KDM4A

Chr 1

lysine demethylase 4A

Also known as: JHDM3A, JMJD2, JMJD2A, TDRD14A

NCBI Gene: 9682ENSG00000066135UniProt: O75164

This gene is a member of the Jumonji domain 2 (JMJD2) family and encodes a protein containing a JmjN domain, a JmjC domain, a JD2H domain, two TUDOR domains, and two PHD-type zinc fingers. This nuclear protein functions as a trimethylation-specific demethylase, converting specific trimethylated histone residues to the dimethylated form, and as a transcriptional repressor. [provided by RefSeq, Apr 2009]

127
ClinVar variants
8
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— KDM4A
⚡
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
8 Pathogenic / Likely Pathogenic· 107 VUS of 127 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.16LOEUF
pLI 1.000
Z-score 6.62
OE 0.07 (0.03–0.16)
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.
3.68Z-score
OE missense 0.58 (0.53–0.63)
351 obs / 606.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.07 (0.03–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.58 (0.53–0.63)
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.0.93
0≤1.21.6
LoF obs/exp: 4 / 58.7Missense obs/exp: 351 / 606.0Syn Z: 0.80

ClinVar Variant Classifications

127 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7
Likely Pathogenic1
VUS107
Likely Benign6
Benign6
7
Pathogenic
1
Likely Pathogenic
107
VUS
6
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
7
0
7
Likely Pathogenic
0
0
1
0
1
VUS
0
103
4
0
107
Likely Benign
0
3
0
3
6
Benign
0
1
1
4
6
Total0107137127

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

View in ClinVar →

Protein Context — Lollipop Plot

KDM4A · 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
Inhibition of KDM4A restricts SQLE transcription and induces oxidative stress imbalance to suppress bladder cancer.
Zhang J et al.·Redox Biol
2024
KDM4A-induced tumor senescence enhances the efficacy of immunotherapy by inhibiting AGT-PHB1 axis-mediated mitophagy in colorectal cancer.
Cai T et al.·Autophagy
2025
Inhibiting the Histone Demethylase Kdm4a Restrains Cardiac Fibrosis After Myocardial Infarction by Promoting Autophagy in Premature Senescent Fibroblasts.
Jin M et al.·Adv Sci (Weinh)
2025
Jumonji histone demethylases are therapeutic targets in small cell lung cancer.
Nguyen A et al.·Oncogene
2024
FGL1: a novel biomarker and target for non-small cell lung cancer, promoting tumor progression and metastasis through KDM4A/STAT3 transcription mechanism.
Liu TY et al.·J Exp Clin Cancer Res
2024Functional
Comprehensive multiplexed autoantibody profiling of patients with advanced urothelial cancer.
Ravi P et al.·J Immunother Cancer
2024Cohort
In-silico guided chemical exploration of KDM4A fragments hits.
Lombino J et al.·Clin Epigenetics
2023
USP7 promotes chemotherapy resistance and DNA damage response through stabilizing and deubiquitinating KDM4A in bladder cancer.
Yang H et al.·Cell Death Dis
2025
E2F1-mediated KDM4A-AS1 up-regulation promotes EMT of hepatocellular carcinoma cells by recruiting ILF3 to stabilize AURKA mRNA.
Shen HM et al.·Cancer Gene Ther
2023
SUV39H1 Regulates KLF4 and Chromatin Remodeling in Smooth Muscle Cell Phenotypic Plasticity.
Chatterjee P et al.·Arterioscler Thromb Vasc Biol
2025Functional
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