L3MBTL3

Chr 6

L3MBTL histone methyl-lysine binding protein 3

NCBI Gene: 84456ENSG00000198945UniProt: Q96JM7

Is a negative regulator of Notch target genes expression, required for RBPJ-mediated transcriptional repression (PubMed:29030483). It recruits KDM1A to Notch-responsive elements and promotes KDM1A-mediated H3K4me demethylation (PubMed:29030483). Involved in the regulation of ubiquitin-dependent degradation of a set of methylated non-histone proteins, including SOX2, DNMT1 and E2F1. It acts as an adapter recruiting the CRL4-DCAF5 E3 ubiquitin ligase complex to methylated target proteins (PubMed:29691401, PubMed:30442713). Required for normal maturation of myeloid progenitor cells (By similarity)

115
ClinVar variants
14
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— L3MBTL3
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 96 VUS of 115 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.27LOEUF
pLI 0.997
Z-score 5.30
OE 0.14 (0.07–0.27)
Highly constrained

Highly LoF-intolerant (top ~10% 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.
1.64Z-score
OE missense 0.78 (0.71–0.85)
333 obs / 428.3 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.0.14 (0.07–0.27)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.78 (0.71–0.85)
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.1.06
0≤1.21.6
LoF obs/exp: 6 / 44.0Missense obs/exp: 333 / 428.3Syn Z: -0.53

ClinVar Variant Classifications

115 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic5
VUS96
Likely Benign2
Benign3
9
Pathogenic
5
Likely Pathogenic
96
VUS
2
Likely Benign
3
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
9
0
9
Likely Pathogenic
0
0
5
0
5
VUS
0
93
3
0
96
Likely Benign
0
1
1
0
2
Benign
0
1
1
1
3
Total095191115

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

View in ClinVar →

Protein Context — Lollipop Plot

L3MBTL3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Uncovering immune cell-associated genes in breast cancer: based on summary data-based Mendelian randomized analysis and colocalization study.
Liu J et al.·Breast Cancer Res
2024
Identification of the genetic mechanism that associates L3MBTL3 to multiple sclerosis.
Alcina A et al.·Hum Mol Genet
2022Functional
Association of SHMT1, MAZ, ERG, and L3MBTL3 Gene Polymorphisms with Susceptibility to Multiple Sclerosis.
Nazari Mehrabani SZ et al.·Biochem Genet
2019
Identification of potential pathogenic genes for urolithiasis through multi-omics Mendelian randomization analysis.
Yan K et al.·Urolithiasis
2024
Exploring the early drivers of pain in Parkinson's disease.
Liu S et al.·Sci Rep
2025
Novel multiple sclerosis susceptibility loci implicated in epigenetic regulation.
Andlauer TF et al.·Sci Adv
2016
Genetic Variants in Epigenetic Pathways and Risks of Multiple Cancers in the GAME-ON Consortium.
Toth R et al.·Cancer Epidemiol Biomarkers Prev
2017
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
L3MBTL3 and STAT3 collaboratively upregulate SNAIL expression to promote metastasis in female breast cancer.
Xiao J et al.·Nat Commun
2025🔓 Open Access
L3MBTL3 Is a Potential Prognostic Biomarker and Correlates with Immune Infiltrations in Gastric Cancer.
Gan L et al.·Cancers (Basel)
2023🔓 Open Access
Association of the L3MBTL3 rs1125970 and rs4897367 Gene Polymorphisms With Coronary Heart Disease Susceptibility in the Chinese Population: A Case-Control Study.
Li Y et al.·J Cardiovasc Pharmacol
2023
L3MBTL3 is induced by HIF-1α and fine tunes the HIF-1α degradation under hypoxia in vitro.
Wang M et al.·Heliyon
2023🔓 Open Access
The structure, binding and function of a Notch transcription complex involving RBPJ and the epigenetic reader protein L3MBTL3.
Hall D et al.·Nucleic Acids Res
2022🔓 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