KDM4B

Chr 19AD

lysine demethylase 4B

Also known as: JMJD2B, MRD65, TDRD14B

NCBI Gene: 23030 ENSG00000127663 UniProt: O94953 OMIM: 609765

The protein functions as a histone demethylase that removes methyl groups from H3K36 and H3K9me2/H3K9me3, regulating chromatin structure and gene expression during brain development. Loss-of-function mutations cause autosomal dominant intellectual developmental disorder 65. The gene is highly intolerant to loss-of-function variants, indicating haploinsufficiency as the likely mechanism of pathogenicity.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Enables histone H3K36 demethylase activity and histone H3K9me2/H3K9me3 demethylase activity. Predicted to be involved in brain development; chromatin remodeling; and regulation of gene expression. Located in cytosol and nucleoplasm. Implicated in autosomal dominant intellectual developmental disorder 65; breast cancer; colorectal cancer; malignant peripheral nerve sheath tumor; and stomach cancer. Biomarker of several diseases, including alopecia areata; lung cancer; medulloblastoma; prostate cancer; and stomach cancer. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.171 OMIM phenotype

Clinical Summary— KDM4B

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Gene-Disease Validity (ClinGen)

intellectual developmental disorder, autosomal dominant 65 · ADStrong

Strong evidence — appropriate for clinical testing

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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

37 unique Pathogenic / Likely Pathogenic· 282 VUS of 438 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?

0.17LOEUF

pLI 1.000

Z-score 6.27

OE 0.07 (0.04–0.17)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.48Z-score

OE missense 0.64 (0.59–0.69)

469 obs / 734.8 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.17)

0≤0.351.4

Missense OE?0.64 (0.59–0.69)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 4 / 53.5Missense obs/exp: 469 / 734.8Syn Z: -0.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKDM4B-related developmental disorderLOFAD

This gene — mechanism propensity

0.2499th %ile

GOF

0.3491th %ile

LOF

0.74top 10%

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

LOFprediction above median · 84% of P/LP variants are LoF · LOEUF 0.17

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

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9

Likely Pathogenic28

VUS282

Likely Benign72

Benign12

Conflicting12

Pathogenic

Likely Pathogenic

282

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	7	2	0	0	9
Likely Pathogenic	24	4	0	0	28
VUS	5	271	5	1	282
Likely Benign	0	22	5	45	72
Benign	1	0	4	7	12
Conflicting	—				12
Total	37	299	14	53	415

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap KDM4B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →