KDM5D

Summary

KDM5D (lysine demethylase 5D, HGNC:11115) is a protein-coding gene on chromosome Yq11.223, encoding Lysine-specific demethylase 5D (Q9BY66). Histone demethylase that specifically demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code.

This gene encodes a protein containing zinc finger domains. A short peptide derived from this protein is a minor histocompatibility antigen which can lead to graft rejection of male donor cells in a female recipient. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8284 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 43 total
• Phenotypes (HPO): 4
• Druggable target: yes
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_004653

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11115
Approved symbol	KDM5D
Name	lysine demethylase 5D
Location	Yq11.223
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0234
Ensembl gene	ENSG00000012817
Ensembl biotype	protein_coding
OMIM	426000
Entrez	8284

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 22 protein_coding, 4 retained_intron

ENST00000317961, ENST00000382806, ENST00000415360, ENST00000440077, ENST00000447300, ENST00000469599, ENST00000478891, ENST00000485154, ENST00000492117, ENST00000541639, ENST00000893725, ENST00000893726, ENST00000893727, ENST00000893728, ENST00000893729, ENST00000893730, ENST00000893731, ENST00000893732, ENST00000893733, ENST00000893734, ENST00000933679, ENST00000933680, ENST00000933681, ENST00000933682, ENST00000944746, ENST00000944747

RefSeq mRNA: 3 — MANE Select: NM_004653 NM_001146705, NM_001146706, NM_004653

CCDS: CCDS14794, CCDS55554, CCDS55555

Canonical transcript exons

ENST00000317961 — 27 exons

Exon	Start	End
ENSE00000652498	19731772	19731930
ENSE00000652501	19732584	19732742
ENSE00000652502	19735352	19735497
ENSE00000652503	19735621	19735750
ENSE00000652506	19741735	19741857
ENSE00000652508	19743162	19743239
ENSE00000891759	19744385	19744553
ENSE00001594027	19706441	19706640
ENSE00001670444	19706794	19706863
ENSE00001786866	19721130	19721311
ENSE00001788914	19741318	19741488
ENSE00001799734	19732046	19732165
ENSE00001805865	19739528	19739662
ENSE00001945799	19703865	19706345
ENSE00003484526	19707934	19708071
ENSE00003488142	19715352	19715499
ENSE00003491684	19715615	19715739
ENSE00003497148	19720872	19721034
ENSE00003534652	19710376	19710472
ENSE00003539670	19707147	19707746
ENSE00003544083	19708875	19709013
ENSE00003591494	19708244	19708423
ENSE00003602862	19715823	19716004
ENSE00003607600	19709451	19709809
ENSE00003664560	19716279	19716473
ENSE00003688313	19716596	19716715
ENSE00003903207	19744671	19744726

Expression profiles

Bgee: expression breadth ubiquitous, 259 present calls, max score 94.96.

FANTOM5 (CAGE): breadth broad, TPM avg 7.6662 / max 160.4107, expressed in 864 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201278	6.0403	856
201280	1.1457	512
201279	0.4802	230

Top tissues by expression

290 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	94.96	gold quality
rectum	UBERON:0001052	93.21	gold quality
right lung	UBERON:0002167	93.15	gold quality
metanephros cortex	UBERON:0010533	92.21	gold quality
blood vessel layer	UBERON:0004797	91.47	gold quality
prostate gland	UBERON:0002367	91.40	gold quality
upper leg skin	UBERON:0004262	90.95	gold quality
mucosa of transverse colon	UBERON:0004991	90.08	gold quality
urethra	UBERON:0000057	89.03	gold quality
trabecular bone tissue	UBERON:0002483	88.50	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	87.90	gold quality
tendon of biceps brachii	UBERON:0008188	87.24	gold quality
right testis	UBERON:0004534	86.79	gold quality
cauda epididymis	UBERON:0004360	86.63	gold quality
corpus callosum	UBERON:0002336	86.46	gold quality
left testis	UBERON:0004533	86.29	gold quality
seminal vesicle	UBERON:0000998	86.08	gold quality
testis	UBERON:0000473	86.01	gold quality
right adrenal gland	UBERON:0001233	85.66	gold quality
mucosa of urinary bladder	UBERON:0001259	85.53	gold quality
right adrenal gland cortex	UBERON:0035827	85.16	gold quality
upper lobe of left lung	UBERON:0008952	84.27	gold quality
vena cava	UBERON:0004087	84.16	gold quality
cardia of stomach	UBERON:0001162	83.92	gold quality
adenohypophysis	UBERON:0002196	83.76	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.65	gold quality
right hemisphere of cerebellum	UBERON:0014890	83.45	gold quality
caput epididymis	UBERON:0004358	83.40	gold quality
adrenal tissue	UBERON:0018303	83.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.16

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets.

Target	Regulation
ADAM2
BBX
BTK
CD74
COP1
ECE1
ERVW-4
KDM5D
LPIN1
MSBP1
RNU6-1
SERPINE1
TPM1

Upstream regulators (CollecTRI, top): BBX, KDM5D

miRNA regulators (miRDB)

44 targeting KDM5D, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-578	99.46	68.36	1787
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4738-3P	98.98	67.98	1846
HSA-MIR-3146	98.85	66.77	601
HSA-MIR-4451	98.82	68.17	1455
HSA-MIR-4646-3P	98.65	66.98	693

Literature-anchored findings (GeneRIF, showing 20)

• The presence of H-Y antibodies correlated with chronic graft-versus-host disease (PMID:15613541)
• HY-specific CD8+ T cells also could be detected directly in the peripheral blood of women with a history of at least two pregnancies that produced males. (PMID:16988213)
• Study shows that JARID1d and MBLR occupy human Engrailed 2 gene and regulate its expression and histone H3 lysine 4 methylation levels. (PMID:17320162)
• Results suggest that SMCY may have a male-specific function as a histone H3K4 demethylase by recruiting a meiosis-regulatory protein to condensed DNA. (PMID:18459961)
• HY-restricting HLA class II alleles is associated with pregnancy outcome in patients with recurrent miscarriage subsequent to firstborn boys. (PMID:19223392)
• compared with other recipient-donor gender combinations, female recipients of male donor kidney transplants in the United States have an increased short-term risk but not long-term risk for adverse outcomes (PMID:19541808)
• Of 820 proteins present in all four replicates of two treatments, the abundance of 209 proteins changed significantly in response to KDM5D suppression (PMID:26215926)
• The expression profiles of KDM5D isoforms were investigated in prostate cancer cell lines along with their gene regulatory network. (PMID:26728332)
• study identifies JARID1D as an anti-invasiveness histone methylation modifier that acts against prostate cancer cell metastasis by repressing metastatic gene programs; results also highlight a preclinical rationale for using JARID1D as a prognostic marker in advanced prostate cancer (PMID:26747897)
• Loss of KDM5D expression leads to docetaxel resistance in prostate cancer. (PMID:27185910)
• loss of the male-specific histone demethylase lysine-specific demethylase 5D (KDM5D) encoded on the Y chromosome epigenetically modifies histone methylation marks and alters gene expression, resulting in aggressive prostate cancer (PMID:29863497)
• KDM5D exhibited pronounced overexpression in blood vessels with cardiovascular disease. (PMID:30826357)
• KDM5D inhibit epithelial-mesenchymal transition of gastric cancer through demethylation in the promoter of Cul4A in male. (PMID:30864186)
• Down-Regulation of a Male-Specific H3K4 Demethylase, KDM5D, Impairs Cardiomyocyte Differentiation. (PMID:31560558)
• ETV4 promotes the progression of gastric cancer through regulating KDM5D. (PMID:32196595)
• X- and Y-Linked Chromatin-Modifying Genes as Regulators of Sex-Specific Cancer Incidence and Prognosis. (PMID:32732223)
• Increased Expression of Y-Encoded Demethylases During Differentiation of Human Male Neural Stem Cells. (PMID:33040644)
• Y disruption, autosomal hypomethylation and poor male lung cancer survival. (PMID:34127738)
• KDM5D inhibits the transcriptional activation of FKBP4 by suppressing the expression of E2F1 in colorectal cancer in males. (PMID:34688635)
• Histone demethylase KDM5D upregulation drives sex differences in colon cancer. (PMID:37344599)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdm4c	ENSDARG00000061504
mus_musculus	Kdm5d	ENSMUSG00000056673
rattus_norvegicus	Kdm5d	ENSRNOG00000060496
drosophila_melanogaster	Kdm5	FBGN0031759
caenorhabditis_elegans		WBGENE00004319

Paralogs (10): JARID2 (ENSG00000008083), KDM4A (ENSG00000066135), KDM5A (ENSG00000073614), KDM4C (ENSG00000107077), KDM5B (ENSG00000117139), KDM5C (ENSG00000126012), KDM4B (ENSG00000127663), KDM4D (ENSG00000186280), KDM4E (ENSG00000235268), KDM4F (ENSG00000255855)

Protein

Protein identifiers

Lysine-specific demethylase 5D — Q9BY66 (reviewed: Q9BY66)

Alternative names: Histocompatibility Y antigen, Histone demethylase JARID1D, Jumonji/ARID domain-containing protein 1D, Protein SmcY, [histone H3]-trimethyl-L-lysine(4) demethylase 5D

All UniProt accessions (5): Q9BY66, A0A384MR42, C9JGA3, E9PFH2, H7BZF9

UniProt curated annotations — full annotation on UniProt →

Function. Histone demethylase that specifically demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code. Does not demethylate histone H3 ‘Lys-9’, H3 ‘Lys-27’, H3 ‘Lys-36’, H3 ‘Lys-79’ or H4 ‘Lys-20’. Demethylates trimethylated and dimethylated but not monomethylated H3 ‘Lys-4’. May play a role in spermatogenesis. Involved in transcriptional repression of diverse metastasis-associated genes; in this function seems to cooperate with ZMYND8. Suppresses prostate cancer cell invasion. Regulates androgen receptor (AR) transcriptional activity by demethylating H3K4me3 active transcription marks.

Subunit / interactions. Interacts with PCGF6, MSH5, ZMYND8, AR.

Subcellular location. Nucleus.

Tissue specificity. Expression is highly down-regulated in metastatic prostate tumors.

Cofactor. Binds 1 Fe(2+) ion per subunit.

Domain organisation. The JmjC domain is required for enzymatic activity.

Miscellaneous. Involved in sensitivity to docetaxel.

Similarity. Belongs to the JARID1 histone demethylase family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q9BY66-1	1	yes
Q9BY66-2	2
Q9BY66-3	3

RefSeq proteins (3): NP_001140177, NP_001140178, NP_004644* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001606	ARID_dom	Domain
IPR001965	Znf_PHD	Domain
IPR003347	JmjC_dom	Domain
IPR003349	JmjN	Domain
IPR004198	Znf_C5HC2	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR013637	Lys_sp_deMease-like_dom	Domain
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR036431	ARID_dom_sf	Homologous_superfamily
IPR048615	KDM5_C-hel	Domain

Pfam: PF00628, PF01388, PF02373, PF02375, PF02928, PF08429, PF21323

Enzyme classification (BRENDA):

• EC 1.14.11.67 — [histone H3]-trimethyl-L-lysine4 demethylase (BRENDA: 13 organisms, 78 substrates, 122 inhibitors, 22 Km, 20 kcat entries)

Substrate kinetics (BRENDA)

17 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[ACETYLATED HISTONE H3 21MER]-N6,N6,N6-TRIMETHYL	0.0168–0.0955	2
[ACETYLATED HISTONE H3 21MER]-N6,N6-DIMETHYL-L-L	0.0547–0.229	2
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE4	0.0107–0.0128	2
[HISTONE H3 N-TERMINAL 13MER] N6,N6,N6-TRIMETHYL	0.489	1
[HISTONE H3 N-TERMINAL 18MER MUTANT K14A/R17A/K1	0.514	1
[HISTONE H3 N-TERMINAL 18MER MUTANT K14AC/K18AC]	0.249	1
[HISTONE H3 N-TERMINAL 18MER] N6,N6,N6-TRIMETHYL	0.0623	1
[HISTONE H3 N-TERMINAL 21MER MUTANT K9A] N6,N6,N	0.0219	1
[HISTONE H3 N-TERMINAL 21MER MUTANT Q5A] N6,N6,N	0.4152	1
[HISTONE H3 N-TERMINAL 21MER MUTANT R2A] N6,N6,N	0.1536	1
[HISTONE H3 N-TERMINAL 21MER MUTANT R8A] N6,N6,N	0.0551	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T3A] N6,N6,N	0.009	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6A] N6,N6,N	0.0965	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6S] N6,N6,N	0.0147	1
[HISTONE H3 N-TERMINAL 21MER MUTANT T6V] N6,N6,N	0.0394	1

Catalyzed reactions (Rhea), 1 shown:

• N(6),N(6),N(6)-trimethyl-L-lysyl(4)-[histone H3] + 3 2-oxoglutarate + 3 O2 = L-lysyl(4)-[histone H3] + 3 formaldehyde + 3 succinate + 3 CO2 (RHEA:60208)

UniProt features (50 total): helix 8, binding site 7, compositionally biased region 4, modified residue 4, cross-link 4, sequence conflict 4, domain 3, strand 3, zinc finger region 3, splice variant 2, mutagenesis site 2, turn 2, region of interest 2, chain 1, sequence variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2E6R	SOLUTION NMR
2YQE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BY66-F1	73.12	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (7): 430; 504; 506; 512; 514; 522; 592

Post-translational modifications (8): 291, 307, 884, 1346, 205, 229, 244, 272

Mutagenesis-validated functional residues (2):

Position	Phenotype
534	abolishes enzymatic activity; when associated with a-536.
536	abolishes enzymatic activity; when associated with a-534.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-3214842	HDMs demethylate histones
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-4839726	Chromatin organization

MSigDB gene sets: 135 (showing top): MCLACHLAN_DENTAL_CARIES_UP, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELLULAR_RESPONSE_TO_LIPID, MODULE_45, GOBP_REGULATION_OF_INTRACELLULAR_STEROID_HORMONE_RECEPTOR_SIGNALING_PATHWAY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, MODULE_503, GOBP_REGULATION_OF_ANDROGEN_RECEPTOR_SIGNALING_PATHWAY, GOBP_HORMONE_MEDIATED_SIGNALING_PATHWAY, GOBP_CELLULAR_RESPONSE_TO_HORMONE_STIMULUS, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, MODULE_157

GO Biological Process (5): T cell antigen processing and presentation (GO:0002457), chromatin remodeling (GO:0006338), regulation of DNA-templated transcription (GO:0006355), regulation of androgen receptor signaling pathway (GO:0060765), chromatin organization (GO:0006325)

GO Molecular Function (10): DNA binding (GO:0003677), zinc ion binding (GO:0008270), histone demethylase activity (GO:0032452), histone H3K4 demethylase activity (GO:0032453), histone H3K4me/H3K4me2/H3K4me3 demethylase activity (GO:0034647), nuclear androgen receptor binding (GO:0050681), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (4): chromatin (GO:0000785), fibrillar center (GO:0001650), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
T cell mediated immunity	1
antigen processing and presentation	1
chromatin organization	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
androgen receptor signaling pathway	1
regulation of intracellular steroid hormone receptor signaling pathway	1
cellular component organization	1
nucleic acid binding	1
transition metal ion binding	1
protein demethylase activity	1
histone modifying activity	1
histone H3 demethylase activity	1
2-oxoglutarate-dependent dioxygenase activity	1
histone H3K4 demethylase activity	1
nuclear receptor binding	1
binding	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
chromosome	1
nucleolus	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Protein interactions and networks

STRING

2641 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDM5D	UTY	O14607	983
KDM5D	DDX3Y	O15523	981
KDM5D	USP9Y	O00507	978
KDM5D	TMSB4Y	O14604	893
KDM5D	ZFY	P08048	864
KDM5D	EIF1AY	O14602	852
KDM5D	PCGF6	Q9BYE7	851
KDM5D	AR	P10275	840
KDM5D	RPS4Y1	P22090	784
KDM5D	KDM6A	O15550	764
KDM5D	DDX3X	O00571	761
KDM5D	SRY	Q05066	745
KDM5D	ZFX	P17010	714
KDM5D	USP9X	Q93008	670
KDM5D	NLGN4Y	Q8NFZ3	669

IntAct

8 interactions, top by confidence:

A	B	Type	Score
KDM5D		psi-mi:“MI:0871”(demethylation reaction)	0.440
PEX14	KDM5D	psi-mi:“MI:0407”(direct interaction)	0.440
KDM5D	AR	psi-mi:“MI:0915”(physical association)	0.400
SPG11	KDM5D	psi-mi:“MI:0915”(physical association)	0.370
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
DISC1	KDM5D	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (12): KMT2A (Negative Genetic), KDM5D (Proximity Label-MS), KDM5D (Affinity Capture-MS), KDM5D (Protein-peptide), KDM5D (Affinity Capture-MS), KDM5D (Affinity Capture-MS), KDM5D (Affinity Capture-MS), HIST3H3 (Biochemical Activity), PCGF6 (Affinity Capture-MS), PCGF6 (Affinity Capture-Western), HIST3H3 (Affinity Capture-Western), HIST3H3 (Phenotypic Enhancement)

ESM2 similar proteins: A0A0R4IB93, A1A5P5, A1Z7K9, A2XDG4, A3AF13, A3KMI0, A6QR55, B2GUZ1, D3ZJ96, F6V6I0, F6Z5C0, F8VPZ3, O22207, P29375, P35123, P51784, Q09879, Q13107, Q14149, Q2HJE4, Q30DN6, Q3UXZ9, Q3V0C5, Q5D006, Q5I043, Q5RCD3, Q5ZID5, Q5ZM45, Q62240, Q6NZP1, Q76LT8, Q80U87, Q80Y84, Q86UV5, Q8BWR4, Q8NFA0, Q8R5C8, Q8R5H1, Q93Y01, Q96RU2

Diamond homologs: A0A1W2PPD8, A1A5Q5, A1YVX4, B2RXH2, C0SUT9, F4I240, F4I6G4, F4KIX0, O64752, O75164, O94953, P29375, P39956, P41229, P41230, P47156, Q03833, Q10RP4, Q1LVC2, Q23541, Q30DN6, Q336N8, Q38JA7, Q3U2K5, Q3UXZ9, Q53WJ1, Q5F3R2, Q5N712, Q5RD88, Q5XUN4, Q61T02, Q62240, Q62315, Q6B0I6, Q6BDA0, Q6IQX0, Q80Y84, Q8BW72, Q8GUI6, Q8VCD7

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
KDM5D	“up-regulates activity”	H3C1	demethylation
KDM5D	“up-regulates activity”	H3-4	demethylation
KDM5D	“up-regulates activity”	H3-3A	demethylation
KDM5D	“up-regulates activity”	“Histone H3”	demethylation
2-oxoglutarate(2-)	“up-regulates activity”	KDM5D	“chemical activation”

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

43 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3946 predictions. Top by Δscore:

Variant	Effect	Δscore
Y:19706435:TCCTA:T	donor_loss	1.0000
Y:19706436:CCTA:C	donor_loss	1.0000
Y:19706437:CTAC:C	donor_loss	1.0000
Y:19706438:TA:T	donor_loss	1.0000
Y:19706442:T:TA	donor_gain	1.0000
Y:19706652:G:GC	acceptor_gain	1.0000
Y:19706655:G:GC	acceptor_gain	1.0000
Y:19706658:CGG:C	acceptor_gain	1.0000
Y:19706659:G:T	acceptor_gain	1.0000
Y:19706660:G:C	acceptor_gain	1.0000
Y:19706660:G:GC	acceptor_gain	1.0000
Y:19706667:G:GC	acceptor_gain	1.0000
Y:19706790:TTACC:T	donor_loss	1.0000
Y:19706791:T:TG	donor_loss	1.0000
Y:19706792:A:AC	donor_gain	1.0000
Y:19706793:C:CC	donor_gain	1.0000
Y:19706804:T:A	donor_gain	1.0000
Y:19706861:GACC:G	acceptor_loss	1.0000
Y:19706862:ACC:A	acceptor_loss	1.0000
Y:19706863:CCTA:C	acceptor_loss	1.0000
Y:19706864:C:CC	acceptor_gain	1.0000
Y:19706865:T:C	acceptor_loss	1.0000
Y:19706868:C:CT	acceptor_gain	1.0000
Y:19706869:G:T	acceptor_gain	1.0000
Y:19707142:CTCA:C	donor_loss	1.0000
Y:19707143:TCAC:T	donor_loss	1.0000
Y:19707144:CA:C	donor_loss	1.0000
Y:19707146:C:CA	donor_loss	1.0000
Y:19707751:C:CT	acceptor_gain	1.0000
Y:19707757:C:CT	acceptor_gain	1.0000

AlphaMissense

10078 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
Y:19715878:A:G	C720R	1.000
Y:19716414:G:C	F632L	1.000
Y:19716414:G:T	F632L	1.000
Y:19716416:A:G	F632L	1.000
Y:19716598:A:G	W612R	1.000
Y:19716598:A:T	W612R	1.000
Y:19716614:G:C	N606K	1.000
Y:19716614:G:T	N606K	1.000
Y:19716632:A:C	N600K	1.000
Y:19716632:A:T	N600K	1.000
Y:19716644:G:C	N596K	1.000
Y:19716644:G:T	N596K	1.000
Y:19716658:G:C	H592D	1.000
Y:19716714:A:T	V573D	1.000
Y:19721016:C:A	W524C	1.000
Y:19721016:C:G	W524C	1.000
Y:19721018:A:G	W524R	1.000
Y:19721018:A:T	W524R	1.000
Y:19721022:C:A	K522N	1.000
Y:19721022:C:G	K522N	1.000
Y:19721141:G:C	N514K	1.000
Y:19721141:G:T	N514K	1.000
Y:19721153:A:C	S510R	1.000
Y:19721153:A:T	S510R	1.000
Y:19721155:T:G	S510R	1.000
Y:19721158:A:G	W509R	1.000
Y:19721158:A:T	W509R	1.000
Y:19721163:T:A	D507V	1.000
Y:19721163:T:G	D507A	1.000
Y:19721164:C:G	D507H	1.000

dbSNP variants (sampled 300 via entrez): RS1000461704 (Y:19726565 A>T), RS1000731402 (Y:19721411 A>G), RS1000803276 (Y:19719743 G>A), RS1001170563 (Y:19744711 C>A), RS1001277147 (Y:19741654 T>C), RS1001643165 (Y:19743050 G>A), RS1002400980 (Y:19714421 T>A), RS1002474535 (Y:19712887 G>A), RS1002794198 (Y:19705786 G>A,C,T), RS1002902294 (Y:19736441 C>T), RS1003204109 (Y:19730543 T>C), RS1003249367 (Y:19737849 A>T), RS1003400461 (Y:19724220 G>T), RS1003644629 (Y:19729359 A>G), RS1004511140 (Y:19730342 G>A)

Disease associations

OMIM: gene MIM:426000 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

4 total (4 of 4 shown, HPO-id order):

HPO	Term
HP:0000027	Azoospermia
HP:0001450	Y-linked inheritance
HP:0003251	Male infertility
HP:0011462	Young adult onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010733_5	Autism	2.000000e-08

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5169191 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 1.14.11.- Histone demethylases

Binding affinities (BindingDB)

3 measured of 17 human assays (17 total across all organisms); most potent 3 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4’-(phenethylcarbamoyl)-[2,2’-bipyridine]-4-carboxylic acid (N3)	IC50	61 nM
2-[5-[(4-chloro-2-methylphenyl)methoxy]pyrazol-1-yl]pyridine-4-carboxylic acid	IC50	550 nM	US-9908865: Histone demethylase inhibitors
3-((1-methyl-1Hpyrrolo[2,3-b]pyridin-3-yl)amino)isonicotinic acid (N12)	IC50	550 nM	US-10336727: Histone demethylase inhibitors

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.57	IC50	27	nM	CHEMBL4078388
6.25	IC50	558	nM	CHEMBL4078388
5.70	IC50	2000	nM	CHEMBL4454253

PubChem BioAssay actives

16 with measured affinity, of 24 total; 12 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	1801992: Demethylase AlphaScreen Assay from Article 10.1038/nchembio.2087: “Structural analysis of human KDM5B guides histone demethylase inhibitor development.”	ic50	0.0150	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxamide	1885335: Inhibition of KDM5D (unknown origin) in presence of 4 uM 2-OG	ic50	0.0270	uM
2-(1-benzylpyrazol-4-yl)oxy-2,3,4a,5,6,7,8,8a-octahydro-1H-pyrido[3,4-d]pyrimidin-4-one	1801992: Demethylase AlphaScreen Assay from Article 10.1038/nchembio.2087: “Structural analysis of human KDM5B guides histone demethylase inhibitor development.”	ic50	0.0770	uM
ethyl 2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylate	1802660: AlphaScreen Assay from Article 10.1016/j.chembiol.2017.02.006: “Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.”	ic50	0.1000	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]-N-ethylpyridine-4-carboxamide	1802660: AlphaScreen Assay from Article 10.1016/j.chembiol.2017.02.006: “Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.”	ic50	0.2000	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]-N,N-dimethylpyridine-4-carboxamide	1802660: AlphaScreen Assay from Article 10.1016/j.chembiol.2017.02.006: “Potent and Selective KDM5 Inhibitor Stops Cellular Demethylation of H3K4me3 at Transcription Start Sites and Proliferation of MM1S Myeloma Cells.”	ic50	1.0000	uM
3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoic acid	1801992: Demethylase AlphaScreen Assay from Article 10.1038/nchembio.2087: “Structural analysis of human KDM5B guides histone demethylase inhibitor development.”	ic50	1.5000	uM
7-oxo-5-phenyl-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1934032: Inhibition of KDM5D (unknown origin ) by HTMS assay	ic50	2.0000	uM
pyridine-2,4-dicarboxylic acid	1801992: Demethylase AlphaScreen Assay from Article 10.1038/nchembio.2087: “Structural analysis of human KDM5B guides histone demethylase inhibitor development.”	ic50	2.5000	uM
3-[[1-[2-(4,4-difluoropiperidin-1-yl)ethyl]-5-fluoroindazol-3-yl]amino]pyridine-4-carboxylic acid	1801869: Formaldehyde Dehydrogenase-Coupled Demethylase (FDH) Assay from Article 10.1016/j.chembiol.2016.06.006: “Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.”	ic50	2.7000	uM
2-(carboxymethylamino)-2-oxoacetic acid	1801992: Demethylase AlphaScreen Assay from Article 10.1038/nchembio.2087: “Structural analysis of human KDM5B guides histone demethylase inhibitor development.”	ic50	5.8000	uM
5-methyl-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1801869: Formaldehyde Dehydrogenase-Coupled Demethylase (FDH) Assay from Article 10.1016/j.chembiol.2016.06.006: “Structural Basis for KDM5A Histone Lysine Demethylase Inhibition by Diverse Compounds.”	ic50	6.0000	uM

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	increases expression	1
tobacco tar	decreases expression	1
potassium chromate(VI)	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
abrine	increases expression	1
incobotulinumtoxinA	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acrolein	increases abundance, affects cotreatment, increases oxidation	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Vehicle Emissions	affects expression, increases abundance	1
Benzo(a)pyrene	affects methylation	1
Doxorubicin	decreases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	increases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	decreases expression	1
Vanadates	increases expression	1
Particulate Matter	affects expression, increases abundance	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5141210	Binding	Inhibition of KDM5D (unknown origin) in presence of 4 uM 2-OG	Recent Advances with KDM4 Inhibitors and Potential Applications. — J Med Chem

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.