KDM1A

protein-coding

lysine demethylase 1A, the group of MicroRNA protein coding host genes|Lysine demethylases

Gene summary

This gene encodes a nuclear protein containing a SWIRM domain, a FAD-binding motif, and an amine oxidase domain. This protein is a component of several histone deacetylase complexes, though it silences genes by functioning as a histone demethylase. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2009]

Previous symbols:

AOF2
KDM1

MANE transcript

NM_001009999.3

Inheritance

ClinVar variants

P:17U:697B:446

Top phenotype

ACTH-independent macronodular adrenal hyperplasia 3

gnomAD constraint

pLI —, LoF o/e 0.15

Max pathogenic AF

—

Genomic locus

chr1:23,019,443-23,083,689

External References & Databases

Ensembl (ENSG00000004487)

Transcript & Mutation Effects

hg38 • Region Span ~64.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: Orphanet

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: G2P

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: ClinGen

*KDM1A* is located on chromosome 1p36.12 and encodes lysine demethylase 1A protein. This protein is part of several histone deacetylase complexes, where it is involved in repressing expression of genes via histone demethylation. Variants in *KDM1A* have been reported in individuals with the following disease entities: palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome (OMIM: 616728) and ACTH-independent macronodular adrenal hyperplasia (OMIM: 620990). Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found key differences in phenotype and a distinct molecular mechanism. Therefore, the two disease entities have been split. The split curation for autosomal dominant ACTH-independent macronodular adrenal hyperplasia will be curated separately. *KDM1A* was first reported in relation to autosomal dominant palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome in 2014 (Tunovic et al., PMID: 24838796). This condition is associated with global developmental delay, brain anomalies (such as delayed myelination and thin corpus callosum), facial anomalies (including ptosis and posteriorly-rotated ears), digit anomalies, vision issues, and short stature. Thirteen variants (missense, nonsense) that have been reported in at least 13 probands in three publications (PMIDs: 24838796, 26656649, 40530541), and in ClinVar (SCV000803417.1, SCV002558982.1, SCV002304455.4, SCV002552609.2, SCV002526560.2, SCV000620108.2, SCV002003366.2, SCV005874571.1, SCV005439830.1) are included in this curation. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (mouse model, expression-level data, and biochemical functional evidence. Mouse model evidence demonstrates that *KDM1A* has a role in seizure susceptibility, status epilepticus, and fatality in response to pilocarpine treatment (PMID: 24735673). This gene is shown to be expressed in human neurons and control neuronal differentiation through H3K9 methylation (PMID: 25684206). Functional evidence indicates that knockdown of an isoform in neurons results in altered demethylation and inhibits neuronal differentiation. In summary, there is definitive evidence supporting the relationship between *KDM1A* and autosomal dominant palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders GCEP on the meeting date 10/28/2025 (SOP Version 11).

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: PanelApp Australia

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: Ambry Genetics

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014751

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

ACTH-independent macronodular adrenal hyperplasia 3AD

Manifestation: Craniofacial; Endocrine; Genitourinary; Musculoskeletal; Neurologic; Oncologic

Intervention: Endocrine; Oncologic

Rationale: The condition can manifest with primary bilateral macronodular adrenal hyperplasia with Cushing syndrome, and medical and surgical management (eg, with adrenalectomy) has been described

Comments: In addition to adrenal manifestations, other types of neoplasia have been described

Refs: 24838796; 26656649;34655521

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KDM1A variants in ClinVar

12 Conditions Cataloged

Inborn genetic diseasesTotal: 992

not providedTotal: 463

not specifiedTotal: 69

Palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndromeTotal: 39

KDM1A-related disorderTotal: 31

ACTH-independent macronodular adrenal hyperplasia 3Total: 7

Intellectual disabilityTotal: 2

Neurodevelopmental and congenital anomaliesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001009999.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			9 clinvar	423 clinvar	2 clinvar	434
missense	2 clinvar	8 clinvar	661 clinvar	21 clinvar		692
nonsense	2 clinvar	1 clinvar	8 clinvar			11
start loss						0
frameshift	1 clinvar	1 clinvar	16 clinvar			18
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar	3 clinvar			5
Total	6	11	697	444	2	1160

Highest pathogenic variant AF is 7.104533e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 132 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001009999.3	RefSeq	NP_001009999.1	21	MANE Select
ENST00000400181.9	Ensembl	ENSP00000383042.5	21	MANE Select
NM_001363654.2	RefSeq	NP_001350583.1	19	Standard
NM_001410762.1	RefSeq	NP_001397691.1	20	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
kdm1a	Danio rerio	Structure: nucleate erythrocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

kdm1a

Danio rerio

Structure: nucleate erythrocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Thermogenesis - Homo sapiens (human)
Androgen receptor signaling pathway
Signal Transduction
Factors involved in megakaryocyte development and platelet production
HDACs deacetylate histones

Biological Process

negative regulation of transcription by RNA polymerase II
alternative mRNA splicing, via spliceosome
positive regulation of neuroblast proliferation
regulation of transcription by RNA polymerase II
protein demethylation

Molecular Function

p53 binding
chromatin binding
histone deacetylase activity
protein binding
transcription factor binding

Cellular Component

nuclear chromosome, telomeric region
nuclear chromatin
nucleus
nucleoplasm
transcription factor complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000400181
Coding exons: 21
Length: 64242
Individuals with no LoFs: 125730
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125747
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	4.68	174	455	0.383	0.0000242	5628
Missense (PolyPhen)		37	171.37	0.21591		1929
Synonymous	1.57	141	167	0.845	0.00000914	1751
Loss of Function	5.46	7	47.7	0.147	0.00000263	563

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000088	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0.00034	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Histone demethylase that demethylates both 'Lys-4' (H3K4me) and 'Lys-9' (H3K9me) of histone H3, thereby acting as a coactivator or a corepressor, depending on the context. Acts by oxidizing the substrate by FAD to generate the corresponding imine that is subsequently hydrolyzed. Acts as a corepressor by mediating demethylation of H3K4me, a specific tag for epigenetic transcriptional activation. Demethylates both mono- (H3K4me1) and di-methylated (H3K4me2) H3K4me. May play a role in the repression of neuronal genes. Alone, it is unable to demethylate H3K4me on nucleosomes and requires the presence of RCOR1/CoREST to achieve such activity. Also acts as a coactivator of androgen receptor (ANDR)-dependent transcription, by being recruited to ANDR target genes and mediating demethylation of H3K9me, a specific tag for epigenetic transcriptional repression. The presence of PRKCB in ANDR-containing complexes, which mediates phosphorylation of 'Thr- 6' of histone H3 (H3T6ph), a specific tag that prevents demethylation H3K4me, prevents H3K4me demethylase activity of KDM1A. Demethylates di-methylated 'Lys-370' of p53/TP53 which prevents interaction of p53/TP53 with TP53BP1 and represses p53/TP53-mediated transcriptional activation. Demethylates and stabilizes the DNA methylase DNMT1. Required for gastrulation during embryogenesis. Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development. Effector of SNAI1-mediated transcription repression of E- cadherin/CDH1, CDN7 and KRT8. Required for the maintenance of the silenced state of the SNAI1 target genes E-cadherin/CDH1 and CDN7. {ECO:0000269|PubMed:12032298, ECO:0000269|PubMed:15620353, ECO:0000269|PubMed:16079795, ECO:0000269|PubMed:17805299, ECO:0000269|PubMed:20228790, ECO:0000269|PubMed:20562920}.;
Disease: DISEASE: Cleft palate, psychomotor retardation, and distinctive facial features (CPRF) [MIM:616728]: A syndrome characterized by cleft palate, developmental delay, psychomotor retardation, and facial dysmorphic features including a prominent forehead, slightly arched eyebrows, elongated palpebral fissures, a wide nasal bridge, thin lips, and widely spaced teeth. Cleft palate is a congenital fissure of the soft and/or hard palate, due to faulty fusion. {ECO:0000269|PubMed:23020937, ECO:0000269|PubMed:24838796, ECO:0000269|PubMed:26656649}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.211

Intolerance Scores

LoFtool: 0.337
RVIS EVS: -0.43
RVIS percentile EVS: 25.15

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.781

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium