KDM5A

Chr 12

lysine demethylase 5A

Also known as: NEDEHC, RBBP-2, RBBP2, RBP2

NCBI Gene: 5927ENSG00000073614UniProt: P29375

This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

Primary Disease Associations & Inheritance

UniProtEl Hayek-Chahrour neurodevelopmental syndrome
349
ClinVar variants
73
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— KDM5A
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

⚡
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
73 Pathogenic / Likely Pathogenic· 230 VUS of 349 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.16LOEUF
pLI 1.000
Z-score 7.94
OE 0.09 (0.05–0.16)
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.
2.25Z-score
OE missense 0.79 (0.74–0.84)
718 obs / 908.6 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.09 (0.05–0.16)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.74–0.84)
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.1.19
0≤1.21.6
LoF obs/exp: 8 / 88.7Missense obs/exp: 718 / 908.6Syn Z: -2.66

ClinVar Variant Classifications

349 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic66
Likely Pathogenic7
VUS230
Likely Benign32
Benign12
Conflicting2
66
Pathogenic
7
Likely Pathogenic
230
VUS
32
Likely Benign
12
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
1
62
0
66
Likely Pathogenic
2
2
3
0
7
VUS
5
194
31
0
230
Likely Benign
0
4
13
15
32
Benign
0
7
2
3
12
Conflicting
—2
Total1020811118349

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

View in ClinVar →

Protein Context — Lollipop Plot

KDM5A · protein map & ClinVar variants

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

Gene2Phenotype Curations

KDM5A-related intellectual developmental disorder

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

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations.
Sharma SV et al.·Cell
2010
Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia.
Bertrums EJM et al.·Haematologica
2023
Epigenetically upregulated NSUN2 confers ferroptosis resistance in endometrial cancer via m(5)C modification of SLC7A11 mRNA.
Chen SJ et al.·Redox Biol
2024
Pediatric non-Down syndrome acute megakaryoblastic leukemia is characterized by distinct genomic subsets with varying outcomes.
de Rooij JD et al.·Nat Genet
2017
Joining the PARty: PARP Regulation of KDM5A during DNA Repair (and Transcription?).
Sanchez A et al.·Bioessays
2022Review
Epigenetics in myelodysplastic syndromes.
Heuser M et al.·Semin Cancer Biol
2018Review
Poly(ADP-ribose) binding and macroH2A mediate recruitment and functions of KDM5A at DNA lesions.
Kumbhar R et al.·J Cell Biol
2021
Uncovering the molecular networks of ferroptosis in the pathogenesis of type 2 diabetes and its complications: a multi-omics investigation.
Dong C et al.·Mol Med
2024
Phase II trial of imatinib mesylate in patients with PDGFRA/B-negative hypereosinophilic syndrome.
Kim DH et al.·Br J Haematol
2024Clinical trial
KDM5A Inhibits Antitumor Immune Responses Through Downregulation of the Antigen-Presentation Pathway in Ovarian Cancer.
Liu H et al.·Cancer Immunol Res
2022
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