KDM6A

Chr XXLD

lysine demethylase 6A

Also known as: KABUK2, UTX, bA386N14.2

NCBI Gene: 7403ENSG00000147050UniProt: O15550

This gene is located on the X chromosome and is the corresponding locus to a Y-linked gene which encodes a tetratricopeptide repeat (TPR) protein. The encoded protein of this gene contains a JmjC-domain and catalyzes the demethylation of tri/dimethylated histone H3. Multiple alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Apr 2014]

Primary Disease Associations & Inheritance

Kabuki syndrome 2MIM #300867
XLD
3
Active trials
41
Pathogenic / LP
341
ClinVar variants
112
Pubs (1 yr)
2.9
Missense Z
0.16
LOEUF· LoF intolerant
Clinical Summary— KDM6A
🧬
Gene-Disease Validity (ClinGen)
Kabuki syndrome 2 · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
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
41 Pathogenic / Likely Pathogenic· 183 VUS of 341 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — KDM6A
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint
0.16LOEUF
pLI 1.000
Z-score 6.51
OE 0.07 (0.03–0.16)
Highly constrained

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

Missense Constraint
2.95Z-score
OE missense 0.63 (0.57–0.69)
317 obs / 502.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.07 (0.03–0.16)
0≤0.351.4
Missense OE0.63 (0.57–0.69)
0≤0.61.4
Synonymous OE0.99
0≤1.21.6
LoF obs/exp: 4 / 57.0Missense obs/exp: 317 / 502.9Syn Z: 0.10
LOF
DN
0.2399th %ile
GOF
0.3491th %ile
LOF
0.81top 5%

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

LOFprediction above median · 54% of P/LP variants are LoF · 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

341 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic13
VUS183
Likely Benign106
Benign10
Conflicting1
28
Pathogenic
13
Likely Pathogenic
183
VUS
106
Likely Benign
10
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
1
16
0
28
Likely Pathogenic
11
0
2
0
13
VUS
2
158
20
3
183
Likely Benign
0
6
49
51
106
Benign
0
2
3
5
10
Conflicting
—1
Total241679059341

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

View in ClinVar →

KDM6A · protein map & ClinVar variants

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

Gene2Phenotype Curations

KDM6A-related Kabuki syndrome

definitive
Monoallelic X HeterozygousLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients