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…

Primary Disease Associations & Inheritance

El Hayek-Chahrour neurodevelopmental syndromeMIM #620820

Clinical highlights

Gene–disease validity (ClinGen)

Limited · congenital heart disease · AD · ClinGen 2024

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.16

LOEUF· LoF intol.

LOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in KDM5A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 36

1,835 rare PASS variants

Rare truncating (LoF)

1 in 1,400

122 rare PASS variants

Rare synonymous (reference)

1 in 54

865 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KDM5A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 1,500
South Asian	~43k	1 in 39	1 in 750
Remaining (unassigned)	~30k	1 in 26	1 in 3,700
European (Finnish)	~27k	1 in 140	1 in 2,000
Admixed American	~22k	1 in 36	1 in 1,200
African / African American	~21k	1 in 47	1 in 2,400
East Asian	~20k	1 in 49	1 in 1,600
Ashkenazi Jewish	~13k	1 in 130	≈ 1 in 4,400
Middle Eastern	~2,884	1 in 48	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 28 coding exons well covered in gnomAD exomes; exons 3, 6, 7, 16 marginal. Genomes: 27 of 28 (exon 16 below).? see exons ↓