KDM5A

Chr 12AR

lysine demethylase 5A

Also known as: NEDEHC, RBBP-2, RBBP2, RBP2

NCBI Gene: 5927 ENSG00000073614 UniProt: P29375 OMIM: 180202

The KDM5A protein is a histone demethylase that specifically removes methyl groups from lysine 4 of histone H3, playing a central role in gene regulation and transcriptional control of developmental genes including Hox proteins and circadian rhythm genes. Mutations cause El Hayek-Chahrour neurodevelopmental syndrome, which follows an autosomal recessive inheritance pattern. This gene is extremely intolerant to loss-of-function variants, indicating that functional copies are critical for normal development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the Jumonji, AT-rich interactive domain 1 (JARID1) histone demethylase protein family. The encoded protein plays a role in gene regulation through the histone code by specifically demethylating lysine 4 of histone H3. The encoded protein interacts with many other proteins, including retinoblastoma protein, and is implicated in the transcriptional regulation of Hox genes and cytokines. This gene may play a role in tumor progression. [provided by RefSeq, Aug 2013]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.161 OMIM phenotype

Clinical Summary— KDM5A

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADLimited

Limited evidence — not for standalone diagnostic reporting

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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

12 unique Pathogenic / Likely Pathogenic· 207 VUS of 309 total submissions

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?

0.16LOEUF

pLI 1.000

Z-score 7.94

OE 0.09 (0.05–0.16)

Highly constrained

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

Missense Constraint?

2.25Z-score

OE missense 0.79 (0.74–0.84)

718 obs / 908.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.09 (0.05–0.16)

0≤0.351.4

Missense OE?0.79 (0.74–0.84)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 8 / 88.7Missense obs/exp: 718 / 908.6Syn Z: -2.66

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedKDM5A-related intellectual developmental disorderOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.2798th %ile

GOF

0.4085th %ile

LOF

0.74top 10%

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

309 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic6

VUS207

Likely Benign34

Benign11

Conflicting2

Pathogenic

Likely Pathogenic

207

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	1	1	0	6
Likely Pathogenic	4	2	0	0	6
VUS	9	197	1	0	207
Likely Benign	0	4	13	17	34
Benign	0	7	1	3	11
Conflicting	—				2
Total	17	211	16	20	266

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 89) ClinVar copy-number / structural variants overlap KDM5A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →