NSUN2

Chr 5AR

NOP2/Sun RNA methyltransferase 2

Also known as: MISU, MRT5, SAKI, TRM4

NCBI Gene: 54888ENSG00000037474UniProt: Q08J23

This gene encodes a methyltransferase that catalyzes the methylation of cytosine to 5-methylcytosine (m5C) at position 34 of intron-containing tRNA(Leu)(CAA) precursors. This modification is necessary to stabilize the anticodon-codon pairing and correctly translate the mRNA. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2011]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 5MIM #611091
AR
784
ClinVar variants
86
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— NSUN2
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
86 Pathogenic / Likely Pathogenic· 191 VUS of 784 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.53LOEUF
pLI 0.000
Z-score 3.93
OE 0.34 (0.22–0.53)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
0.03Z-score
OE missense 1.00 (0.92–1.08)
428 obs / 430.0 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.0.34 (0.22–0.53)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.92–1.08)
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.1.02
0≤1.21.6
LoF obs/exp: 14 / 41.2Missense obs/exp: 428 / 430.0Syn Z: -0.16

ClinVar Variant Classifications

784 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic74
Likely Pathogenic12
VUS191
Likely Benign181
Benign10
Conflicting11
74
Pathogenic
12
Likely Pathogenic
191
VUS
181
Likely Benign
10
Benign
11
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
1
61
0
74
Likely Pathogenic
7
1
4
0
12
VUS
4
169
14
4
191
Likely Benign
0
3
74
104
181
Benign
0
2
7
1
10
Conflicting
—11
Total23176160109479

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

View in ClinVar →

Protein Context — Lollipop Plot

NSUN2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

NSUN2-related intellectual disability

strong
ARUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, autosomal recessive 5

MIM #611091

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
NSUN2 lactylation drives cancer cell resistance to ferroptosis through enhancing GCLC-dependent glutathione synthesis.
Niu K et al.·Redox Biol
2025
Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m(5)C modification of SLC7A11 mRNA.
Chen SJ et al.·Redox Biol
2024
NSUN2-mediated cytosine-5 methylation of FSP1 protects acute myeloid leukemia cells from ferroptosis.
Ye W et al.·Mol Cancer
2025
NSUN2-mediated RNA methylation: Molecular mechanisms and clinical relevance in cancer.
Li P et al.·Cell Signal
2024Review
DNA methyltransferase 1 modulates mitochondrial function through bridging m(5)C RNA methylation.
Wang J et al.·Mol Cell
2025
NSUN2-mediated m(5) C RNA methylation dictates retinoblastoma progression through promoting PFAS mRNA stability and expression.
Zuo S et al.·Clin Transl Med
2023
Aberrant CircTMEM45A Facilitates Inflammatory Progression of Esophageal Squamous Cell Carcinoma through m5C-Mediated NLRP3 Activation.
Meng L et al.·Cancer Res
2025
Novel molecular mechanisms of immune evasion in hepatocellular carcinoma: NSUN2-mediated increase of SOAT2 RNA methylation.
Jiang J et al.·Cancer Commun (Lond)
2025Functional
Aberrant NSUN2-mediated m5C modification of exosomal LncRNA MALAT1 induced RANKL-mediated bone destruction in multiple myeloma.
Yu M et al.·Commun Biol
2024
NONO regulates m(5)C modification and alternative splicing of PTEN mRNAs to drive gastric cancer progression.
Zhao G et al.·J Exp Clin Cancer Res
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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