000000e-15
GCST004132_22	Crohn’s disease	2.000000e-20
GCST004691_14	Huntington’s disease progression	6.000000e-06
GCST004744_11	Lung adenocarcinoma	4.000000e-06
GCST004748_51	Lung cancer	1.000000e-08
GCST004785_22	Vitiligo	2.000000e-18
GCST005038_68	Allergic disease (asthma, hay fever or eczema)	1.000000e-09
GCST006196_2	Type 1 diabetes in high risk HLA genotype individuals (time to event)	4.000000e-06
GCST010571_89	Autoimmune thyroid disease	2.000000e-37

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004230	endometrial neoplasm
EFO:0006917	spontaneous preterm birth
EFO:0006921	birth measurement
EFO:0008336	disease progression measurement
EFO:0000409	disease free survival

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C567845	Leukoencephalopathy, Cystic, Without Megalencephaly (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	5
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
methylmercuric chloride	decreases expression	2
bisphenol A	affects expression, affects cotreatment, increases methylation	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cisplatin	affects cotreatment, increases expression, affects response to substance	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
triphenyl phosphate	affects expression	1
deoxynivalenol	decreases expression	1
glycidyl methacrylate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
pyrrolidine dithiocarbamic acid	affects cotreatment, decreases expression, decreases reaction	1
ochratoxin A	increases expression	1
aflatoxin B2	decreases methylation	1
nickel sulfate	increases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2JI	HAP1 RNASET2 (-) 1	Cancer cell line	Male
CVCL_E2JJ	HAP1 RNASET2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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