KDM1A

Chr 1AD

lysine demethylase 1A

Also known as: AIMAH3, AOF2, BHC110, CPRF, KDM1, LSD1

NCBI Gene: 23028 ENSG00000004487 OMIM: 609132

This protein functions as a histone demethylase and component of histone deacetylase complexes that silences gene expression. Loss-of-function mutations cause autosomal dominant cleft palate with psychomotor retardation and distinctive facial features, as well as ACTH-independent macronodular adrenal hyperplasia. The high constraint scores (pLI 0.997, LOEUF 0.276) support haploinsufficiency as the pathogenic mechanism.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.282 OMIM phenotypes

Clinical Summary— KDM1A

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Gene-Disease Validity (ClinGen)

palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome · ADDefinitive

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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ClinVar Variants

16 unique Pathogenic / Likely Pathogenic· 615 VUS of 1162 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.28LOEUF

pLI 0.997

Z-score 5.46

OE 0.15 (0.08–0.28)

Highly constrained

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

Missense Constraint?

4.68Z-score

OE missense 0.38 (0.34–0.43)

174 obs / 454.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.15 (0.08–0.28)

0≤0.351.4

Missense OE?0.38 (0.34–0.43)

0≤0.61.4

Synonymous OE?0.85

0≤1.21.6

LoF obs/exp: 7 / 47.7Missense obs/exp: 174 / 454.7Syn Z: 1.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateKDM1A-related GIP-dependent primary bilateral macronodular adrenal hyperplasia with Cushing's syndromeLOFAD

strongKDM1A-related developmental delay and distinctive facial featuresOTHERAD

This gene — mechanism propensity

0.2997th %ile

GOF

0.4184th %ile

LOF

0.71top 10%

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

LOFprediction above median · 44% of P/LP variants are LoF · LOEUF 0.28

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

1162 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic9

VUS615

Likely Benign464

Benign25

Conflicting16

Pathogenic

Likely Pathogenic

615

VUS

464

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	3	0	0	7
Likely Pathogenic	3	5	1	0	9
VUS	24	566	19	6	615
Likely Benign	0	4	84	376	464
Benign	0	2	21	2	25
Conflicting	—				16
Total	31	580	125	384	1,136

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

View in ClinVar →

5 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap KDM1A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →