KDM6B

Chr 17AD

lysine demethylase 6B

Also known as: JMJD3, NEDCFSA, NEDSST

NCBI Gene: 23135 ENSG00000132510 UniProt: O15054 OMIM: 611577

This histone demethylase specifically removes methyl groups from lysine 27 of histone H3, playing a central role in gene expression regulation and chromatin remodeling during development. Mutations cause Stolerman neurodevelopmental syndrome with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants, indicating critical developmental importance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a lysine-specific demethylase that specifically demethylates di- or tri-methylated lysine 27 of histone H3 (H3K27me2 or H3K27me3). H3K27 trimethylation is a repressive epigenetic mark controlling chromatin organization and gene silencing. This protein can also demethylate non-histone proteins such as retinoblastoma protein. Through its demethylation actvity this gene influences cellular differentiation and development, tumorigenesis, inflammatory diseases, and neurodegenerative diseases. This protein has two classical nuclear localization signals at its N-terminus. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Feb 2017]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.141 OMIM phenotype

Clinical Summary— KDM6B

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Gene-Disease Validity (ClinGen)

syndromic intellectual disability · ARLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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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

118 unique Pathogenic / Likely Pathogenic· 477 VUS of 841 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.14LOEUF

pLI 1.000

Z-score 7.02

OE 0.06 (0.03–0.14)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

1.32Z-score

OE missense 0.89 (0.84–0.94)

924 obs / 1043.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.06 (0.03–0.14)

0≤0.351.4

Missense OE?0.89 (0.84–0.94)

0≤0.61.4

Synonymous OE?1.31

0≤1.21.6

LoF obs/exp: 4 / 65.2Missense obs/exp: 924 / 1043.6Syn Z: -5.07

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongKDM6B-related developmental disorderLOFAD

limitedKDM6B-related intellectual developmental disorderOTHERAR

This gene — mechanism propensity

0.18100th %ile

GOF

0.2795th %ile

LOF

0.87top 5%

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

LOFprediction above median · 1 literature citation · 81% of P/LP variants are LoF · LOEUF 0.14 · ClinGen HI: Sufficient evidence for dosage pathogenicity

Literature Evidence

LOFKdm6b Haploinsufficiency Causes ASD/ADHD-Like Behavioral Deficits in Mice1

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

References

1.PMID 35711692 ↗

ClinVar Variant Classifications

841 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43

Likely Pathogenic75

VUS477

Likely Benign189

Benign28

Conflicting14

Pathogenic

Likely Pathogenic

477

VUS

189

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	40	2	1	0	43
Likely Pathogenic	56	17	2	0	75
VUS	21	429	21	6	477
Likely Benign	0	95	15	79	189
Benign	0	17	2	9	28
Conflicting	—				14
Total	117	560	41	94	826

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

View in ClinVar →

22 pathogenic / likely-pathogenic (of 31) ClinVar copy-number / structural variants overlap KDM6B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →