RNASET2

Chr 6AR

ribonuclease T2

Also known as: RNASE6PL, bA514O12.3

NCBI Gene: 8635ENSG00000026297UniProt: O00584

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Leukoencephalopathy, cystic, without megalencephalyMIM #612951
AR
235
ClinVar variants
65
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— RNASET2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
65 Pathogenic / Likely Pathogenic· 83 VUS of 235 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.96LOEUF
pLI 0.000
Z-score 1.68
OE 0.53 (0.31–0.96)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.24Z-score
OE missense 0.94 (0.82–1.09)
133 obs / 141.1 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.53 (0.31–0.96)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.82–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 8 / 15.0Missense obs/exp: 133 / 141.1Syn Z: -0.44

ClinVar Variant Classifications

235 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic6
VUS83
Likely Benign59
Benign19
Conflicting9
59
Pathogenic
6
Likely Pathogenic
83
VUS
59
Likely Benign
19
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
4
1
54
0
59
Likely Pathogenic
2
0
4
0
6
VUS
1
54
27
1
83
Likely Benign
1
5
24
29
59
Benign
0
3
10
6
19
Conflicting
—9
Total86311936235

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

RNASET2 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

RNASET2-related leukoencephalopathy, cystic, without megalencephaly

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
RIBONUCLEASE T2; RNASET2
MIM #612944 · *

Leukoencephalopathy, cystic, without megalencephaly

MIM #612951

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Systematic proteome-wide Mendelian randomization using the human plasma proteome to identify therapeutic targets for lung adenocarcinoma.
Zhang L et al.·J Transl Med
2024
Pathogenic Roles for RNASET2 in Clear Cell Renal Cell Carcinoma.
Peak T et al.·Lab Invest
2024
Innate Immune Response Regulation by the Human RNASET2 Tumor Suppressor Gene.
Acquati F et al.·Front Immunol
2019Review
RNaseT2 knockout rats exhibit hippocampal neuropathology and deficits in memory.
Sinkevicius KW et al.·Dis Model Mech
2018
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.
Biener-Ramanujan E et al.·Front Immunol
2022
Novel RNASET2 Pathogenic Variants in an East Asian Child with Delayed Psychomotor Development.
Sun Y et al.·Fetal Pediatr Pathol
2018
Interferon-driven brain phenotype in a mouse model of RNaseT2 deficient leukoencephalopathy.
Kettwig M et al.·Nat Commun
2021Functional
RNASET2-deficient leukoencephalopathy mimicking congenital CMV infection and Aicardi-Goutieres syndrome: a case report with a novel pathogenic variant.
Kameli R et al.·Orphanet J Rare Dis
2019Case report
Exploring potential therapeutic targets for cardiomyopathy: A proteome-wide Mendelian randomization analysis.
Ji Y et al.·Medicine (Baltimore)
2025
New insights into hypoxia-related mechanisms involved in different microvascular patterns of bronchopulmonary carcinoids and poorly differentiated neuroendocrine carcinomas. Role of ribonuclease T2 (RNASET2) and HIF-1α.
Uccella S et al.·Hum Pathol
2018Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Integrative multi-omics Mendelian randomization and functional validation identifies RNASET2 as a novel therapeutic target for autoimmune thyroiditis.
Jiang B et al.·Front Endocrinol (Lausanne)
2026🔓 Open AccessFunctional
Unlocking microglia pyroptosis in a model of type I interferon-driven neuroinflammation: lessons from Rnaset2-/- mice.
Wendland K et al.·Cell Death Dis
2025🔓 Open AccessFunctional
The human RNASET2 alarmin-like molecule differentially affects prostate cancer cells behavior in both cell autonomous and non-cell autonomous manners.
Roncoroni R et al.·J Transl Med
2025🔓 Open Access
A Multi-omic study integrating plasma protein, multiple tissues, and single-cell identifies RNASET2 as a key gene for lung cancer.
Shi J et al.·Discov Oncol
2025🔓 Open Access
RNASET2 Deficiency Induces Hepatocellular Carcinoma Metastasis through Cholesterol-Triggered MET Activation.
Xu Y et al.·Adv Sci (Weinh)
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools