KDM5C

Chr XXLR

lysine demethylase 5C

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

NCBI Gene: 8242 ENSG00000126012 UniProt: P41229 OMIM: 314690

This protein is a histone demethylase that regulates gene transcription and chromatin remodeling through its DNA-binding domains. Loss-of-function mutations cause X-linked intellectual developmental disorder, Claes-Jensen type, inherited in an X-linked recessive pattern. The high constraint scores (pLI 0.999, LOEUF 0.166) indicate the gene is highly intolerant to loss-of-function variants, consistent with pathogenic mutations disrupting normal chromatin regulation.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismXLRLOEUF 0.171 OMIM phenotype

Clinical Summary— KDM5C

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Gene-Disease Validity (ClinGen)

X-linked syndromic intellectual disability · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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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 6.38

OE 0.07 (0.04–0.17)

Highly constrained

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

Missense Constraint?

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?

LoF OE?0.07 (0.04–0.17)

0≤0.351.4

Missense OE?0.44 (0.40–0.48)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 4 / 55.1Missense obs/exp: 293 / 666.9Syn Z: -0.58

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveKDM5C-related syndromic intellectual developmental disorderLOFXLR

This gene — mechanism propensity

0.2599th %ile

GOF

0.5367th %ile

LOF

0.72top 10%

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

LOFprediction above median · LOEUF 0.17 · ClinGen HI: Sufficient evidence for dosage pathogenicity

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