PHF8

Summary

PHF8 (PHD finger protein 8, HGNC:20672) is a protein-coding gene on chromosome Xp11.22, encoding Histone lysine demethylase PHF8 (Q9UPP1). Histone lysine demethylase with selectivity for mono- and dimethylated residues. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a histone lysine demethylase that preferentially acts on histones in the monomethyl or dimethyl states. The encoded protein requires Fe(2+) ion, 2-oxoglutarate, and oxygen for its catalytic activity. The protein has an N-terminal PHD finger and a central Jumonji C domain. This gene is thought to function as a transcription activator. Defects in this gene are a cause of syndromic X-linked Siderius type intellectual disability (MRXSSD) and over-expression of this gene is associated with several forms of cancer. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 23133 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic X-linked intellectual disability Siderius type (Definitive, ClinGen)
• GWAS associations: 1
• Clinical variants (ClinVar): 377 total — 17 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015107

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20672
Approved symbol	PHF8
Name	PHD finger protein 8
Location	Xp11.22
Locus type	gene with protein product
Status	Approved
Aliases	ZNF422, KIAA1111, JHDM1F, KDM7B
Ensembl gene	ENSG00000172943
Ensembl biotype	protein_coding
OMIM	300560
Entrez	23133

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 18 protein_coding, 4 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000322659, ENST00000338154, ENST00000338946, ENST00000357988, ENST00000396282, ENST00000413386, ENST00000415025, ENST00000425862, ENST00000433120, ENST00000437224, ENST00000443302, ENST00000445025, ENST00000448003, ENST00000453905, ENST00000462182, ENST00000470103, ENST00000490635, ENST00000494928, ENST00000686349, ENST00000687283, ENST00000687764, ENST00000691629, ENST00000874043, ENST00000930622, ENST00000930623, ENST00000930624, ENST00000930625

RefSeq mRNA: 4 — MANE Select: NM_015107 NM_001184896, NM_001184897, NM_001184898, NM_015107

CCDS: CCDS14355, CCDS55419, CCDS55420

Canonical transcript exons

ENST00000338154 — 22 exons

Exon	Start	End
ENSE00001598508	54022758	54022843
ENSE00001603471	53962844	53962939
ENSE00001603472	54016595	54016736
ENSE00001625206	53985816	53985949
ENSE00001725156	54014377	54014563
ENSE00001729072	53995693	53995782
ENSE00001735686	53984914	53985227
ENSE00001758523	53940180	53940516
ENSE00001782598	53987766	53987944
ENSE00001786542	53944134	53944243
ENSE00001791619	54017661	54017821
ENSE00001794181	53993601	53993903
ENSE00001800747	53992736	53992839
ENSE00001803249	53987078	53987163
ENSE00001805788	53999870	53999961
ENSE00003512898	54002155	54002261
ENSE00003559737	54002595	54002682
ENSE00003577166	54011122	54011284
ENSE00003602569	54042631	54042820
ENSE00003786108	54022259	54022367
ENSE00003898718	54043762	54044473
ENSE00003898887	53936680	53939246

Expression profiles

Bgee: expression breadth ubiquitous, 251 present calls, max score 93.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.3915 / max 118.9985, expressed in 1789 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199382	4.2945	1549
199379	3.7202	1345
199376	2.2586	1202
199377	1.4949	900
199378	0.5543	335
199374	0.4833	186
199381	0.4238	203
199380	0.1525	70
199375	0.0092	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	93.33	gold quality
sural nerve	UBERON:0015488	92.89	gold quality
left testis	UBERON:0004533	92.65	gold quality
testis	UBERON:0000473	92.18	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.05	gold quality
tendon of biceps brachii	UBERON:0008188	90.42	silver quality
calcaneal tendon	UBERON:0003701	89.92	gold quality
colonic epithelium	UBERON:0000397	89.34	gold quality
tendon	UBERON:0000043	89.20	gold quality
right lobe of liver	UBERON:0001114	88.95	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.34	gold quality
right uterine tube	UBERON:0001302	88.30	gold quality
corpus epididymis	UBERON:0004359	87.66	gold quality
left ovary	UBERON:0002119	86.99	gold quality
secondary oocyte	CL:0000655	86.56	gold quality
ovary	UBERON:0000992	86.54	gold quality
granulocyte	CL:0000094	86.29	gold quality
body of pancreas	UBERON:0001150	85.75	gold quality
bone marrow cell	CL:0002092	85.72	gold quality
right ovary	UBERON:0002118	85.66	gold quality
tonsil	UBERON:0002372	85.08	gold quality
right lung	UBERON:0002167	84.50	gold quality
pancreas	UBERON:0001264	84.45	gold quality
blood	UBERON:0000178	84.42	gold quality
body of uterus	UBERON:0009853	84.39	gold quality
buccal mucosa cell	CL:0002336	84.24	gold quality
liver	UBERON:0002107	84.17	gold quality
endocervix	UBERON:0000458	84.09	gold quality
islet of Langerhans	UBERON:0000006	83.90	gold quality
choroid plexus epithelium	UBERON:0003911	83.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.57

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
CDC20	Unknown
KDM5C	Activation

Upstream regulators (CollecTRI, top): MBD2

miRNA regulators (miRDB)

139 targeting PHF8, 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-1277-5P	100.00	73.95	5056
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-6124	99.87	69.78	3551
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• an important function of PHF8 is in midline formation and in the development of cognitive abilities, and may have a role in X linked mental retardation associated with cleft lip/palate (PMID:16199551)
• A novel missense mutation c.836C>T of the PHF8 gene was identified in a Finnish family with multiple-affected male patients with X-linked mental retardation (PMID:17661819)
• deletion of the PHF8 gene is associated with the X-linked mental retardation Siderius-Hamel syndrome and the larger size of the Xp11.22 deletion including genes FAM120C and WNK3 may be involved in the pathogenesis of autism. (PMID:18498374)
• PHF8 is a histone lysine demethylase with di-/monomethyl state selectivity. Clinical PHF8 mutants disrupt PHF8 activity. Oxygen-dependence of PHF8 activity suggests link with increased incidence of cleft lip/palate from maternal hypoxia during gestation. (PMID:19843542)
• PHF8 is an Fe(II) and 2-oxoglutarate-dependent N(epsilon)-methyl lysine demethylase. (PMID:19843542)
• Results rationalize the lack of activity for the clinically observed F279S PHF8 variant and they will help to identify inhibitors selective for specific N(epsilon)-methyl lysine demethylase subfamilies. (PMID:20067792)
• Molecular mechanism underlying PHF8-associated developmental and neurological diseases. (PMID:20101266)
• PHF8 exerts a positive effect on rDNA transcription, with transcriptional activation requiring both the JmjC domain and the PHD finger. PHF8 demethylates H3K9me1/2, and its catalytic activity is stimulated by adjacent H3K4me3 (PMID:20208542)
• A functional link between the histone demethylase PHF8 and the transcription factor ZNF711 in X-linked mental retardation is reported. (PMID:20346720)
• Results show that PHF8 can act as a transcriptional coactivator and that its activation function largely depends on binding of the PHD to H3K4me3. (PMID:20421419)
• H3K9me2 level was elevated in the promoter region of the rDNA gene in PHF8 knockdown cells and reduced significantly when the wild type but not the catalytically inactive H247A mutant PHF8 was overexpressed. (PMID:20531378)
• PHF8 is a histone demethylase and coactivator for RARalpha and that the F279S mutation identified in an XLMR patient results in loss of its demethylase activity. (PMID:20548336)
• PHF8 demethylates H4K20me1 and H3K9me1 both in vitro and in vivo, and both H3K4me3-binding and catalytic functions of PHF8 are important for its ability to positively regulate gene expression (PMID:20622853)
• identification and characterization of an H4K20me1 demethylase, PHF8, has revealed an intimate link between this enzyme and two distinct events in cell cycle progression (PMID:20622854)
• a role of PHF8 in cell migration and invasion (PMID:22120715)
• Results show that PHF8 controls the expression of genes involved in cell adhesion and cytoskeleton organization such as RhoA, Rac1 and GSK3beta. (PMID:22850744)
• study identified the histone demethylase PHF8 as a coactivator that is specifically recruited by RAR-alpha fusions to activate expression of their downstream targets upon all-trans retinoic acid treatment in acute promyelocytic leukemia (PMID:23518351)
• PHF8 is regulated by APC(cdc20) and plays an important role in the G2/M transition. (PMID:23979597)
• knockdown of PHF8 led to a reduction in the number of migratory and invasive cells. Furthermore, downregulation of PHF8 attenuated the tumorigenicity of ESCC cells in vivo. (PMID:24146981)
• PHF8 promotes lung cancer cell growth and survival by regulating miR-21. (PMID:25065740)
• PHF2 is likely to repress rDNA transcription by competing with PHF8 for binding of ribosomal DNA promoter and by recruiting H3K9me2/3 methyltransferase SUV39H1. (PMID:25204660)
• PHF8 reduces the H3K9me2 level at the E2F4 transcriptional start site, demonstrating a direct function of PHF8 in endothelial E2F4 gene regulation (PMID:26751588)
• USP7 promotes breast carcinogenesis by stabilizing PHF8 and upregulating cyclin A2. and the interaction between USP7 and PHF8 is augmented during DNA damage. (PMID:27183383)
• Our data reveal novel mechanisms that underlie the regulation of PHF8 and KDM3A during NED and in CRPC, and support the candidacy of PHF8 as a therapeutic target in CRPC. (PMID:27689328)
• Knockdown or knockout of PHF8 by RNAi or CRISPR-Cas9 system reduced the activation of HIF1alpha. (PMID:28734980)
• the PHF8 oncogene is involved in the progression of CRC. The preliminary findings indicated that PHF8, as a potential target of miR-488, can be suppressed by the overexpression of miR-488. Low levels of miR-488 and high levels of PHF8 were correlated with poor overall survival rates in patients with CRC. (PMID:28765946)
• PIP2-binding mutant of PHF8 has increased the activity of rDNA promoter (20%) and expression of pre-rRNA genes (47S-100%; 45S-66%). (PMID:29246768)
• Thus, PHF8 forms a positive feedback loop with the MEK/ERK pathway, and PHF8 knockdown enhances the lethality of PD184352 in ALL cells. In conclusion, this study identifies oncogenic functions of PHF8 in adult ALL and suggests a novel epigenetic strategy for disease intervention. (PMID:29330049)
• These findings suggested that PHF8 played an oncogenic role in facilitating FIP200-dependent autophagic degradation of E-cadherin, EMT and metastasis in hepatocellular carcinoma (HCC). PHF8 might be a promising target for prevention, treatment and prognostic prediction of HCC. (PMID:30180906)
• PHF8 knockdown generates the immunosuppressive alternative splice product soluble HLA-G, which is secreted by endothelial cells to elicit a potential inhibitory effect on inflammation (PMID:30758047)
• these results demonstrated that PHF8 was a novel oncogene in hepatocellular carcinoma (PMID:30764899)
• Contribution of synergism between PHF8 and HER2 signalling to breast cancer development and drug resistance. (PMID:31923801)
• MicroRNA-383 inhibits proliferation, migration, and invasion in hepatocellular carcinoma cells by targeting PHF8. (PMID:32441881)
• Targeting the histone demethylase PHF8-mediated PKCalpha-Src-PTEN axis in HER2-negative gastric cancer. (PMID:32958674)
• Histone demethylase PHF8 drives neuroendocrine prostate cancer progression by epigenetically upregulating FOXA2. (PMID:33009820)
• CK2 kinase-mediated PHF8 phosphorylation controls TopBP1 stability to regulate DNA replication. (PMID:33010150)
• MYC Regulates PHF8, Which Promotes the Progression of Gastric Cancer by Suppressing miR-22-3p. (PMID:33111613)
• Histone demethylase PHF8 promotes cell growth and metastasis of non-small-cell lung cancer through activating Wnt/beta-catenin signaling pathway. (PMID:34100557)
• Analysis of a Set of KDM5C Regulatory Genes Mutated in Neurodevelopmental Disorders Identifies Temporal Coexpression Brain Signatures. (PMID:34356104)
• Disrupting PHF8-TOPBP1 connection elicits a breast tumor-specific vulnerability to chemotherapeutics. (PMID:35051531)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	phf8	ENSDARG00000006584
mus_musculus	Phf8	ENSMUSG00000041229
rattus_norvegicus	Phf8	ENSRNOG00000002708
rattus_norvegicus	Phf8l	ENSRNOG00000026582
caenorhabditis_elegans		WBGENE00005013
caenorhabditis_elegans		WBGENE00017920

Paralogs (4): KDM7A (ENSG00000006459), KDM2B (ENSG00000089094), KDM2A (ENSG00000173120), PHF2 (ENSG00000197724)

Protein

Protein identifiers

Histone lysine demethylase PHF8 — Q9UPP1 (reviewed: Q9UPP1)

Alternative names: Lysine demethylase 7B, PHD finger protein 8, [histone H3]-dimethyl-L-lysine(36) demethylase PHF8, [histone H3]-dimethyl-L-lysine(9) demethylase PHF8

All UniProt accessions (12): Q9UPP1, A0A8I5KT77, A0A8I5KVK1, A0A8J8YW94, B0QZE1, B0QZZ2, B0QZZ3, B0QZZ4, H0Y3N9, H0Y589, H0Y7M8, Q5JPR8

UniProt curated annotations — full annotation on UniProt →

Function. Histone lysine demethylase with selectivity for mono- and dimethylated residues. It plays an essential role in cell cycle progression and rDNA transcription. Demethylates mono- and dimethylated histone H3 ‘Lys-9’ residue (H3K9Me1 and H3K9Me2) and monomethylated histone H4 ‘Lys-20’ residue (H4K20Me1). Acts as a transcription activator as H3K9Me1, H3K9Me2, H3K27Me2 and H4K20Me1 are epigenetic repressive marks. Displays a very low intrinsic activity toward dimethylated H3 ‘Lys-27’ (H3K27Me2). May also have weak activity toward dimethylated H3 ‘Lys-36’ (H3K36Me2), however, the relevance of this result remains unsure in vivo. Involved in cell cycle progression by being required to control G1-S transition. Acts as a coactivator of rDNA transcription, by activating polymerase I (pol I) mediated transcription of rRNA genes. Specifically binds trimethylated ‘Lys-4’ of histone H3 (H3K4me3), affecting histone demethylase specificity: has weak activity toward H3K9Me2 in absence of H3K4me3, while it has high activity toward H3K9me2 when binding H3K4me3. Positively modulates transcription of histone demethylase KDM5C, acting synergistically with transcription factor ARX; synergy may be related to enrichment of histone H3K4me3 in regulatory elements. Required for brain development, probably by regulating expression of neuron-specific genes.

Subunit / interactions. Interacts with POLR1B, UBTF, SETD1A, HCFC1, E2F1 and ZNF711. Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression.

Subcellular location. Nucleus. Nucleolus.

Post-translational modifications. Phosphorylation at Ser-69 and Ser-120 are required for dissociation from chromatin and accumulation of H4K20Me1 levels during prophase.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Siderius type (MRXSSD) [MIM:300263] A syndrome characterized by mild to borderline intellectual disability with or without cleft lip/cleft palate. The disease is caused by variants affecting the gene represented in this entry.

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

Domain organisation. The PHD-type zinc finger mediates the binding to H3K4me3. Binding to H3K4me3 promotes its access to H3K9me2. The linker region is a critical determinant of demethylase specificity. It enables the active site of JmjC to reach the target H3K9me2 when the PHD-type zinc finger binds to H3K4me3.

Similarity. Belongs to the JHDM1 histone demethylase family. JHDM1D subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q9UPP1-1	1	yes
Q9UPP1-2	2
Q9UPP1-3	3
Q9UPP1-4	4
Q9UPP1-5	5

RefSeq proteins (4): NP_001171825, NP_001171826, NP_001171827, NP_055922* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001965	Znf_PHD	Domain
IPR003347	JmjC_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR019786	Zinc_finger_PHD-type_CS	Conserved_site
IPR019787	Znf_PHD-finger	Domain
IPR041070	JHD	Domain
IPR050690	JHDM1_Histone_Demethylase	Family

Pfam: PF00628, PF02373, PF17811

Enzyme classification (BRENDA):

• EC 1.14.11.65 — [histone H3]-dimethyl-L-lysine9 demethylase (BRENDA: 9 organisms, 67 substrates, 84 inhibitors, 4 Km, 4 kcat entries)
• EC 1.14.18.B1 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
[HISTONE H3]-N6,N6-DIMETHYL-L-LYSINE9	0.106–0.1061	2
[HISTONE H3]-N6-METHYL-L-LYSINE9	0.095–0.0952	2

Catalyzed reactions (Rhea), 4 shown:

• N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + 2 2-oxoglutarate + 2 O2 = L-lysyl(9)-[histone H3] + 2 formaldehyde + 2 succinate + 2 CO2 (RHEA:60188)
• N(6),N(6)-dimethyl-L-lysyl(9)-[histone H3] + 2-oxoglutarate + O2 = N(6)-methyl-L-lysyl(9)-[histone H3] + formaldehyde + succinate + CO2 (RHEA:60192)
• N(6)-methyl-L-lysyl(9)-[histone H3] + 2-oxoglutarate + O2 = L-lysyl(9)-[histone H3] + formaldehyde + succinate + CO2 (RHEA:60196)
• N(6)-methyl-L-lysyl(20)-[histone H4] + 2-oxoglutarate + O2 = L-lysyl(20)-[histone H4] + formaldehyde + succinate + CO2 (RHEA:67804)

UniProt features (95 total): helix 22, strand 15, modified residue 13, mutagenesis site 8, compositionally biased region 7, turn 7, region of interest 6, splice variant 6, binding site 5, sequence variant 2, chain 1, domain 1, zinc finger region 1, sequence conflict 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
7CMZ	X-RAY DIFFRACTION	1.7
3K3O	X-RAY DIFFRACTION	2.1
2WWU	X-RAY DIFFRACTION	2.15
3KV4	X-RAY DIFFRACTION	2.19
3K3N	X-RAY DIFFRACTION	2.4
4DO0	X-RAY DIFFRACTION	2.55

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPP1-F1	63.30	0.36

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 (5): 280; 283; 285; 300; 355

Post-translational modifications (13): 69, 120, 651, 704, 705, 706, 722, 804, 826, 834, 854, 857, 880

Mutagenesis-validated functional residues (8):

Position	Phenotype
43	abolishes binding to h3k4me3; when associated with a-50.
50	abolishes binding to h3k4me3; when associated with a-43. abolishes binding to h3k4me3; when associated with a-65.
65	abolishes binding to h3k4me3; when associated with a-50.
69	impairs phosphorylation by cdk1 and dissociation from chromatin when cells enter mitosis; when associated with a-120.
120	impairs phosphorylation by cdk1 and dissociation from chromatin when cells enter mitosis; when associated with a-69.
283–285	abolishes histone methyltransferase activity.
283	abolishes histone methyltransferase activity.
943	reduces transcriptional activation activity.

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3214842	HDMs demethylate histones
R-HSA-2299718	Condensation of Prophase Chromosomes

MSigDB gene sets: 305 (showing top): YAATNRNNNYNATT_UNKNOWN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, BROWNE_HCMV_INFECTION_24HR_UP, BACOLOD_RESISTANCE_TO_ALKYLATING_AGENTS_DN, GOBP_NUCLEUS_ORGANIZATION, GOBP_CELL_CYCLE_G1_S_PHASE_TRANSITION, GOBP_MITOTIC_CELL_CYCLE, CCCNNNNNNAAGWT_UNKNOWN, HFH1_01, GOBP_HEAD_DEVELOPMENT, ATF4_Q2, AACTTT_UNKNOWN

GO Biological Process (9): G1/S transition of mitotic cell cycle (GO:0000082), chromatin remodeling (GO:0006338), regulation of transcription by RNA polymerase II (GO:0006357), brain development (GO:0007420), positive regulation of DNA-templated transcription (GO:0045893), positive regulation of transcription by RNA polymerase I (GO:0045943), positive regulation of transcription by RNA polymerase II (GO:0045944), negative regulation of rDNA heterochromatin formation (GO:0061188), chromatin organization (GO:0006325)

GO Molecular Function (17): chromatin binding (GO:0003682), transcription coregulator activity (GO:0003712), iron ion binding (GO:0005506), zinc ion binding (GO:0008270), histone demethylase activity (GO:0032452), histone H3K9 demethylase activity (GO:0032454), histone H4K20 demethylase activity (GO:0035575), histone H3K36 demethylase activity (GO:0051864), histone H3K27me2/H3K27me3 demethylase activity (GO:0071558), histone H3K4me3 reader activity (GO:0140002), histone H3K36me/H3K36me2 demethylase activity (GO:0140680), histone H3K9me/H3K9me2 demethylase activity (GO:0140683), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213), histone H3 demethylase activity (GO:0141052)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), nuclear membrane (GO:0031965), Set1C/COMPASS complex (GO:0048188)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin modifying enzymes	1
Mitotic Prophase	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
2-oxoglutarate-dependent dioxygenase activity	4
histone H3 demethylase activity	3
regulation of DNA-templated transcription	2
transcription by RNA polymerase II	2
positive regulation of DNA-templated transcription	2
binding	2
transition metal ion binding	2
nuclear lumen	2
mitotic cell cycle	1
mitotic cell cycle phase transition	1
cell cycle G1/S phase transition	1
chromatin organization	1
central nervous system development	1
animal organ development	1
head development	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
regulation of transcription by RNA polymerase I	1
transcription by RNA polymerase I	1
regulation of transcription by RNA polymerase II	1
rDNA heterochromatin formation	1
negative regulation of heterochromatin formation	1
regulation of rDNA heterochromatin formation	1
cellular component organization	1
transcription regulator activity	1
protein demethylase activity	1
histone modifying activity	1
histone H4 demethylase activity	1
histone H3 reader activity	1
histone H3K36 demethylase activity	1
histone H3K9 demethylase activity	1
catalytic activity	1
cation binding	1
oxidoreductase activity	1
histone demethylase activity	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
intracellular membraneless organelle	1
nucleus	1
nuclear envelope	1

Protein interactions and networks

STRING

2269 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHF8	HCFC1	P51610	955
PHF8	KMT2A	Q03164	861
PHF8	FAM120C	Q9NX05	851
PHF8	PHF6	Q8IWS0	839
PHF8	NCAPG2	Q86XI2	814
PHF8	NCAPD3	P42695	796
PHF8	SETD1A	O15047	766
PHF8	WNK3	Q9BYP7	716
PHF8	KDM4A	O75164	701
PHF8	H4C16	P02304	694
PHF8	H3C1	P02295	682
PHF8	H3-3A	P06351	681
PHF8	H3C14	Q71DI3	681
PHF8	H3-5	Q6NXT2	681
PHF8	H3-4	Q16695	681
PHF8	H3-7	Q5TEC6	681

IntAct

75 interactions, top by confidence:

A	B	Type	Score
MAD2L1BP	LBR	psi-mi:“MI:0914”(association)	0.730
PHF8	ZNF711	psi-mi:“MI:0915”(physical association)	0.690
AMPD2	SDC2	psi-mi:“MI:0914”(association)	0.640
NOTCH1	KDM1A	psi-mi:“MI:0914”(association)	0.560
RPN1	APBB1	psi-mi:“MI:0914”(association)	0.530
SUPT5H	POLR2D	psi-mi:“MI:0914”(association)	0.530
MAGEA10	POTEF	psi-mi:“MI:0914”(association)	0.530
SNAPC4	KDM5C	psi-mi:“MI:0914”(association)	0.530
PHF8	AMPD2	psi-mi:“MI:0914”(association)	0.530
PHF8	ARX	psi-mi:“MI:0915”(physical association)	0.520
RBPJ	PHF8	psi-mi:“MI:0915”(physical association)	0.500
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
PHF8	NOTCH1	psi-mi:“MI:0914”(association)	0.460
NOTCH1	SMARCA4	psi-mi:“MI:0914”(association)	0.460
Dlg4	PHF8	psi-mi:“MI:0407”(direct interaction)	0.440
PHF8		psi-mi:“MI:0915”(physical association)	0.400
E2F1	SETD1A	psi-mi:“MI:0915”(physical association)	0.400
PHF8	HMGN2	psi-mi:“MI:0915”(physical association)	0.400
PHF8	H1-5	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (235): PHF8 (Protein-peptide), PHF8 (Reconstituted Complex), PHF8 (Affinity Capture-MS), PHF8 (Affinity Capture-MS), PHF8 (Reconstituted Complex), CENPB (Affinity Capture-MS), INCENP (Affinity Capture-MS), EIF6 (Affinity Capture-MS), PLEC (Affinity Capture-MS), XPC (Affinity Capture-MS), TRIM26 (Affinity Capture-MS), HIST2H2BE (Affinity Capture-MS), TRIP12 (Affinity Capture-MS), H2AFY (Affinity Capture-MS), MRPS27 (Affinity Capture-MS)

ESM2 similar proteins: A0A0R4IXF6, A1A5R8, A9ZLX4, D3YXJ0, E9PUQ8, G3UZ78, O00750, O15164, O54828, P30052, P40818, P48984, P52963, P59997, P97496, Q02225, Q08AX9, Q08BR4, Q08D35, Q16760, Q1LUC3, Q2I6J1, Q3UWM4, Q498F0, Q5JSH3, Q5JTW2, Q5RHD1, Q60665, Q64398, Q68FF0, Q6INA9, Q6NSI8, Q6NVE8, Q6PDG5, Q6ZMT4, Q7ZVP1, Q80U87, Q86XP1, Q8C5W4, Q8N7X0

Diamond homologs: A2WXR5, A2XTW9, A2Y0Q2, A2Y4R8, B8ADZ3, B8AMA8, B8B8C5, B8B8I3, B8BJV8, O74508, O81488, Q12830, Q2R837, Q40359, Q5EA28, Q5XEM9, Q60DW3, Q6BER5, Q6YTY3, Q6Z7F4, Q75IR6, Q7F2Z1, Q7XUW3, Q80TJ7, Q84TV4, Q8C9B9, Q8H383, Q8LA16, Q8S8M9, Q9BTC0, Q9CWW7, Q9FFF5, Q9M2B4, Q9P0U4, Q9SRM4, Q9UPP1, Q9W0T1, Q9W352, P0CF52, P0CH95

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
CDC20	“down-regulates quantity by destabilization”	PHF8	binding
APC-c	“down-regulates quantity by destabilization”	PHF8	polyubiquitination
CSNK2A1	“up-regulates activity”	PHF8	phosphorylation
PHF8	“up-regulates quantity by stabilization”	TOPBP1	binding
MAPK1	“down-regulates activity”	PHF8	phosphorylation
2-oxoglutarate(2-)	“up-regulates activity”	PHF8	“chemical activation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 89 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Transcriptional regulation by RUNX1	5	11.6×	5e-03
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	11.6×	5e-03
Pre-NOTCH Transcription and Translation	5	9.8×	1e-02

GO biological processes:

GO term	Partners	Fold	FDR
chromatin remodeling	7	6.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	10
Uncertain significance	168
Likely benign	61
Benign	7

Top pathogenic / likely-pathogenic (27)

Variant ID	HGVS	Classification
10797	NM_015107.3(PHF8):c.943_946+8del	Pathogenic
10798	NM_015107.3(PHF8):c.631C>T (p.Arg211Ter)	Pathogenic
10799	NM_015107.3(PHF8):c.529A>T (p.Lys177Ter)	Pathogenic
10800	NM_015107.3(PHF8):c.836T>C (p.Phe279Ser)	Pathogenic
235852	NM_015107.3(PHF8):c.1141+5G>C	Pathogenic
2572004	NM_015107.3(PHF8):c.738dup (p.His247fs)	Pathogenic
3384386	NM_015107.3(PHF8):c.464_465del (p.Lys155fs)	Pathogenic
3600622	NM_015107.3(PHF8):c.1957C>T (p.Arg653Ter)	Pathogenic
374402	NM_015107.3(PHF8):c.377del (p.Leu126fs)	Pathogenic
451824	NM_015107.3(PHF8):c.122dup (p.Ala42fs)	Pathogenic
521817	NM_015107.3(PHF8):c.2225dup (p.Ser742fs)	Pathogenic
817250	NM_015107.3(PHF8):c.192dup (p.Arg65fs)	Pathogenic
817465	NM_015107.3(PHF8):c.1772dup (p.Ile592fs)	Pathogenic
817490	NM_015107.3(PHF8):c.368dup (p.Pro124fs)	Pathogenic
817530	NM_015107.3(PHF8):c.2713C>T (p.Gln905Ter)	Pathogenic
984633	NM_015107.3(PHF8):c.1880del (p.Lys627fs)	Pathogenic
987442	NM_015107.3(PHF8):c.1615C>T (p.Gln539Ter)	Pathogenic
1305647	NM_015107.3(PHF8):c.1312C>T (p.Arg438Cys)	Likely pathogenic
2431835	NM_015107.3(PHF8):c.1995+1G>A	Likely pathogenic
2630075	NM_015107.3(PHF8):c.783+2del	Likely pathogenic
3065563	NM_015107.3(PHF8):c.2656C>T (p.Gln886Ter)	Likely pathogenic
3382447	NM_015107.3(PHF8):c.1516C>T (p.Arg506Ter)	Likely pathogenic
3598414	NM_015107.3(PHF8):c.1324-2A>C	Likely pathogenic
3776255	NM_015107.3(PHF8):c.2129+1G>C	Likely pathogenic
4280332	NM_015107.3(PHF8):c.718C>T (p.Arg240Ter)	Likely pathogenic
666346	NM_015107.3(PHF8):c.2444-2A>G	Likely pathogenic
930732	NM_015107.3(PHF8):c.2455del (p.Leu819fs)	Likely pathogenic

SpliceAI

4176 predictions. Top by Δscore:

Variant	Effect	Δscore
X:53940325:T:TA	donor_gain	1.0000
X:53940514:CTC:C	acceptor_gain	1.0000
X:53940517:CTG:C	acceptor_loss	1.0000
X:53940518:T:A	acceptor_loss	1.0000
X:53944129:CCTA:C	donor_loss	1.0000
X:53944131:TA:T	donor_loss	1.0000
X:53944132:A:AT	donor_loss	1.0000
X:53944133:CCTG:C	donor_gain	1.0000
X:53944239:GCGGG:G	acceptor_gain	1.0000
X:53944240:CGGG:C	acceptor_gain	1.0000
X:53944240:CGGGC:C	acceptor_gain	1.0000
X:53944241:GGG:G	acceptor_gain	1.0000
X:53944241:GGGCT:G	acceptor_loss	1.0000
X:53944242:GGCT:G	acceptor_loss	1.0000
X:53944244:C:CC	acceptor_gain	1.0000
X:53944244:CTGCA:C	acceptor_loss	1.0000
X:53944245:T:A	acceptor_loss	1.0000
X:53962839:ATTAC:A	donor_loss	1.0000
X:53962840:TTA:T	donor_loss	1.0000
X:53962841:TACCT:T	donor_loss	1.0000
X:53962842:ACCT:A	donor_loss	1.0000
X:53962843:C:CG	donor_loss	1.0000
X:53962935:ATAGA:A	acceptor_gain	1.0000
X:53962936:TAGA:T	acceptor_gain	1.0000
X:53962937:AGA:A	acceptor_gain	1.0000
X:53962938:GA:G	acceptor_gain	1.0000
X:53962940:C:CA	acceptor_loss	1.0000
X:53962940:C:CC	acceptor_gain	1.0000
X:53962943:C:CT	acceptor_gain	1.0000
X:53984902:AGCTG:A	donor_gain	1.0000

AlphaMissense

6725 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:53939186:A:G	I1052T	1.000
X:53939192:A:G	L1050P	1.000
X:53939192:A:T	L1050Q	1.000
X:53939195:A:C	I1049S	1.000
X:53939195:A:G	I1049T	1.000
X:53939195:A:T	I1049N	1.000
X:53939201:C:T	G1047D	1.000
X:53939204:A:G	L1046P	1.000
X:53939204:A:T	L1046H	1.000
X:53939206:T:A	R1045S	1.000
X:53939206:T:G	R1045S	1.000
X:53939207:C:G	R1045T	1.000
X:53939212:C:A	K1043N	1.000
X:53939212:C:G	K1043N	1.000
X:53944153:G:T	A913D	1.000
X:53944165:A:G	L909S	1.000
X:53985183:A:G	M761T	1.000
X:53985192:A:C	I758S	1.000
X:53985192:A:G	I758T	1.000
X:53985192:A:T	I758N	1.000
X:53985861:A:G	L731P	1.000
X:53985861:A:T	L731H	1.000
X:53985864:A:G	L730P	1.000
X:53985864:A:T	L730Q	1.000
X:53995718:A:G	L469P	1.000
X:53995730:A:G	L465P	1.000
X:53999884:A:G	W443R	1.000
X:53999884:A:T	W443R	1.000
X:53999916:C:T	G432D	1.000
X:54002169:A:G	L412P	1.000

dbSNP variants (sampled 300 via entrez): RS1000030663 (X:54049069 G>A), RS1000092088 (X:53957434 T>C), RS1000099117 (X:54018872 A>G), RS1000104228 (X:54031595 A>C), RS1000125921 (X:53983473 G>C), RS1000139168 (X:54044075 G>A,C), RS1000152452 (X:53982889 A>C), RS1000239777 (X:54043791 G>A), RS1000370107 (X:54034685 G>A,T), RS1000475805 (X:54042011 T>C), RS1000527629 (X:54041594 C>T), RS1000531291 (X:53957218 C>T), RS1000640356 (X:53990335 C>T), RS1000689547 (X:53972624 C>G), RS1000712627 (X:53992286 T>C)

Disease associations

OMIM: gene MIM:300560 | disease phenotypes: MIM:300263

GenCC curated gene-disease

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Siderius type	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
syndromic X-linked intellectual disability Siderius type	Definitive	XL

Mondo (2): syndromic X-linked intellectual disability Siderius type (MONDO:0010286), intellectual disability (MONDO:0001071)

Orphanet (2): X-linked intellectual disability, Siderius type (Orphanet:85287), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000175	Cleft palate
HP:0000202	Orofacial cleft
HP:0000204	Cleft upper lip
HP:0000252	Microcephaly
HP:0000276	Long face
HP:0000336	Prominent supraorbital ridges
HP:0000340	Sloping forehead
HP:0000455	Broad nasal tip
HP:0000582	Upslanted palpebral fissure
HP:0000664	Synophrys
HP:0000750	Delayed speech and language development
HP:0001166	Arachnodactyly
HP:0001176	Large hands
HP:0001177	Preaxial hand polydactyly
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001419	X-linked recessive inheritance
HP:0001611	Hypernasal speech
HP:0001763	Pes planus
HP:0002162	Low posterior hairline
HP:0002650	Scoliosis
HP:0002942	Thoracic kyphosis
HP:0008734	Decreased testicular size
HP:0010511	Long toe
HP:0410030	Cleft lip

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST000862_1	Bipolar disorder and schizophrenia	4.000000e-07

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C537333	Siderius X-linked mental retardation syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1938212 (SINGLE PROTEIN), CHEMBL3038496 (PROTEIN FAMILY)

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

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
daminozide	Inhibition	6.26	pIC50

Binding affinities (BindingDB)

26 measured of 60 human assays (60 total across all organisms); most potent 26 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
2-(1-methylimidazol-4-yl)-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2-chlorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[5-(4-fluorophenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-(1-phenylethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[2-(2-methoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[2-(2-ethoxyphenyl)ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-(1H-triazol-4-yl)-2-[1-[2-[2-(2,2,2-trifluoroethoxy)phenyl]ethyl]imidazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[2-[2-(cyclopropylmethoxy)phenyl]ethyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-[2-[1-(1,2,3,4-tetrahydronaphthalen-1-ylmethyl)imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-[2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-iodo-1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(5-fluoro-1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2,3-dichlorophenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[[2-chloro-3-(trifluoromethyl)phenyl]methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[5-(4-fluoro-3-methoxyphenyl)-1-methylimidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2-fluoro-3-methylphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridin	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[(2-fluoro-3-methoxyphenyl)methyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethyl)phenyl]ethyl]imidazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-[1-[2-(2-chlorophenyl)-2-methylpropyl]imidazol-4-yl]-4-(1H-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-(1H-triazol-4-yl)-2-[1-[2-[2-(trifluoromethoxy)phenyl]ethyl]imidazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-(5-fluoro-1H-triazol-4-yl)-2-[1-(2-naphthalen-1-ylethyl)imidazol-4-yl]pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
1-benzyl-4-{1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl}-1H-imidazole	IC50	300 nM	US-9896436: Histone demethylase inhibitors
2-(5-bromo-1-(2-chlorobenzyl)-1H-imidazol-4-yl)-4-(2H-1,2,3-triazol-4-yl)pyridine	IC50	300 nM	US-9896436: Histone demethylase inhibitors
4-[2-[5-[2-(cyclopropylmethoxy)-4-fluorophenyl]-1-methylimidazol-4-yl]pyridin-4-yl]-1H-triazole-5-carbonitrile	IC50	5500 nM	US-10071984: Histone demethylase inhibitors

ChEMBL bioactivities

111 potent at pChembl≥5 of 126 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.00	IC50	100	nM	CHEMBL4281254
7.00	IC50	100	nM	CHEMBL4294926
7.00	IC50	100	nM	CHEMBL4281520
7.00	IC50	100	nM	CHEMBL4283877
7.00	IC50	100	nM	CHEMBL4279714
7.00	IC50	100	nM	CHEMBL4280770
7.00	IC50	100	nM	CHEMBL4294188
7.00	IC50	100	nM	CHEMBL4279343
7.00	IC50	100	nM	CHEMBL4292796
7.00	IC50	100	nM	CHEMBL4279599
7.00	IC50	100	nM	CHEMBL4278569
7.00	IC50	100	nM	CHEMBL4292673
7.00	IC50	100	nM	CHEMBL4288982
7.00	IC50	100	nM	CHEMBL4288588
7.00	IC50	100	nM	CHEMBL4287550
7.00	IC50	100	nM	CHEMBL4282591
7.00	IC50	100	nM	CHEMBL4281556
7.00	IC50	100	nM	CHEMBL4293177
7.00	IC50	100	nM	CHEMBL4283694
7.00	IC50	100	nM	CHEMBL4283711
7.00	IC50	100	nM	CHEMBL4287368
7.00	IC50	100	nM	CHEMBL4292067
7.00	IC50	100	nM	CHEMBL4286546
7.00	IC50	100	nM	CHEMBL4286675
7.00	IC50	100	nM	CHEMBL4290290
6.32	IC50	480	nM	CHEMBL2164246
6.26	IC50	550	nM	CHEMBL2164243
6.26	IC50	550	nM	CHEMBL4281254
6.26	IC50	550	nM	CHEMBL4294926
6.26	IC50	550	nM	CHEMBL4281520
6.26	IC50	550	nM	CHEMBL4283877
6.26	IC50	550	nM	CHEMBL4279714
6.26	IC50	550	nM	CHEMBL4280770
6.26	IC50	550	nM	CHEMBL4294188
6.26	IC50	550	nM	CHEMBL4279343
6.26	IC50	550	nM	CHEMBL4292796
6.26	IC50	550	nM	CHEMBL6058262
6.26	IC50	550	nM	CHEMBL5914501
6.26	IC50	550	nM	CHEMBL4292673
6.26	IC50	550	nM	CHEMBL4288982
6.26	IC50	550	nM	CHEMBL4288588
6.26	IC50	550	nM	CHEMBL5818227
6.26	IC50	550	nM	CHEMBL4282591
6.26	IC50	550	nM	CHEMBL4281556
6.26	IC50	550	nM	CHEMBL4293177
6.26	IC50	550	nM	CHEMBL4283694
6.26	IC50	550	nM	CHEMBL4283711
6.26	IC50	550	nM	CHEMBL4287368
6.26	IC50	550	nM	CHEMBL4292067
6.26	IC50	550	nM	CHEMBL4286546

PubChem BioAssay actives

20 with measured affinity, of 107 total; 18 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-[[(1-ethyl-2-oxopyrrolidin-3-yl)methylamino]methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
2-[(2-methyl-5,6,8,9-tetrahydroimidazo[1,2-d][1,4]diazepin-7-yl)methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
2-[[[(3S)-2-oxo-1-[(1R)-1-phenylethyl]piperidin-3-yl]methylamino]methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
2-[[[(3S)-2-oxo-1-[(1R)-1-phenylethyl]pyrrolidin-3-yl]methylamino]methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
2-[[[(3S)-1-[(1R)-1-(4-methoxyphenyl)ethyl]-2-oxopiperidin-3-yl]methylamino]methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
2-[[[(3R)-2-oxo-1-[(1R)-1-phenylethyl]piperidin-3-yl]methylamino]methyl]pyridine-4-carboxylic acid	1288262: Inhibition of human PHF8 preincubated for 10 mins followed by substrate addition by AlphaLISA assay	ic50	0.2500	uM
4-hydrazinyl-4-oxobutanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	0.4800	uM
4-(2,2-dimethylhydrazinyl)-4-oxobutanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	0.5500	uM
3-[9-cyclopropylnonanoyl(hydroxy)amino]propanoic acid	770460: Inhibition of KDM7B (unknown origin) using H3K4me3K9me2 and 2-oxoglutarate as substrate after 1 hr by matrix-assisted laser desorption ionization time of flight mass spectrometry	ic50	1.2000	uM
[(5S)-6-[[(2S)-5-amino-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S,3R)-1-[[2-[[2-[[(2S)-6-amino-1-[[(2S)-1-[(2S)-2-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-5-amino-1-[[(2S)-1-[[(1S)-1-carboxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]carbamoyl]pyrrolidin-1-yl]-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-2-oxoethyl]amino]-2-oxoethyl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]amino]-5-carbamimidamido-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-5-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-aminopropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]amino]-6-oxohexyl]-trimethylazanium	1496241: Displacement of C-terminally biotinylated-H3K4me3 (1 to 21 residues) peptide from KDM7B (PHD) (unknown origin) preincubated for 15 mins followed by peptide addition measured after 1 hr by luminescence-based AlphaScreen assay	ic50	1.7000	uM
4-(hydroxyamino)-4-oxobutanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	1.7000	uM
4,6-dioxoheptanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	2.3000	uM
4-(2-methylhydrazinyl)-4-oxobutanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	3.4000	uM
ethyl 3-[[2-pyridin-2-yl-6-(1,2,4,5-tetrahydro-3-benzazepin-3-yl)pyrimidin-4-yl]amino]propanoate	2145045: Inhibition of PHF8 (1 to 1024 residues)(unknown origin) by Alphalisa assay	ic50	4.2000	uM
4-(dimethylaminooxy)-4-oxobutanoic acid	698701: Inhibition of human PHF8 expressed in Escherichia coli using methyl lysine peptide substrate by AlphaScreen assay	ic50	6.9000	uM
7-oxo-5-phenyl-6-propan-2-yl-1H-pyrazolo[1,5-a]pyrimidine-3-carbonitrile	1627997: Inhibition of KDM7B (unknown origin) ARTKQTAR(KMe1)STGGKAPRKQLA-NovaTagPEG-biotin/2-OG as substrate/co-factor by TR-FRET assay	ic50	7.7000	uM
3-[9-cycloheptylnonanoyl(hydroxy)amino]propanoic acid	770460: Inhibition of KDM7B (unknown origin) using H3K4me3K9me2 and 2-oxoglutarate as substrate after 1 hr by matrix-assisted laser desorption ionization time of flight mass spectrometry	ic50	9.1000	uM
(E)-4-[hydroxy-[4-[[4-(naphthalen-1-ylcarbamoyloxymethyl)phenyl]methylamino]butyl]amino]-4-oxobut-2-enoic acid	639780: Inhibition of KDM7B	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases mutagenesis	3
sodium arsenite	increases abundance, increases expression, affects cotreatment	2
Quercetin	decreases expression, increases phosphorylation	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
arsenite	affects binding, decreases reaction	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Arsenic	increases expression, affects cotreatment, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Caffeine	decreases phosphorylation	1
Cisplatin	decreases expression	1
Doxorubicin	decreases expression	1
Manganese	affects cotreatment, increases abundance, increases expression	1
Methapyrilene	decreases methylation	1
Nitric Oxide	increases expression	1
Silicon Dioxide	increases expression	1
Dihydrotestosterone	increases expression	1
Urethane	increases expression	1

ChEMBL screening assays

26 unique, capped per target: 26 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1942543	Binding	Inhibition of KDM7B	Lysine demethylases inhibitors. — J Med Chem

Cellosaurus cell lines

8 cell lines: 5 cancer cell line, 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A5I0	SEES3-1V human PHF8, clone1	Embryonic stem cell	Male
CVCL_A5I1	SEES3-1V human PHF8, clone2	Embryonic stem cell	Male
CVCL_A5I2	SEES3-1V human PHF8, clone3	Embryonic stem cell	Male
CVCL_B7YP	Abcam Raji PHF8 KO	Cancer cell line	Male
CVCL_B9ZE	Abcam THP-1 PHF8 KO	Cancer cell line	Male
CVCL_C7B3	Abcam PC-3 PHF8 KO	Cancer cell line	Male
CVCL_TD21	HAP1 PHF8 (-) 1	Cancer cell line	Male
CVCL_TD22	HAP1 PHF8 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	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
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)
NCT02486081	Not specified	COMPLETED	Development and Application-Smart Football for Movement Evaluation and Training in the Special Education Population
NCT02504502	Not specified	COMPLETED	Enhancing Genomic Laboratory Reports to Enhance Communication and Empower Patients
NCT02513277	Not specified	COMPLETED	Diabetes Screening & Prevention for People With Learning (Intellectual) Disabilities:STOP Diabetes Study
NCT02561754	Not specified	COMPLETED	Weight Management for Adolescents With IDD
NCT02591446	Not specified	COMPLETED	Transcranial Magnetic Stimulation Studies in Autism Spectrum Disorders
NCT02714868	Not specified	COMPLETED	Evaluation of Project TEAM (Teens Making Environmental and Activity Modifications)
NCT02721394	Not specified	UNKNOWN	FCT With Young Children With ID in the UK: A Feasibility Project V.1
NCT02746614	Not specified	COMPLETED	Psychomotor Therapy Effects in Adaptive Behavior and Motor Proficiency in Intellectual Disability
NCT02836405	Not specified	COMPLETED	TMS for the Investigation of Brain Plasticity in Autism Spectrum Disorders