KDM5C

Summary

KDM5C (lysine demethylase 5C, HGNC:11114) is a protein-coding gene on chromosome Xp11.22, encoding Lysine-specific demethylase 5C (P41229). Histone demethylase that specifically demethylates ‘Lys-4’ of histone H3, thereby playing a central role in histone code. It is haploinsufficient (ClinGen: sufficient evidence).

This gene is a member of the SMCY homolog family and encodes a protein with one ARID domain, one JmjC domain, one JmjN domain and two PHD-type zinc fingers. The DNA-binding motifs suggest this protein is involved in the regulation of transcription and chromatin remodeling. Mutations in this gene have been associated with X-linked cognitive disability. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8242 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 1,259 total — 105 pathogenic, 94 likely-pathogenic (top 2% of genes corpus-wide)
• Regional missense constraint (gnomAD): 5 of 14 regions constrained (≈26% of expected missense variation)
• GTEx eGene: eQTL in 22 tissues, sQTL in 1 (q < 0.05)
• Phenotypes (HPO): 68
• ChEMBL bioactivity: 1 clinical-phase molecule tested; no curated mechanism-of-action drug
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 7 cancer types (inferred from mutation patterns)
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• Transcription factor: yes — 13 downstream targets (CollecTRI)
• MANE Select transcript: NM_004187
• Interaction hub: 2,274 STRING partners (top 5% of genes corpus-wide)

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11114
Approved symbol	KDM5C
Name	lysine demethylase 5C
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	DXS1272E, XE169
Ensembl gene	ENSG00000126012
Ensembl biotype	protein_coding
OMIM	314690
Entrez	8242

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 22 protein_coding, 7 retained_intron, 6 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

MANE Select: ENST00000375401

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 1, TSL 3: 7, TSL 4: 1, TSL 5: 4

ENST00000375401, ENST00000349663, ENST00000375379, ENST00000375383, ENST00000404049, ENST00000428012, ENST00000429877, ENST00000452825, ENST00000465402, ENST00000467093, ENST00000477109, ENST00000481369, ENST00000495519, ENST00000497100, ENST00000497995, ENST00000685423, ENST00000685539, ENST00000685641, ENST00000687695, ENST00000687928, ENST00000688699, ENST00000691505, ENST00000693277, ENST00000861450, ENST00000861451, ENST00000861452, ENST00000861453, ENST00000861454, ENST00000935430, ENST00000935431, ENST00000977947, ENST00001025839, ENST00001025840, ENST00001025842, ENST00001082872, ENST00001082874, ENST00001082879, ENST00001132591

RefSeq mRNA: 8 — MANE Select: NM_004187 NM_001146702, NM_001282622, NM_001353978, NM_001353979, NM_001353981, NM_001353982, NM_001353984, NM_004187

CCDS: CCDS14351, CCDS55417, CCDS65269, CCDS87747, CCDS94610, CCDS94611

Canonical transcript exons

ENST00000375401 — 26 exons

Exon	Start	End
ENSE00000000310	53224740	53225207
ENSE00000860394	53215795	53215976
ENSE00000860395	53214689	53214847
ENSE00000860397	53211497	53211655
ENSE00000860404	53198490	53198637
ENSE00000860405	53197771	53197876
ENSE00000860406	53196686	53197044
ENSE00000860410	53194139	53194738
ENSE00000860411	53193773	53193851
ENSE00001466943	53192158	53193332
ENSE00001605274	53194931	53195068
ENSE00001614347	53198764	53198888
ENSE00001636291	53217143	53217277
ENSE00001667228	53195231	53195410
ENSE00001690780	53195916	53196054
ENSE00001691478	53217796	53217966
ENSE00001764157	53193437	53193636
ENSE00001774049	53211787	53211906
ENSE00003467496	53218276	53218398
ENSE00003509543	53210414	53210576
ENSE00003537132	53201550	53201744
ENSE00003568454	53201854	53201973
ENSE00003598899	53216074	53216197
ENSE00003634992	53198977	53199158
ENSE00003648103	53220839	53220916
ENSE00003671874	53210676	53210857

Expression profiles

Bgee: expression breadth ubiquitous, 279 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.4394 / max 169.7409, expressed in 1816 samples.

Highest expression (Bgee): sural nerve, stromal cell of endometrium, uterine tube, body of uterus, lower esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

KDM5C is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 22 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 23 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	eqtl	9.9e-32	-0.27	X:53227398:A:G
Muscle Skeletal	eqtl	4.7e-21	+0.25	X:53207753:A:G
Nerve Tibial	eqtl	9.6e-07	+0.14	X:53198161:A:G
Thyroid	eqtl	1.3e-06	+0.14	X:53192077:T:TG
Brain Cerebellum	eqtl	2.0e-05	+0.21	X:53198966:C:A
Brain Cerebellar Hemisphere	eqtl	2.9e-05	+0.18	X:53198966:C:A
Pituitary	eqtl	3.5e-05	+0.22	X:53196569:A:G
Esophagus Mucosa	eqtl	4.8e-05	+0.10	X:53192077:T:TG
Pancreas	eqtl	5.1e-05	+0.19	X:53227029:C:T
Brain Cortex	eqtl	5.3e-05	+0.20	X:53192077:T:TG
Esophagus Gastroesophageal Junction	eqtl	6.4e-05	+0.15	X:53166906:G:A
Heart Left Ventricle	eqtl	4.7e-03	+0.13	X:53144541:C:A
Colon Sigmoid	eqtl	5.6e-03	-0.40	X:53231664:A:G
Spleen	eqtl	1.2e-02	-0.26	X:53186135:T:C
Stomach	eqtl	1.5e-02	+0.15	X:53158488:T:C
Brain Putamen basal ganglia	eqtl	1.5e-02	-0.08	X:53870562:A:G
Minor Salivary Gland	eqtl	1.6e-02	+0.11	X:53757206:T:A
Liver	eqtl	1.7e-02	-0.21	X:53141420:A:G
Cells Cultured fibroblasts	eqtl	2.3e-02	+0.08	X:53192077:T:TG
Esophagus Muscularis	eqtl	2.9e-02	+0.09	X:53264405:T:C

FANTOM5 promoters

1 alternative TSS:

Promoter ID	TPM avg	Samples expressed
199323	33.4394	1816

Top tissues by expression

showing 100 of 292 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
sural nerve	UBERON:0015488	97.91	gold quality
stromal cell of endometrium	CL:0002255	95.85	gold quality
right uterine tube	UBERON:0001302	95.65	gold quality
body of uterus	UBERON:0009853	95.23	gold quality
lower esophagus mucosa	UBERON:0035834	95.22	gold quality
left ovary	UBERON:0002119	95.05	gold quality
granulocyte	CL:0000094	95.03	gold quality
right ovary	UBERON:0002118	94.84	gold quality
ectocervix	UBERON:0012249	94.80	gold quality
skin of leg	UBERON:0001511	94.60	gold quality
skin of abdomen	UBERON:0001416	94.39	gold quality
endometrium epithelium	UBERON:0004811	94.14	gold quality
endocervix	UBERON:0000458	94.02	gold quality
left uterine tube	UBERON:0001303	93.91	gold quality
mucosa of stomach	UBERON:0001199	93.88	gold quality
smooth muscle tissue	UBERON:0001135	93.82	gold quality
lymph node	UBERON:0000029	93.58	gold quality
gastrocnemius	UBERON:0001388	93.53	gold quality
vagina	UBERON:0000996	93.52	gold quality
cortical plate	UBERON:0005343	93.46	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.34	gold quality
minor salivary gland	UBERON:0001830	93.32	gold quality
cerebellar hemisphere	UBERON:0002245	93.26	gold quality
cerebellar cortex	UBERON:0002129	93.22	gold quality
tongue squamous epithelium	UBERON:0006919	93.20	silver quality
right lobe of thyroid gland	UBERON:0001119	93.17	gold quality
muscle of leg	UBERON:0001383	93.14	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.11	gold quality
olfactory bulb	UBERON:0002264	93.08	silver quality
left lobe of thyroid gland	UBERON:0001120	93.02	gold quality
esophagus mucosa	UBERON:0002469	92.97	gold quality
body of stomach	UBERON:0001161	92.96	gold quality
left adrenal gland	UBERON:0001234	92.94	gold quality
adenohypophysis	UBERON:0002196	92.89	gold quality
left adrenal gland cortex	UBERON:0035825	92.88	gold quality
ganglionic eminence	UBERON:0004023	92.67	gold quality
body of pancreas	UBERON:0001150	92.66	gold quality
esophagus	UBERON:0001043	92.64	gold quality
adrenal gland	UBERON:0002369	92.62	gold quality
right adrenal gland cortex	UBERON:0035827	92.58	gold quality
ovary	UBERON:0000992	92.55	gold quality
saliva-secreting gland	UBERON:0001044	92.52	gold quality
ventricular zone	UBERON:0003053	92.51	gold quality
thyroid gland	UBERON:0002046	92.50	gold quality
adrenal tissue	UBERON:0018303	92.48	gold quality
stomach	UBERON:0000945	92.47	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	92.47	gold quality
pituitary gland	UBERON:0000007	92.45	gold quality
transverse colon	UBERON:0001157	92.43	gold quality
islet of Langerhans	UBERON:0000006	92.37	gold quality
lower esophagus	UBERON:0013473	92.36	gold quality
adrenal cortex	UBERON:0001235	92.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.35	gold quality
muscle layer of sigmoid colon	UBERON:0035805	92.34	gold quality
cerebellum	UBERON:0002037	92.31	gold quality
descending thoracic aorta	UBERON:0002345	92.30	gold quality
monocyte	CL:0000576	92.29	gold quality
upper lobe of left lung	UBERON:0008952	92.29	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.19	gold quality
right adrenal gland	UBERON:0001233	92.18	gold quality
paraflocculus	UBERON:0005351	92.15	gold quality
uterine cervix	UBERON:0000002	92.05	gold quality
mouth mucosa	UBERON:0003729	91.99	gold quality
diaphragm	UBERON:0001103	91.97	gold quality
leukocyte	CL:0000738	91.96	gold quality
mononuclear cell	CL:0000842	91.94	gold quality
small intestine	UBERON:0002108	91.92	gold quality
tibial nerve	UBERON:0001323	91.80	gold quality
ascending aorta	UBERON:0001496	91.80	gold quality
tibial artery	UBERON:0007610	91.77	gold quality
popliteal artery	UBERON:0002250	91.76	gold quality
pancreas	UBERON:0001264	91.75	gold quality
thoracic aorta	UBERON:0001515	91.75	gold quality
zone of skin	UBERON:0000014	91.71	gold quality
tonsil	UBERON:0002372	91.71	gold quality
hindlimb stylopod muscle	UBERON:0004252	91.71	gold quality
aorta	UBERON:0000947	91.70	gold quality
spleen	UBERON:0002106	91.70	gold quality
metanephros cortex	UBERON:0010533	91.60	gold quality
apex of heart	UBERON:0002098	91.59	gold quality
right lung	UBERON:0002167	91.58	gold quality
vermiform appendix	UBERON:0001154	91.53	gold quality
gall bladder	UBERON:0002110	91.47	gold quality
upper lobe of lung	UBERON:0008948	91.38	gold quality
caecum	UBERON:0001153	91.31	gold quality
left coronary artery	UBERON:0001626	91.29	gold quality
right coronary artery	UBERON:0001625	91.17	gold quality
type B pancreatic cell	CL:0000169	90.98	gold quality
coronary artery	UBERON:0001621	90.98	gold quality
bone marrow cell	CL:0002092	90.88	gold quality
omental fat pad	UBERON:0010414	90.86	gold quality
peritoneum	UBERON:0002358	90.84	gold quality
rectum	UBERON:0001052	90.69	gold quality
fundus of stomach	UBERON:0001160	90.53	gold quality
colonic epithelium	UBERON:0000397	90.40	gold quality
muscle organ	UBERON:0001630	90.35	gold quality
intestine	UBERON:0000160	90.31	gold quality
right atrium auricular region	UBERON:0006631	90.26	gold quality
fallopian tube	UBERON:0003889	90.25	gold quality
colon	UBERON:0001155	90.05	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.97
E-MTAB-6058	no	108.74

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 61 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	45.7
Cerebral cortex	tissue	44.8
Choroid plexus	tissue	44.2
Thalamus	tissue	43.4
Hypothalamus	tissue	41.9
Medulla oblongata	tissue	41.7
Retrosplenial cortex	tissue	41.5
Occipital cortex	tissue	41.3
Postcentral gyrus	tissue	40.6
Thymus	tissue	40.5
Amygdala	tissue	40.0
Midbrain	tissue	40.0
Basal ganglia	tissue	39.5
Hippocampal formation	tissue	39.5
Pons	tissue	39.3
Putamen	tissue	37.3
Hippocampus	tissue	36.4
Nucleus accumbens	tissue	36.3
Locus coeruleus	tissue	35.9
Substantia nigra	tissue	35.6
Spinal cord	tissue	35.1
Skeletal muscle	tissue	32.2
Parathyroid gland	tissue	31.9
Bone marrow	tissue	31.5
Skin 1	tissue	31.4
Vagina	tissue	30.6
Lymph node	tissue	30.4
Pituitary gland	tissue	27.8
Salivary gland	tissue	27.5
Appendix	tissue	26.4
Pancreas	tissue	25.9
Spleen	tissue	25.9
Ovary	tissue	25.6
Endometrium 1	tissue	25.5
Tonsil	tissue	25.3
Smooth muscle	tissue	24.8
Fallopian tube	tissue	24.7
Tongue	tissue	24.2
Duodenum	tissue	24.2
Adrenal gland	tissue	24.1
Cervix	tissue	23.4
Placenta	tissue	22.8
Retina	tissue	22.6
Esophagus	tissue	21.8
Thyroid gland	tissue	20.9
Adipose tissue	tissue	20.7
Stomach 1	tissue	20.6
Urinary bladder	tissue	19.6
Small intestine	tissue	19.1
Colon	tissue	18.7
Lung	tissue	18.6
Seminal vesicle	tissue	17.6
Breast	tissue	17.4
Prostate	tissue	17.1
Gallbladder	tissue	16.5
Heart muscle	tissue	15.9
Rectum	tissue	14.8
Epididymis	tissue	13.8
Kidney	tissue	13.7
Liver	tissue	13.3

Brain sub-regions (HPA Brain Atlas): detected in 185; highest nTPM — Flocculonodular lobe (45.7), Temporo-occipital transitional zone (44.8), Cerebellar cortex (44.5), Vermis (44.3), Area parastriata, superior (43.9).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

13 targets:

Target	Regulation
BDNF	Repression
EHMT2
EP400
FGFR1
HTT
KDM5C
KRT9
MBD2
ME3
PTEN	Repression
RRP8
SCN2A	Repression
SYN1	Repression

Upstream regulators (CollecTRI, top): ARX, BRD4, EPAS1, HIF1A, KDM5C, MBD2, PHF8, ZNF711

miRNA regulators (miRDB)

Targeting KDM5C by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 125 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-10395-5P	99.86	67.35	676
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6785-5P	99.82	68.68	4428

Functional genomics

Regional missense constraint (gnomAD)

ENST00000375401 splits into 14 regions with different missense tolerance; 5 are missense-constrained (≈26% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
X:53,192,970–53,193,463	115 / 120.9	0.95	no
X:53,193,464–53,193,528	3 / 16.4	0.18	yes (p 9.4e-04)
X:53,193,529–53,194,276	88 / 85.6	1.03	no
X:53,194,277–53,194,454	12 / 54.5	0.22	yes (p 8.5e-09)
X:53,194,455–53,194,671	48 / 59.7	0.80	no
X:53,194,672–53,196,773	66 / 162.9	0.41	no
X:53,196,774–53,198,839	123 / 169.0	0.73	no
X:53,198,840–53,201,668	42 / 98.9	0.42	no
X:53,201,669–53,211,841	41 / 205.9	0.20	yes (p 1.4e-30)
X:53,211,842–53,216,095	71 / 115.0	0.62	no
X:53,216,096–53,216,171	0 / 18.7	0.00	yes (p 1.6e-05)
X:53,216,172–53,218,349	55 / 118.0	0.47	no
X:53,218,350–53,224,763	2 / 38.4	0.05	yes (p 4.2e-09)
X:53,224,764–53,224,889	15 / 37.0	0.41	no
ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• JARID1C may have a role in X-Linked Mental Retardation (PMID:16538222)
• JARID1C appears to be one of the more frequently mutated genes in X-linked mental retardation. (PMID:16541399)
• We show that the X-linked mental retardation gene SMCX, which encodes a JmjC-domain protein, reversed histone H3 lysine 4 to di- and mono- but not unmethylated products. (PMID:17320160)
• has H3K4 tri-demethylase activity; functions as transcriptional repressor; loss of JARID1C/SMCX activity impairs REST-mediated neuronal gene regulation, thereby contributing to SMCX-associated X-linked mental retardation (PMID:17468742)
• Thus, SMCX is a novel Smad3 corepressor that may antagonize the tumor suppressing activity of the TGF-beta/Smad3 signaling pathway and thereby contribute to tumorigenesis. (PMID:18078810)
• male patients with mental retardation, short stature and hyperreflexia should be considered candidates for mutations in the JARID1C gene. (PMID:18697827)
• human NOT4 can polyubiquitinate human JARID1C/SMCX, a homolog of Jhd2, suggesting that this is likely a conserved mechanism (PMID:19346402)
• The two novel changes impair JARID1C protein function and are disease-causing mutations in the families reported. (PMID:19826449)
• identification of inactivating mutations in two genes–SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C, a histone H3 lysine 4 demethylase–as well as mutations in the histone H3 lysine 27 demethylase, UTX in clear cell renal cell carcinoma (PMID:20054297)
• the JmjN domain of Jhd2 is important for its protein stability, and the plant homeodomain (PHD) finger mediates its chromatin association independent of H3K4 methylation (PMID:20538609)
• we describe clinical and genetic findings of a Brazilian family co-segregating a novel nonsense mutation (c.2172C>A) in exon 15 of KDM5C gene (PMID:21575681)
• Data show that von Hippel-Lindau (VHL) inactivation decreases H3K4Me3 levels through JARID1C, which alters gene expression and suppresses tumor growth. (PMID:21725364)
• Herein we present a large family with X Linked Intellectual Disability caused by a novel mutation c.2T > C in the start codon of the KDM5C gene (PMID:22326837)
• The KDM5C mutation carriers had higher mean scores on the abstract/visual and quantitative sections of the Stanford-Binet Intelligence Scale: Fourth Edition and lower mean short term memory scores. (PMID:22611640)
• We established that ARX polyA alterations damage the regulation of KDM5C expression. (PMID:23246292)
• DNA methylation at these three genes in blood correlated with dosage of KDM5C. (PMID:23356856)
• Mutation frequencies among CT images of clear cell RCCs were as follows: KDM5C, 6.9% (16 of 233). (PMID:24029645)
• Results indicate a KDM5C pathogenic mutational frequency of 0.7% among males with probable X-linked intellectual disability (XLID). (PMID:24583395)
• KDM5C is functionally involved in proliferation control of prostate cancer cells (PMID:25016185)
• These findings suggest that E2 recruits histone-modifying cellular proteins to the HPV LCR, resulting in transcriptional repression of E6 and E7. (PMID:25222147)
• Mutations in KDM5C gene in patients are described and their effect on gene expression, stability and catalytic activity is examined. Patient fibroblasts do not show global changes in histone methylation but several up-regulated genes were identified. (PMID:25666439)
• Data indicate the role for histone demethylase KDM5C/JARID1C in a specific phase of DNA replication in mammalian cells, through its demethylase activity on histone H3K4me3. (PMID:25712104)
• the extent of the duplicated regions in each case encompassing a minimum of three known disease genes TSPYL2, KDM5C and IQSEC2, is reported. (PMID:26059843)
• BRMS1 expression in human breast cancer is negatively correlated with JARID1C expression. Our results, for the first time, portray a pivotal role of JARID1C in regulating metastatic behaviors of breast cancer cells (PMID:26182878)
• Expression of KDM5C in hepatocellular carcinoma tumor cells promoted cell migration and tumor invasion. (PMID:26503415)
• these data suggest that inactivation of JARID1C in renal cancer leads to heterochromatin disruption, genomic rearrangement, and aggressive ccRCCs. (PMID:26551685)
• study of non-synonymous mutations in the KDM5C ARID domain and evaluates effects of 2 syndromic Claes-Jensen-type disease-associated missense mutations (A77T and D87G) and 3 non-classified missense mutations (R108W, N142S, and R179H); analysis indicates, among the non-classified mutations, R108W is possibly a disease-associated mutation, and N142S and R179H are probably harmless (PMID:26580603)
• KDM5C is overexpressed in breast cancer cells and miR-138 regulates its expression. (PMID:26621457)
• Characterization of a Linked Jumonji Domain of the KDM5/JARID1 Family of Histone H3 Lysine 4 Demethylases. (PMID:26645689)
• The two mutations are present on the same maternal haplotype, suggesting that a postzygotic somatic mutation or a reversion error occurred at an early embryonic stage in the mother, leading to switched KDM5C mutations in the affected siblings. (PMID:26919706)
• Findings reveal a RACK7/KDM5C-regulated, dynamic interchange between histone H3K4me1 and H3K4me3 at active enhancers, representing an additional layer of regulation of enhancer activity. Authors propose that RACK7/KDM5C functions as an enhancer “brake” to ensure appropriate enhancer activity, which, when compromised, could contribute to tumorigenesis. (PMID:27058665)
• Results suggest that KDM5C mutations predispose to X-linked intellectual disability which accounts for 1-4% of cases in male patient. (PMID:27211531)
• The predicted structure of KDM5C was used to investigate the effects of disease-causing mutations, and it was shown that the mutations alter domain stability and inter-domain interactions. (PMID:27696497)
• Mutation in KDM5C gene is associated with cancer more frequently in males. (PMID:27869828)
• In vitro models indicated that KDM5C suppressed miR-320a transcription by directly binding to the promoter of miR-320a to prevent histone methylation. KITLG, an essential gene for ovarian development and primordial germ cell survival, was a direct target of miR-320a and that it was downregulated in 45,X fetal gonadal tissues. (PMID:27896428)
• SETD2 and KDM5C mutations were associated with prolonged overall survival in patients with metastatic clear cell renal cell carcinoma (PMID:28408295)
• HPV16 E6 protein interacts with histone demethylase KDM5C in ovarian cancer.HPV16 E6 protein destabilizes the KDM5C.KDM5C regulates cervical cancer cell EGFR and c-MET expression by modulating their super-enhancer H3K4 methylation dynamics. (PMID:29339538)
• In colon cancer cells, KDM5c might downregulate ABCC1 expression by demethylating the ABCC1 H3K4me3 in the TSS region, which can promote multidrug resistance (PMID:30257334)
• The BRD4-KDM5C-PTEN may be a new oncogenic pathway in CRPC development. (PMID:30921702)
• This article reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of IDH1/2, JARID1C/KDM5C and UTX/KDM6A. [review] (PMID:31221981)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	kdm4c	ENSDARG00000061504
drosophila_melanogaster	Kdm5	FBGN0031759
caenorhabditis_elegans		WBGENE00004319

Paralogs (10): JARID2 (ENSG00000008083), KDM5D (ENSG00000012817), KDM4A (ENSG00000066135), KDM5A (ENSG00000073614), KDM4C (ENSG00000107077), KDM5B (ENSG00000117139), KDM4B (ENSG00000127663), KDM4D (ENSG00000186280), KDM4E (ENSG00000235268), KDM4F (ENSG00000255855)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:99781) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 20 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal heart morphology	1
abnormal coat/ hair morphology	1
decreased body weight	1
decreased body size	1
increased aggression towards mice	1
abnormal social investigation	1
decreased anxiety-related response	1
abnormal developmental patterning	1
decreased mean corpuscular volume	1
increased circulating testosterone level	1
impaired contextual conditioning behavior	1
impaired cued conditioning behavior	1
abnormal dendritic spine morphology	1
abnormal impulsive behavior control	1
preweaning lethality, complete penetrance	1
abnormal eye anterior chamber depth	1
impaired spatial learning	1
abnormal pyramidal neuron dendrite morphology	1
decreased dendritic spine density	1
abnormal dendritic mushroom spine morphology	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Mus musculus	P58269	100.0%	Diamond
Pongo abelii	Q5RD88	99.3%	Diamond
Pan troglodytes	Q5XUN4	98.8%	Diamond
Canis lupus familiaris	Q38JA7	97.6%	Diamond
Rattus norvegicus	P56163	97.0%	Diamond
Sus scrofa	A1YVX4	95.2%	Diamond
Cricetulus griseus	P41228	93.9%	Diamond
Gallus gallus	P58268	93.3%	Diamond
Bos taurus	Q2T9V9	92.9%	Diamond
Xenopus laevis	Q9W638	89.9%	Diamond
Arabidopsis thaliana	Q9SU24	87.9%	Diamond
Xenopus tropicalis	Q5XGD9	87.3%	Diamond
Ciona intestinalis	Q4H3P5	81.5%	Diamond
Caenorhabditis briggsae	Q61T02	73.3%	Diamond
Ricinus communis	B9RU15	69.6%	Diamond
Oryza sativa Japonica Group	Q5SMU7	64.0%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
MIR6894	ncRNA	102466759
IQSEC2	protein-coding	23096
MIR6895	ncRNA	102465539
KANTR	protein-coding	102723508
GPR173	protein-coding	54328
TSPYL2	protein-coding	64061

Protein

Protein identifiers

Lysine-specific demethylase 5C — P41229 (reviewed: P41229)

Alternative names: Histone demethylase JARID1C, Jumonji/ARID domain-containing protein 1C, Protein SmcX, Protein Xe169, [histone H3]-trimethyl-L-lysine(4) demethylase 5C

All UniProt accessions (10): A0A6M4C8G8, A0A8I5KPH7, A0A8I5KQR8, A0A8I5KTT1, A0A8I5KXH7, A0A8I5KYW1, A0A8I5QL21, F8WDK1, F8WF56, P41229

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’. Participates in transcriptional repression of neuronal genes by recruiting histone deacetylases and REST at neuron-restrictive silencer elements. Represses the CLOCK-BMAL1 heterodimer-mediated transcriptional activation of the core clock component PER2.

Subunit / interactions. Part of two distinct complexes, one containing E2F6, and the other containing REST. Interacts with ZMYND8.

Subcellular location. Nucleus.

Tissue specificity. Expressed in all tissues examined. Highest levels found in brain and skeletal muscle.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Claes-Jensen type (MRXSCJ) [MIM:300534] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSCJ patients manifest intellectual disability associated with variable features such as slowly progressive spastic paraplegia, seizures, facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The inhibitor KDOAM-25 and others inhibit its demethylase activity, resulting to cell cycle arrest in myeloma cells.

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

Domain organisation. The first PHD-type zinc finger domain recognizes and binds H3-K9Me3. Both the JmjC domain and the JmjN domain are required for enzymatic activity.

Miscellaneous. Escapes X-inactivation.

Similarity. Belongs to the JARID1 histone demethylase family.

Isoforms (5)

UniProt ID	Names	Canonical?
P41229-1	1	yes
P41229-2	2
P41229-3	3
P41229-4	4
P41229-5	5

RefSeq proteins (8): NP_001140174, NP_001269551, NP_001340907, NP_001340908, NP_001340910, NP_001340911, NP_001340913, NP_004178* (*=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)

• 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 (109 total): helix 30, strand 11, sequence variant 11, turn 8, compositionally biased region 7, binding site 7, modified residue 6, cross-link 6, splice variant 5, sequence conflict 5, region of interest 4, domain 3, zinc finger region 3, mutagenesis site 2, chain 1

Structure

Experimental structures (PDB)

2 structures by resolution:

PDB	Title	Method	Resolution (Å)
5FWJ	Crystal structure of human JARID1C in complex with KDM5-C49	X-RAY DIFFRACTION	2.1
2JRZ	Solution structure of the Bright/ARID domain from the human JARID1C protein.	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P41229-F1	72.50	0.25

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Oxidoreductases, Predicted intracellular proteins, Plasma proteins, Transcription factors, Helix-turn-helix domains, Cancer-related genes, Mutated cancer genes, Mutational cancer driver genes, Disease related genes, Potential drug targets, Human disease related genes, Mental and behavioural disorders

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IF supported

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)

Position	Role
440	2-oxoglutarate
514	Fe cation
516	Fe cation
522	2-oxoglutarate
524	2-oxoglutarate
532	2-oxoglutarate
602	Fe cation

Post-translational modifications (12)

Type	Positions
Phosphoserine	287, 301, 317, 893, 897, 1359
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	205, 229, 244, 274, 295, 1127

Mutagenesis-validated functional residues (2)

Position	Phenotype
514–516	abolishes lysine-specific histone demethylase activity.
514	abolishes lysine-specific histone demethylase activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

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

MSigDB gene sets: 368 (showing top): TGGTGCT_MIR29A_MIR29B_MIR29C, GGTGTGT_MIR329, TGCGCANK_UNKNOWN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, MODULE_45, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, MODULE_16, MODULE_308, NKX62_Q2, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, TGCTGAY_UNKNOWN, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN, MODULE_123, TGANTCA_AP1_C, RYTTCCTG_ETS2_B

GO Biological Process (7): chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), regulation of DNA-templated transcription (GO:0006355), negative regulation of DNA-templated transcription (GO:0045892), rhythmic process (GO:0048511), chromatin organization (GO:0006325), methylation (GO:0032259)

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), protein binding (GO:0005515), methyltransferase activity (GO:0008168), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (3): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Chromatin modifying enzymes	1
Chromatin organization	1

GO top-level categories

27 GO namespaces:

Category	Terms
DNA-templated transcription	2
cellular anatomical structure	2
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
biological_process	1
cellular component organization	1
metabolic process	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
binding	1
transferase activity, transferring one-carbon groups	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 4 of 20 annotations. The rest are phylogenetic / computational / electronic (IEA).

4 experimentally-supported GO terms:

GO term	NS	Evidence
nucleoplasm	CC	direct assay
nucleus	CC	direct assay
histone H3K4 demethylase activity	MF	direct assay
zinc ion binding	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 2,274 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KDM5C	KDM6A	O15550	871
KDM5C	ARID1A	O14497	861
KDM5C	SETD2	Q9BYW2	844
KDM5C	PBRM1	Q86U86	769
KDM5C	UTY	O14607	743
KDM5C	IQSEC2	Q5JU85	729
KDM5C	EHMT2	Q96KQ7	722
KDM5C	USP9Y	O00507	712
KDM5C	H3-3A	P06351	710
KDM5C	H3C14	Q71DI3	710
KDM5C	H3-5	Q6NXT2	710
KDM5C	H3C1	P02295	710
KDM5C	H3-4	Q16695	710
KDM5C	H3-7	Q5TEC6	710
KDM5C	ARID5A	Q03989	695

IntAct

Human interaction partners of KDM5C in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

23 partners by confidence:

Partner	Interaction type	MIscore	Records
E2F6	association	0.600	1
REST	physical association	0.560	1
SNAPC4	association	0.530	1
TRIM28	association	0.530	1
E2	physical association	0.500	1
PEX14	direct interaction	0.440	1
HLA-F	association	0.350	2
CSNK2A1	association	0.350	1
LHX6	association	0.350	1
NCOR1	association	0.350	1
NEBL	association	0.350	1
SCML4	association	0.350	1
SPAG6	association	0.350	1
UBB	association	0.350	1
FBXW7	proximity	0.270	4
SMAD4	proximity	0.270	4
SMARCA4	proximity	0.270	4
SPOP	proximity	0.270	4
AKT1	proximity	0.270	1
BRAF	proximity	0.270	1
EGFR	proximity	0.270	1
PTEN	proximity	0.270	1
TP53	proximity	0.270	1

BioGRID (177 interactions; top human partners by supporting records): TRIM11 (Affinity Capture-Western; 4 records), ARHGAP25 (Affinity Capture-MS; 3 records), HIST2H3A (Reconstituted Complex; 3 records), HLA-F (Affinity Capture-MS; 3 records), IER2 (Affinity Capture-MS; 3 records), LHX6 (Affinity Capture-MS; 3 records), SCML4 (Affinity Capture-MS; 3 records), BRD4 (Negative Genetic; 2 records), CUL3 (Affinity Capture-MS; 2 records), DEF8 (Affinity Capture-MS; 2 records), E2F6 (Affinity Capture-MS; 2 records), KIAA1683 (Affinity Capture-MS; 2 records), MAX (Affinity Capture-MS; 2 records), OLFM2 (Affinity Capture-MS; 2 records), PBRM1 (Affinity Capture-Western; 2 records)

SIGNOR signaling

13 signaling interactions:

A	Effect	B	Mechanism
KDM5C	“up-regulates activity”	H3C1	demethylation
KDM5C	“up-regulates activity”	H3-4	demethylation
BRD4	“up-regulates quantity by expression”	KDM5C	“transcriptional regulation”
KDM5C	“down-regulates quantity by repression”	PTEN	“transcriptional regulation”
KDM5C	“up-regulates activity”	“Histone H3”	demethylation
CNOT4	“down-regulates quantity by destabilization”	KDM5C	ubiquitination
HIF1A	“up-regulates quantity by expression”	KDM5C	“transcriptional regulation”
RNF4	“up-regulates activity”	KDM5C	sumoylation
EPAS1	“up-regulates quantity by expression”	KDM5C	“transcriptional regulation”
KDM5C	“down-regulates quantity by repression”	SCN2A	“transcriptional regulation”
KDM5C	“down-regulates quantity by repression”	SYN1	“transcriptional regulation”
KDM5C	“down-regulates quantity by repression”	BDNF	“transcriptional regulation”
2-oxoglutarate(2-)	“up-regulates activity”	KDM5C	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 23 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of gene expression	5	8.8×	1e-02

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 7 cancer types — CCRCC, HNSC, LUAD, OVT, PAAD, PCM, RCC.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for KDM5C: 1,259 ClinVar records (199 pathogenic / likely pathogenic); 1 GWAS association. Per-variant detail is on Sugi Variant.

ClinVar

1,259 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	105
Likely pathogenic	94
Uncertain significance	435
Likely benign	290
Benign	68

Top pathogenic / likely-pathogenic (15)

Showing the 15 best-reviewed of 199 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
374324	NM_004187.5(KDM5C):c.1439C>T (p.Pro480Leu)	Pathogenic	criteria provided, multiple submitters, no conflicts	7
431128	NM_004187.5(KDM5C):c.2482C>T (p.Arg828Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
817677	NM_004187.5(KDM5C):c.3392_3393del (p.Glu1131fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	6
489301	NM_004187.5(KDM5C):c.3058C>T (p.Gln1020Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
1685906	NM_004187.5(KDM5C):c.994C>T (p.Arg332Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	3
397527	NM_004187.5(KDM5C):c.769_770del (p.Leu257fs)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
520414	NM_004187.5(KDM5C):c.595C>T (p.Gln199Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
523819	NM_004187.5(KDM5C):c.2332C>T (p.Arg778Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
986020	NM_004187.5(KDM5C):c.2575C>T (p.Gln859Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1455486	NM_004187.5(KDM5C):c.2908C>T (p.Gln970Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1710735	NM_004187.5(KDM5C):c.202C>T (p.Arg68Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
1992549	NM_004187.5(KDM5C):c.1762C>T (p.Gln588Ter)	Pathogenic	criteria provided, multiple submitters, no conflicts	2
29997	NM_004187.5(KDM5C):c.1660C>A (p.Pro554Thr)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
1699148	NM_004187.5(KDM5C):c.2248C>T (p.Arg750Trp)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	3
372737	NM_004187.5(KDM5C):c.2092G>A (p.Glu698Lys)	Likely pathogenic	criteria provided, multiple submitters, no conflicts	2

Per-variant reference — Sugi Variant

Explore KDM5C’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 32 predictions of 1,986):

Position(s)	Effect	Δscore	Sites
X:53193435–53193436	donor_loss	1.0000	4
X:53193644–53193645	acceptor_gain	1.0000	2
X:53193649	acceptor_gain	1.0000
X:53193780–53193781	donor_loss	1.0000	5
X:53193852–53193853	acceptor_loss	1.0000	6
X:53194749	acceptor_gain	1.0000
X:53195069–53195070	acceptor_loss	1.0000	6
X:53195076	acceptor_gain	1.0000
X:53195229–53195230	donor_loss	1.0000	5
X:53195419	acceptor_gain	1.0000

AlphaMissense

5,089 missense substitutions predicted likely pathogenic (of 10,118 scored), across 1,068 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M497	9	0.989	1.000
M506	9	0.984	0.999
M310	9	0.956	0.998
M549	9	0.955	0.999
M245	9	0.946	0.997
M651	9	0.945	0.999
M308	9	0.944	0.998
M400	9	0.940	0.996
M670	9	0.893	0.999
M759	9	0.893	0.996
M411	9	0.835	0.959
H350	8	0.999	1.000
F385	8	0.999	1.000
H514	8	0.999	1.000
D517	8	0.999	1.000
H518	8	0.999	1.000
H602	8	0.999	1.000
D402	8	0.998	1.000
D443	8	0.998	1.000
D702	8	0.998	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

1 prognostic cancer types:

Cancer	Prognostic	p-value
Liver Hepatocellular Carcinoma (TCGA)	unfavorable	3.09e-05

Disease associations

OMIM: gene MIM:314690 | disease phenotypes: MIM:300534, MIM:147920, MIM:254500

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
syndromic X-linked intellectual disability Claes-Jensen type	Definitive	X-linked	5

ClinGen Gene-Disease Validity

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

1 validity classifications:

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (10 panels, 8 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

10 panels:

Panel	Rating
DDG2P	green
Fetal anomalies	green
Hereditary spastic paraplegia	green
Hereditary spastic paraplegia, childhood onset	green
Hypotonic infant	green
Intellectual disability	green
Leukodystrophy, childhood onset	green
Paediatric disorders	green
Adult-onset neurological disorders	amber
Hereditary spastic paraplegia, adult onset	amber

Mondo (4): syndromic X-linked intellectual disability Claes-Jensen type (MONDO:0010355), intellectual disability (MONDO:0001071), Kabuki syndrome (MONDO:0016512), plasma cell myeloma (MONDO:0009693)

Orphanet (6): KDM5C-related syndromic X-linked intellectual disability (Orphanet:85279), Kabuki syndrome (Orphanet:2322), Multiple myeloma (Orphanet:29073), AL amyloidosis (Orphanet:85443), Rare genetic intellectual disability (Orphanet:183757), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

showing 60 of 68 phenotypes (HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000221	Furrowed tongue
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000297	Facial hypotonia
HP:0000303	Mandibular prognathia
HP:0000319	Smooth philtrum
HP:0000327	Hypoplasia of the maxilla
HP:0000347	Micrognathia
HP:0000350	Small forehead
HP:0000400	Macrotia
HP:0000411	Protruding ear
HP:0000426	Prominent nasal bridge
HP:0000486	Strabismus
HP:0000490	Deeply set eye
HP:0000540	Hypermetropia
HP:0000545	Myopia
HP:0000574	Thick eyebrow
HP:0000582	Upslanted palpebral fissure
HP:0000699	Diastema
HP:0000711	Restlessness
HP:0000717	Autism
HP:0000718	Aggressive behavior
HP:0000744	Low frustration tolerance
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000767	Pectus excavatum
HP:0001081	Cholelithiasis
HP:0001156	Brachydactyly
HP:0001176	Large hands
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001347	Hyperreflexia
HP:0001371	Flexion contracture
HP:0001419	X-linked recessive inheritance
HP:0001508	Failure to thrive
HP:0001762	Talipes equinovarus
HP:0001773	Short foot
HP:0002205	Recurrent respiratory infections
HP:0002232	Patchy alopecia
HP:0002362	Shuffling gait
HP:0002395	Lower limb hyperreflexia
HP:0002788	Recurrent upper respiratory tract infections
HP:0002967	Cubitus valgus
HP:0003487	Babinski sign
HP:0004279	Short palm
HP:0004322	Short stature
HP:0004325	Decreased body weight
HP:0006895	Lower limb hypertonia
HP:0007020	Progressive spastic paraplegia
HP:0007021	Pain insensitivity
HP:0007565	Multiple cafe-au-lait spots
HP:0008124	Talipes calcaneovarus

GWAS associations

1 associations:

Study	Trait	p-value
GCST90002394_16	Monocyte percentage of white cells	4e-9

EFO canonical traits (from GWAS)

1 canonical traits:

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors

4 disease descriptors:

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009101	Multiple Myeloma	C04.557.595.500; C14.907.454.460; C15.378.147.780.650; C15.378.463.515.460; C20.683.515.845; C20.683.780.650
C537705	Kabuki syndrome *(supp.)*
C564494	Mental Retardation, X-Linked, Syndromic, Jarid1c-Related *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2163176 (SINGLE PROTEIN), CHEMBL6066033 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

Phase ≥1, by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 7,750 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

1 molecules by phase:

Molecule	Name	Phase	Patents
CHEMBL70927	DEFERIPRONE	4	7,750

PharmGKB: 1 entry (CPIC guideline: no)

GtoPdb / IUPHAR curated pharmacology

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

Target class: enzyme — Histone demethylases

Most potent curated ligand interactions (4 total), top 4:

Ligand	Action	Affinity	Parameter
IOX2	Inhibition	6.8	pIC50
GSK-J1	Inhibition	6.26	pIC50
PBIT	Inhibition	5.31	pIC50
GSK-J4	Inhibition	4.82	pIC50

Binding affinities (BindingDB)

156 measured of 198 human assays (201 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
[(3R)-3-[6-methyl-4-(1-methylpyrazol-4-yl)-2-pyridinyl]pyrrolidin-1-yl]-(5-propan-2-yl-1H-pyrazol-3-yl)methanone	IC50	0.84 nM	US-10022354: Pyrrolidine amide compounds as histone demethylase inhibitors
CHEMBL4303308	IC50	1.7 nM
GSKJ1	IC50	2.8 nM
CHEMBL3183531	IC50	4.2 nM
CHEMBL5199483	IC50	8.8 nM
CHEMBL5277258	IC50	10 nM
CHEMBL5273040	IC50	24 nM
CHEMBL5277129	IC50	30 nM
CHEMBL5285505	IC50	50 nM
CHEMBL4440395	IC50	59 nM
CHEMBL3621881	IC50	63 nM
CHEMBL4438034	IC50	68 nM
CHEMBL4466130	IC50	77 nM
CHEMBL5206280	IC50	79 nM
CHEMBL4558689	IC50	88 nM
8-(1-methyl-1Himidazol-4-yl)-2-(4,4,4-trifluorobutoxy)pyrido[3,4-d]pyrimidin-4-ol (N10)	IC50	100 nM
CHEMBL3775237	IC50	100 nM
CHEMBL3775889	IC50	100 nM
CHEMBL4590283	IC50	103 nM
CHEMBL3774665	IC50	109 nM
CHEMBL3775121	IC50	110 nM
4’-(phenethylcarbamoyl)-[2,2’-bipyridine]-4-carboxylic acid (N3)	IC50	110 nM
CHEMBL3775814	IC50	118 nM
CHEMBL3775545	IC50	123 nM
CHEMBL3621878	IC50	126 nM
CHEMBL3775548	IC50	128 nM
CHEMBL4559561	IC50	131 nM
CHEMBL3775451	IC50	136 nM
CHEMBL4561958	IC50	136 nM
CHEMBL3774456	IC50	138 nM
CHEMBL4520178	IC50	141 nM
CHEMBL4435185	IC50	143 nM
CHEMBL3774940	IC50	144 nM
CHEMBL3775277	IC50	145 nM
CHEMBL3775040	IC50	147 nM
CHEMBL3775516	IC50	158 nM
CHEMBL3775953	IC50	175 nM
CHEMBL4476629	IC50	178 nM
CHEMBL3774392	IC50	181 nM
CHEMBL4464471	IC50	184 nM
CHEMBL4522584	IC50	188 nM
CHEMBL1440422	IC50	190 nM
CHEMBL4538741	IC50	212 nM
CHEMBL4572027	IC50	218 nM
CHEMBL4553540	IC50	246 nM
CHEMBL4549505	IC50	259 nM
CHEMBL4473678	IC50	282 nM
CHEMBL1982368	IC50	290 nM
CHEMBL3775362	IC50	300 nM
CHEMBL3775145	IC50	390 nM

ChEMBL bioactivities

170 potent at pChembl≥5 of 192 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.23	IC50	5.84	nM	CHEMBL4536443
8.21	IC50	6.24	nM	CHEMBL4542928
8.06	IC50	8.8	nM	CHEMBL5199483
8.00	IC50	9.92	nM	CHEMBL3787669
7.92	IC50	12	nM	CHEMBL3774692
7.87	IC50	13.6	nM	CHEMBL5569973
7.85	IC50	14	nM	CHEMBL4438830
7.85	IC50	14	nM	CHEMBL4454253
7.68	IC50	21	nM	CHEMBL3775040
7.68	IC50	21	nM	CHEMBL3775451
7.66	IC50	22	nM	CHEMBL3775516
7.64	IC50	23	nM	CHEMBL3775899
7.64	IC50	23	nM	CHEMBL3774940
7.62	IC50	24	nM	CHEMBL3775814
7.61	IC50	24.8	nM	CHEMBL4782583
7.60	IC50	25	nM	CHEMBL5287732
7.57	IC50	27	nM	CHEMBL4078388
7.52	IC50	30	nM	CHEMBL3108956
7.52	IC50	30	nM	CHEMBL3775362
7.52	IC50	30	nM	CHEMBL4592908
7.50	IC50	32	nM	CHEMBL3774665
7.47	IC50	34	nM	CHEMBL3775545
7.46	IC50	35	nM	CHEMBL4440395
7.42	IC50	38	nM	CHEMBL4516101
7.39	IC50	41	nM	CHEMBL3774392
7.39	IC50	41	nM	CHEMBL3775465
7.34	IC50	46	nM	CHEMBL3775668
7.32	IC50	48	nM	CHEMBL4585876
7.30	IC50	50	nM	CHEMBL3775956
7.30	IC50	50	nM	CHEMBL3775277
7.29	IC50	51	nM	CHEMBL3775894
7.28	IC50	52	nM	CHEMBL3775953
7.28	IC50	53	nM	CHEMBL4466130
7.27	IC50	54	nM	CHEMBL3775121
7.27	IC50	54	nM	CHEMBL4558689
7.26	IC50	55	nM	CHEMBL4088737
7.24	IC50	57	nM	CHEMBL3775130
7.23	IC50	59	nM	CHEMBL4567766
7.23	IC50	59	nM	CHEMBL3787669
7.22	IC50	60	nM	CHEMBL3775095
7.20	IC50	63.1	nM	CHEMBL3771180
7.20	IC50	63	nM	CHEMBL4520178
7.19	IC50	64	nM	CHEMBL3774922
7.19	IC50	65	nM	CHEMBL3774537
7.19	IC50	65	nM	CHEMBL4088737
7.18	IC50	65.5	nM	CHEMBL3785583
7.17	IC50	67	nM	CHEMBL3775977
7.16	IC50	70	nM	CHEMBL3775548
7.16	IC50	69	nM	CHEMBL4078388
7.12	IC50	76	nM	CHEMBL3775135

PubChem BioAssay actives

205 with measured affinity, of 282 total; 50 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
5-[4-[[hexyl(methyl)amino]methyl]phenyl]-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1624962: Inhibition of full-length human N-terminal FLAG/His-tagged KDM5C (2 to 1560 residues) expressed in baculovirus infected Sf9 insect cells using H3(1-21)K4(Me3)-GGK(Biotin)/2-OG as substrate measured after 1 hr by Alphalisa assay	ic50	0.0058	uM
5-[4-[2-[hexyl(methyl)amino]ethyl]phenyl]-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1624962: Inhibition of full-length human N-terminal FLAG/His-tagged KDM5C (2 to 1560 residues) expressed in baculovirus infected Sf9 insect cells using H3(1-21)K4(Me3)-GGK(Biotin)/2-OG as substrate measured after 1 hr by Alphalisa assay	ic50	0.0062	uM
2-[1-[2-[hexyl(methyl)amino]ethyl]triazol-4-yl]pyridine-4-carboxylic acid	1872462: Inhibition of N-terminal FLAG/His-tagged full-length human KDM5C (2 to 1560 residues) expressed in baculovirus infected Sf9 insect cells using peptide substrate incubated for 2 hrs by Alpha Screen assay	ic50	0.0088	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106950: Inhibition of KDM5C (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0099	uM
2-(2-amino-1,3-thiazol-4-yl)pyridine-4-carboxylic acid	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0120	uM
2-[[[2-[2-[butyl(methyl)amino]ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxylic acid	2106950: Inhibition of KDM5C (unknown origin) incubated for 2 hrs by Alphascreen assay	ic50	0.0136	uM
8-[4-[2-[4-[3-[2-(dimethylamino)ethyl]phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0140	uM
7-oxo-5-phenyl-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1627990: Inhibition of KDM5C (unknown origin) using ART(Kme3)QTARKSTGGKAPRKQLA-NovaTagPEG-biotin/2-OG as substrate/co-factor by TR-FRET assay	ic50	0.0140	uM
8-[4-[2-[4-(1,3-benzodioxol-5-ylmethyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0210	uM
8-[4-[2-[4-[(4-fluorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0210	uM
8-[4-[2-[4-[[4-(trifluoromethyl)phenyl]methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0220	uM
8-[4-[2-[4-[(4-chlorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0230	uM
8-[4-[2-[4-[(3,4-dichlorophenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0230	uM
4-[1-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]piperidin-4-yl]benzonitrile	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0240	uM
1-(4-methoxyphenyl)-N-(2-methyl-2-morpholin-4-ylpropyl)-3-phenylpyrazole-4-carboxamide	1690875: Inhibition of KDM5C (unknown origin)	ic50	0.0248	uM
[(3R)-3-[6-methyl-4-(1-methylpyrazol-4-yl)-2-pyridinyl]pyrrolidin-1-yl]-(5-propan-2-yl-1H-pyrazol-3-yl)methanone	1934024: Inhibition of KDM5C (unknown origin ) by Alphascreen assay	ic50	0.0250	uM
2-[[[2-[2-(dimethylamino)ethyl-ethylamino]-2-oxoethyl]amino]methyl]pyridine-4-carboxamide	1885333: Inhibition of KDM5C (unknown origin) in presence of 4 uM 2-OG	ic50	0.0270	uM
lithium 2-[(furan-2-ylmethylamino)methyl]pyridine-4-carboxylate	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0300	uM
8-[4-[2-[4-[3-(pyrrolidin-1-ylmethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0300	uM
2-(4-methoxycarbonyl-2-pyridinyl)pyridine-4-carboxylic acid	1066182: Inhibition of recombinant JARID1C (unknown origin) incubated for 15 mins prior to substrate addition by AlphaScreen method	ic50	0.0300	uM
8-[4-[2-[4-(4-methylsulfonylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0320	uM
8-[4-[2-[4-(4-methoxyphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0340	uM
8-[4-[2-[4-[3-(2-morpholin-4-ylethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0350	uM
8-[4-[2-[4-[3-(pyrrolidin-1-ylmethyl)-5-(trifluoromethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0380	uM
8-[4-[2-(4-benzylpiperidin-1-yl)ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0410	uM
8-[4-[2-[4-[(3-methoxyphenyl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0410	uM
8-[4-[2-(4-thiophen-2-ylpiperidin-1-yl)ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0460	uM
8-[4-[2-[4-[4-[2-(dimethylamino)ethyl]phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0480	uM
8-[4-[2-[4-(pyridin-3-ylmethyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0500	uM
8-[4-[2-(4-pyridin-4-ylpiperidin-1-yl)ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0500	uM
8-[4-[2-[4-(3,5-dichlorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0510	uM
8-[4-[2-[4-(4-fluorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0520	uM
8-[4-[2-[4-[4-(2-morpholin-4-ylethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0530	uM
8-[4-[2-[4-(2,4-difluorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0540	uM
8-[4-[2-[4-(3-pyrimidin-5-ylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0540	uM
N-[(3R)-1-(5-propan-2-yl-1H-pyrazole-3-carbonyl)pyrrolidin-3-yl]cyclopropanecarboxamide	1453522: Inhibition of recombinant human N-terminal FLAG-tagged KDM5C expressed in baculovirus infected Sf9 insect cells using H3K4me3 peptide as substrate after 30 to 45 mins by TR-FRET assay	ic50	0.0550	uM
8-[4-[2-[4-[(5-cyclopropyl-1,2,4-oxadiazol-3-yl)methyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0570	uM
8-[4-[2-[4-(3-pyridin-3-ylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0590	uM
lithium 2-[(benzylamino)methyl]pyridine-4-carboxylate	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0600	uM
8-[4-[2-[4-(3-tert-butylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0630	uM
2-(1-benzylpyrazol-4-yl)oxy-3H-pyrido[3,4-d]pyrimidin-4-one	1281025: Inhibition of KDM5C catalytic domain (1 -764 aa) (unknown origin) expressed in Sf9 cells using H3K4Me3 peptide as substrate by RFMS assay	ic50	0.0631	uM
4-[[methyl-[3-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]propyl]amino]methyl]benzonitrile	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0640	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	0.0650	uM
8-[4-[2-[4-(3-chlorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0650	uM
5-(1-tert-butylpyrazol-4-yl)-7-oxo-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1627221: Inhibition of KDM5C (unknown origin)	ic50	0.0655	uM
8-[4-[2-[4-(4-chlorophenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0670	uM
8-[4-[2-[4-[3-(trifluoromethyl)phenyl]piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0700	uM
4-[[methyl-[2-[1-(4-oxo-3H-pyrido[3,4-d]pyrimidin-8-yl)pyrazol-4-yl]ethyl]amino]methyl]benzonitrile	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0760	uM
8-[4-[2-[(4-fluorophenyl)methyl-methylamino]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1282545: Inhibition of KDM5C (unknown origin) using biotin-H3K4me3 as substrate preincubated for 15 mins followed by substrate addition measured after 20 mins by alphascreen assay	ic50	0.0780	uM
8-[4-[2-[4-(3-pyridin-2-ylphenyl)piperidin-1-yl]ethyl]pyrazol-1-yl]-3H-pyrido[3,4-d]pyrimidin-4-one	1556104: Inhibition of KDM5C (unknown origin) assessed as decrease in demethylation of substrate using peptide (H3(1-21)K4-Me3-GGKBiotin) as substrate and 2OG as cosubstrate pre-incubated for 15 mins before substrate addition followed by centrifugation for 15 secs and measured after 20 mins by Alphascreen assay	ic50	0.0790	uM

CTD chemical–gene interactions

36 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
FR900359	decreases phosphorylation	1
TAK-243	affects sumoylation	1
dicrotophos	increases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	decreases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
coumarin	decreases phosphorylation	1
fumonisin B1	increases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
(((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) methane-1-thione	decreases expression	1
abrine	increases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Bortezomib	decreases expression	1
Decitabine	increases expression	1
Sunitinib	increases expression	1
Fulvestrant	increases methylation, decreases methylation, affects cotreatment	1
Air Pollutants	affects expression, increases abundance	1
Ethanol	decreases expression	1
Arsenic	affects methylation	1
Caffeine	decreases phosphorylation	1
Catechin	affects cotreatment, decreases expression	1

ChEMBL screening assays

49 unique, capped per target: 49 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2167518	Binding	Inhibition of human KDM5C catalytic domain expressed in Sf9 cells using methyl lysine peptide substrate by AlphaScreen assay	Plant growth regulator daminozide is a selective inhibitor of human KDM2/7 histone demethylases. — *J Med Chem*

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 2 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2ZM	Abcam HEK293T KDM5C KO 1	Transformed cell line	Female
CVCL_B2ZN	Abcam HEK293T KDM5C KO 2	Transformed cell line	Female
CVCL_C6MY	USZ22-EMC2	Cancer cell line	Male
CVCL_SU45	HAP1 KDM5C (-) 1	Cancer cell line	Male
CVCL_SU46	HAP1 KDM5C (-) 2	Cancer cell line	Male
CVCL_SU47	HAP1 KDM5C (-) 3	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 299 trials:

NCT	Phase	Status	Title
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT05657860	Phase 4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	Phase 4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	Phase 4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	Phase 4	RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02559102	Phase 3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	Phase 3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	Phase 3	RECRUITING	Reducing Missed Appointments
NCT07377032	Phase 3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02270736	Phase 3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02909959	Phase 2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	Phase 2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT02304302	Phase 2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	Phase 2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	Phase 2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	Phase 2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00503191	Phase 1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	Phase 1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	Phase 1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT05273320	Phase 1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	Phase 1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	Phase 1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	Phase 1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	Phase 1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01783041	Phase 2/3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	Phase 2/3	COMPLETED	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	Early Phase 1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	COMPLETED	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice
NCT03381027	Not specified	COMPLETED	BABY SMART (Study of Massage Therapy, Sleep And neurodevelopMenT)
NCT03388294	Not specified	COMPLETED	Evaluation of a Novel Intervention for Infants At Risk for Neurodevelopmental Disorders
NCT03410810	Not specified	UNKNOWN	Childhood Outcomes of Preterm Brain Abnormalities
NCT03492060	Not specified	RECRUITING	Longitudinal Study of Neurogenetic Disorders
NCT03577756	Not specified	COMPLETED	Neurodevelopmental Assessment of Infants With Cystic Fibrosis
NCT03654248	Not specified	COMPLETED	Let’s Get Organized in Adult Psychiatric/habilitation Care

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for KDM5C across ~30M SureChEMBL compounds — explore on Sugi Predict.