KDM5C

Chr XXLR

lysine demethylase 5C

Also known as: DXS1272E, JARID1C, MRX13, MRXJ, MRXS16, MRXSCJ, MRXSJ, SMCX

NCBI Gene: 8242ENSG00000126012UniProt: P41229

This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, X-linked syndromic, Claes-Jensen typeMIM #300534
XLR
532
ClinVar variants
76
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— KDM5C
🧬
Gene-Disease Validity (ClinGen)
X-linked syndromic intellectual disability · 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
76 Pathogenic / Likely Pathogenic· 266 VUS of 532 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.17LOEUF
pLI 1.000
Z-score 6.38
OE 0.07 (0.04–0.17)
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.
5.15Z-score
OE missense 0.44 (0.40–0.48)
293 obs / 666.9 exp
Constrained

Extremely missense-constrained (top ~0.01%)

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.0.07 (0.04–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.40–0.48)
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.1.05
0≤1.21.6
LoF obs/exp: 4 / 55.1Missense obs/exp: 293 / 666.9Syn Z: -0.58

ClinVar Variant Classifications

532 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic36
Likely Pathogenic40
VUS266
Likely Benign155
Benign30
Conflicting5
36
Pathogenic
40
Likely Pathogenic
266
VUS
155
Likely Benign
30
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
18
1
17
0
36
Likely Pathogenic
20
11
9
0
40
VUS
2
233
27
4
266
Likely Benign
0
14
45
96
155
Benign
0
6
9
15
30
Conflicting
—5
Total40265107115532

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

View in ClinVar →

Protein Context — Lollipop Plot

KDM5C · protein map & ClinVar variants

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

Gene2Phenotype Curations

KDM5C-related syndromic intellectual developmental disorder

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Intellectual developmental disorder, X-linked syndromic, Claes-Jensen type

MIM #300534

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — KDM5C
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
A neoantigen vaccine generates antitumour immunity in renal cell carcinoma.
Braun DA et al.·Nature
2025Clinical trial
Molecular Subsets in Renal Cancer Determine Outcome to Checkpoint and Angiogenesis Blockade.
Motzer RJ et al.·Cancer Cell
2020
De novo variants underlying monogenic syndromes with intellectual disability in a neurodevelopmental cohort from India.
Pande S et al.·Eur J Hum Genet
2024Cohort
KDM5C: A dual-edged epigenetic regulator in cancer biology-context-dependent roles and therapeutic implications.
Tu FY et al.·Biochem Pharmacol
2025Review
Clinical Features and Genetic Characteristics of XLID Patients With KDM5C Gene Mutations: Insights on Phenotype-Genotype Correlations From 175 Previous Cases and Identification of a Novel Variant.
Ghasemi MR et al.·Mol Genet Genomic Med
2025Review
KDM5C-Mediated Recruitment of BRD4 to Chromatin Regulates Enhancer Activation and BET Inhibitor Sensitivity.
Qiang Y et al.·Cancer Res
2024
KDM5C and KDM5D mutations have different consequences in clear cell renal cell carcinoma cells.
Müller M et al.·Commun Biol
2025
Skewed X-chromosome inactivation in unsolved neurodevelopmental disease cases can guide re-evaluation For X-linked genes.
Giovenino C et al.·Eur J Hum Genet
2023Cohort
KDM5C mutational screening among males with intellectual disability suggestive of X-Linked inheritance and review of the literature.
Gonçalves TF et al.·Eur J Med Genet
2014Review
A novel KDM5C mutation associated with intellectual disability: molecular mechanisms and clinical implications.
Meng Y et al.·Ital J Pediatr
2025Functional
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