KDM2A

Chr 11

lysine demethylase 2A

Also known as: CXXC8, FBL11, FBL7, FBXL11, JHDM1A, LILINA

NCBI Gene: 22992 ENSG00000173120 UniProt: Q9Y2K7

The protein functions as a histone demethylase that specifically removes methyl groups from lysine-36 of histone H3, playing a central role in gene regulation and maintaining chromosomal stability during cell division. Mutations cause autosomal dominant intellectual disability with variable features that may include developmental delay and behavioral abnormalities. This gene is highly constrained against loss-of-function mutations in the general population, indicating that such variants are likely to be pathogenic when identified in patients.

ResearchSummary from RefSeq, UniProt

This gene encodes a member of the F-box protein family which is characterized by an approximately 40 amino acid motif, the F-box. The F-box proteins constitute one of the four subunits of ubiquitin protein ligase complex called SCFs (SKP1-cullin-F-box), which function in phosphorylation-dependent ubiquitination. The F-box proteins are divided into 3 classes: Fbws containing WD-40 domains, Fbls containing leucine-rich repeats, and Fbxs containing either different protein-protein interaction modules or no recognizable motifs. The protein encoded by this gene belongs to the Fbls class and, in addition to an F-box, contains at least six highly degenerated leucine-rich repeats. This family member plays a role in epigenetic silencing. It nucleates at CpG islands and specifically demethylates both mono- and di-methylated lysine-36 of histone H3. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2012]

ResearchGenerating clinical summary…

Clinical highlights

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

0.04

LOEUF· LoF intol.

LOF

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.04LOEUF

pLI 1.000

Z-score 7.50

OE 0.00 (0.00–0.04)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

5.31Z-score

OE missense 0.43 (0.39–0.48)

302 obs / 696.3 exp

Constrained

Extremely missense-constrained (top ~0.01%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.04)

0≤0.351.4

Missense OE?0.43 (0.39–0.48)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 0 / 65.5Missense obs/exp: 302 / 696.3Syn Z: -0.41

Background carrier burden — how many people carry a rare variant somewhere in KDM2A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 140

862 rare PASS variants

Rare truncating (LoF)

1 in 3,700

22 rare PASS variants

Rare synonymous (reference)

1 in 110

577 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for KDM2A. 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 150	1 in 6,000
South Asian	~43k	1 in 84	1 in 2,200
Remaining (unassigned)	~30k	1 in 130	1 in 3,600
European (Finnish)	~27k	1 in 320	≈ 1 in 8,900
Admixed American	~22k	1 in 90	1 in 4,500
African / African American	~21k	1 in 140	1 in 400
East Asian	~20k	1 in 120	1 in 3,800
Ashkenazi Jewish	~13k	1 in 250	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 220	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): 18 of 20 coding exons well covered in gnomAD exomes; exons 10, 13 marginal. Genomes: all 20.? see exons ↓