KDM4A

Chr 1

lysine demethylase 4A

Also known as: JHDM3A, JMJD2, JMJD2A, TDRD14A

NCBI Gene: 9682 ENSG00000066135 UniProt: O75164 OMIM: 609764

This histone demethylase specifically removes trimethyl groups from lysine-9 and lysine-36 residues of histone H3, regulating gene expression through chromatin modification. Mutations cause autosomal dominant neurodevelopmental disorder with intellectual disability, seizures, and behavioral abnormalities. The gene is extremely intolerant to loss-of-function variants, indicating that proper dosage is critical for normal neurodevelopment.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.16

Clinical Summary— KDM4A

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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.

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ClinVar Variants

105 VUS of 147 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.03–0.16)

0≤0.351.4

Missense OE?0.58 (0.53–0.63)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 4 / 58.7Missense obs/exp: 351 / 606.0Syn Z: 0.80

This gene — mechanism propensity

0.2399th %ile

GOF

0.3193th %ile

LOF

0.74top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.16

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

147 submitted variants in ClinVar

ClinVar

Classification Summary

VUS105

Likely Benign6

Benign6

105

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	105	0	0	105
Likely Benign	3	0	3	6
Benign	1	1	4	6
Total	109	1	7	117

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap KDM4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →