PCGF6

Summary

PCGF6 (polycomb group ring finger 6, HGNC:21156) is a protein-coding gene on chromosome 10q24.33, encoding Polycomb group RING finger protein 6 (Q9BYE7). Transcriptional repressor.

The protein encoded by this gene contains a RING finger motif, which is most closely related to those of polycomb group (PcG) proteins RNF110/MEL-18 and BMI1. PcG proteins are known to form protein complexes and function as transcription repressors. This protein has been shown to interact with some PcG proteins and act as a transcription repressor. The activity of this protein is found to be regulated by cell cycle dependent phosphorylation. Alternatively spliced transcript variants encoding different isoforms have been identified.

Source: NCBI Gene 84108 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 60 total
• GTEx eGene: eQTL in 8 tissues, sQTL in 1 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.01 (unconstrained)
• MANE Select transcript: NM_001011663
• Notable: 60 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21156
Approved symbol	PCGF6
Name	polycomb group ring finger 6
Location	10q24.33
Locus type	gene with protein product
Status	Approved
Aliases	MBLR
Ensembl gene	ENSG00000156374
Ensembl biotype	protein_coding
OMIM	607816
Entrez	84108

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 11 nonsense_mediated_decay, 8 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

MANE Select: ENST00000369847

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

ENST00000369847, ENST00000337211, ENST00000490296, ENST00000492755, ENST00000647574, ENST00000873328, ENST00000917132, ENST00000970394, ENST00000983392, ENST00000983393, ENST00000983394, ENST00001046426, ENST00001046427, ENST00001046428, ENST00001046429, ENST00001046430, ENST00001090033, ENST00001090034, ENST00001090035, ENST00001090036, ENST00001141974

RefSeq mRNA: 2 — MANE Select: NM_001011663 NM_001011663, NM_032154

CCDS: CCDS31275, CCDS7546

Canonical transcript exons

ENST00000369847 — 10 exons

Exon	Start	End
ENSE00001192255	103350707	103351140
ENSE00001281792	103302796	103303961
ENSE00001281861	103347238	103347297
ENSE00003486860	103314186	103314272
ENSE00003487442	103345024	103345132
ENSE00003492085	103333925	103333952
ENSE00003497812	103347395	103347450
ENSE00003513780	103348716	103348812
ENSE00003590449	103348900	103348999
ENSE00003616258	103326534	103326632

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 88.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.7406 / max 105.2971, expressed in 1783 samples.

Highest expression (Bgee): primordial germ cell in gonad, ventricular zone, gastrocnemius, male germ line stem cell (sensu Vertebrata) in testis, muscle of leg.

Genetic regulation across tissues (GTEx eQTL / sQTL)

PCGF6 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 8 tissues and its splicing (sQTL) in 1 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

9 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Skin Sun Exposed Lower leg	eqtl	3.0e-03	+0.11	10:103434329:C:T
Muscle Skeletal	eqtl	5.4e-03	+0.08	10:103085115:T:C
Brain Frontal Cortex BA9	eqtl	7.1e-03	-0.73	10:103544990:A:T
Cells Cultured fibroblasts	eqtl	8.8e-03	+0.06	10:103350983:A:AGGAGGC
Testis	sqtl	9.5e-03	+1.44	10:104056637:G:C
Artery Aorta	eqtl	2.6e-02	-0.14	10:103560205:TA:T
Whole Blood	eqtl	3.2e-02	+0.11	10:103417157:A:G
Esophagus Mucosa	eqtl	3.2e-02	-0.12	10:103204136:C:T
Minor Salivary Gland	eqtl	4.9e-02	-0.38	10:102707852:G:C

FANTOM5 promoters

3 alternative TSS:

Promoter ID	TPM avg	Samples expressed
111222	9.7225	1745
111223	2.5352	1363
111221	0.4830	264

Top tissues by expression

showing 100 of 134 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.01	gold quality
ventricular zone	UBERON:0003053	82.96	gold quality
gastrocnemius	UBERON:0001388	82.78	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.48	gold quality
muscle of leg	UBERON:0001383	82.32	gold quality
skeletal muscle tissue	UBERON:0001134	82.20	gold quality
stromal cell of endometrium	CL:0002255	81.34	gold quality
muscle tissue	UBERON:0002385	80.99	gold quality
smooth muscle tissue	UBERON:0001135	80.96	gold quality
endometrium	UBERON:0001295	80.71	gold quality
ganglionic eminence	UBERON:0004023	80.26	gold quality
tibial artery	UBERON:0007610	79.52	gold quality
popliteal artery	UBERON:0002250	79.51	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.48	gold quality
hindlimb stylopod muscle	UBERON:0004252	79.46	gold quality
lower esophagus muscularis layer	UBERON:0035833	79.28	gold quality
lower esophagus	UBERON:0013473	79.26	gold quality
cortical plate	UBERON:0005343	78.80	gold quality
right lobe of liver	UBERON:0001114	78.77	gold quality
mucosa of stomach	UBERON:0001199	78.67	gold quality
myometrium	UBERON:0001296	78.61	gold quality
subcutaneous adipose tissue	UBERON:0002190	78.60	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	78.46	gold quality
calcaneal tendon	UBERON:0003701	78.43	gold quality
urinary bladder	UBERON:0001255	78.12	gold quality
adipose tissue	UBERON:0001013	77.90	gold quality
body of uterus	UBERON:0009853	77.89	gold quality
ectocervix	UBERON:0012249	77.83	gold quality
left coronary artery	UBERON:0001626	77.76	gold quality
descending thoracic aorta	UBERON:0002345	77.72	gold quality
islet of Langerhans	UBERON:0000006	77.44	gold quality
right coronary artery	UBERON:0001625	77.40	gold quality
liver	UBERON:0002107	77.32	gold quality
body of pancreas	UBERON:0001150	77.28	gold quality
pancreas	UBERON:0001264	77.22	gold quality
thoracic mammary gland	UBERON:0005200	77.18	gold quality
endocervix	UBERON:0000458	77.13	gold quality
left uterine tube	UBERON:0001303	77.13	gold quality
omental fat pad	UBERON:0010414	76.94	gold quality
leukocyte	CL:0000738	76.80	gold quality
monocyte	CL:0000576	76.76	gold quality
thoracic aorta	UBERON:0001515	76.75	gold quality
uterine cervix	UBERON:0000002	76.63	gold quality
ascending aorta	UBERON:0001496	76.60	gold quality
colon	UBERON:0001155	76.56	gold quality
esophagus	UBERON:0001043	76.53	gold quality
testis	UBERON:0000473	76.47	gold quality
lymph node	UBERON:0000029	76.32	gold quality
placenta	UBERON:0001987	76.29	gold quality
right testis	UBERON:0004534	76.24	gold quality
heart	UBERON:0000948	75.96	gold quality
heart left ventricle	UBERON:0002084	75.88	gold quality
left testis	UBERON:0004533	75.87	gold quality
right adrenal gland cortex	UBERON:0035827	75.84	gold quality
ovary	UBERON:0000992	75.83	gold quality
left adrenal gland cortex	UBERON:0035825	75.81	gold quality
right ovary	UBERON:0002118	75.77	gold quality
tibial nerve	UBERON:0001323	75.76	gold quality
intestine	UBERON:0000160	75.73	gold quality
left ovary	UBERON:0002119	75.69	gold quality
cerebellar cortex	UBERON:0002129	75.65	gold quality
cerebellar hemisphere	UBERON:0002245	75.60	gold quality
left adrenal gland	UBERON:0001234	75.57	gold quality
cerebellum	UBERON:0002037	75.57	gold quality
rectum	UBERON:0001052	75.46	gold quality
vermiform appendix	UBERON:0001154	75.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	75.06	gold quality
duodenum	UBERON:0002114	75.03	gold quality
vagina	UBERON:0000996	74.98	gold quality
multicellular organism	UBERON:0000468	74.94	gold quality
adrenal gland	UBERON:0002369	74.90	gold quality
gall bladder	UBERON:0002110	74.85	gold quality
mucosa of transverse colon	UBERON:0004991	74.85	gold quality
right adrenal gland	UBERON:0001233	74.84	gold quality
right atrium auricular region	UBERON:0006631	74.71	gold quality
granulocyte	CL:0000094	74.53	gold quality
body of stomach	UBERON:0001161	74.47	gold quality
transverse colon	UBERON:0001157	74.44	gold quality
prostate gland	UBERON:0002367	74.41	gold quality
right lung	UBERON:0002167	74.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	74.40	gold quality
fundus of stomach	UBERON:0001160	74.38	gold quality
esophagus mucosa	UBERON:0002469	74.14	gold quality
prefrontal cortex	UBERON:0000451	74.00	gold quality
tonsil	UBERON:0002372	74.00	gold quality
fallopian tube	UBERON:0003889	74.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	73.83	gold quality
stomach	UBERON:0000945	73.82	gold quality
adrenal tissue	UBERON:0018303	73.68	gold quality
small intestine	UBERON:0002108	73.47	gold quality
lung	UBERON:0002048	73.43	gold quality
minor salivary gland	UBERON:0001830	73.36	gold quality
lower esophagus mucosa	UBERON:0035834	73.30	gold quality
saliva-secreting gland	UBERON:0001044	73.26	gold quality
upper lobe of left lung	UBERON:0008952	73.20	gold quality
Brodmann (1909) area 9	UBERON:0013540	73.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	73.14	gold quality
skin of abdomen	UBERON:0001416	73.10	gold quality
spleen	UBERON:0002106	72.99	gold quality
zone of skin	UBERON:0000014	72.96	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.62

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Liver	tissue	10.8
Testis	tissue	8.3
Skeletal muscle	tissue	8.2
Smooth muscle	tissue	7.0
Adipose tissue	tissue	6.8
Tongue	tissue	6.5
Endometrium 1	tissue	5.7
Thymus	tissue	5.4
Breast	tissue	5.3
Lymph node	tissue	5.2
Heart muscle	tissue	5.1
Pancreas	tissue	5.1
Vagina	tissue	5.0
Urinary bladder	tissue	5.0
Seminal vesicle	tissue	4.9
Appendix	tissue	4.8
Ovary	tissue	4.7
Tonsil	tissue	4.7
Placenta	tissue	4.5
Bone marrow	tissue	4.3
Esophagus	tissue	4.1
Rectum	tissue	4.1
Parathyroid gland	tissue	4.1
Kidney	tissue	4.1
Duodenum	tissue	4.1
Cervix	tissue	4.0
Colon	tissue	4.0
Gallbladder	tissue	4.0
Prostate	tissue	3.9
Skin 1	tissue	3.8
Spleen	tissue	3.7
Small intestine	tissue	3.7
Cerebellum	tissue	3.3
Pituitary gland	tissue	3.2
Epididymis	tissue	3.1
Frontal cortex	tissue	3.1
Adrenal gland	tissue	3.1
Stomach 1	tissue	3.0
Lung	tissue	3.0
Thyroid gland	tissue	2.9
Caudate putamen	tissue	2.8
Fallopian tube	tissue	2.7
Salivary gland	tissue	2.6
Nucleus accumbens	tissue	2.5
Retina	tissue	2.4
Corpus callosum	tissue	2.2
Postcentral gyrus	tissue	2.2
Spinal cord	tissue	2.1
Olfactory bulb	tissue	2.1
Medulla oblongata	tissue	2.0
Superior colliculi	tissue	2.0
Amygdala	tissue	1.9
Hypothalamus	tissue	1.9
Hippocampus	tissue	1.9
Hippocampal formation	tissue	1.9
Septum	tissue	1.9
Cerebral cortex	tissue	1.8
Motor cortex	tissue	1.8
Putamen	tissue	1.8
Midbrain	tissue	1.8

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (6.9), Dorsal funiculus (white matter) (4.0), Corpus callosum, genu (white matter) (3.9), Corpus callosum, splenium (white matter) (3.9), Lateral funiculus (white matter) (3.8).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting PCGF6 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 50 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-3686	99.90	70.53	2432
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-5093	99.67	69.26	2291
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-409-3P	99.50	66.33	1192
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-4735-5P	99.43	68.49	1780
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-377-3P	99.37	70.18	1905

Functional genomics

gnomAD constraint: pLI 0.000119, LOEUF 1.01, missense Z 0.419 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000369847 splits into 2 regions with different missense tolerance; 0 are missense-constrained. Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
10:103,303,908–103,326,620	49 / 93.0	0.53	no
10:103,326,621–103,351,066	307 / 350.1	0.88	no

Literature-anchored findings (GeneRIF, showing 7)

• regulation by cell cycle-dependent phosphorylation (PMID:12167161)
• Thus, we did not find evidence for uniquely interacting partner proteins using this approach, but did identify four new lamin A/C interactive partners (PMID:16248985)
• Study shows that JARID1d and MBLR occupy human Engrailed 2 gene and regulate its expression and histone H3 lysine 4 methylation levels. (PMID:17320162)
• MEL-18 bound to HSF2 inhibits its sumoylation by binding to and inhibiting the activity of UBC9 enzymes in the vicinity of HSF2. (PMID:18211895)
• Mel-18 overexpression showed reduced glycogen synthase kinase-3beta phosphorylation, beta-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level (PMID:18519679)
• Pcgf6 acts as a master regulator to maintain embryonic stem cell identity. (PMID:27247273)
• PCGF6 controls neuroectoderm specification of human pluripotent stem cells by activating SOX2 expression. (PMID:35933409)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcgf6	ENSDARG00000069681
mus_musculus	Pcgf6	ENSMUSG00000025050
rattus_norvegicus	Pcgf6	ENSRNOG00000020250
rattus_norvegicus	Pcgf6l1	ENSRNOG00000033458
drosophila_melanogaster	Psc	FBGN0005624
drosophila_melanogaster	Su(z)2	FBGN0265623

Paralogs (7): PCGF1 (ENSG00000115289), RNF2 (ENSG00000121481), BMI1 (ENSG00000168283), PCGF5 (ENSG00000180628), PCGF3 (ENSG00000185619), RING1 (ENSG00000204227), PCGF2 (ENSG00000277258)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1918291) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 18 distinct phenotype terms.

Mouse phenotype (MP)	Records
rib fusion	1
increased rib number	1
abnormal placenta development	1
decreased trophoblast giant cell number	1
placental labyrinth hypoplasia	1
abnormal placenta labyrinth morphology	1
abnormal pluripotent precursor cell morphology	1
embryonic growth retardation	1
small placenta	1
cervical vertebral transformation	1
thoracic vertebral transformation	1
abnormal rostral-caudal axis patterning	1
abnormal sternocostal joint morphology	1
abnormal preimplantation embryo development	1
abnormal arcus anterior morphology	1
prenatal lethality, incomplete penetrance	1
decreased nucleated erythrocyte cell number	1
decreased spongiotrophoblast cell number	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
Pongo abelii	Q5R8L2	100.0%	Diamond
Felis catus	Q9TST0	99.4%	Diamond
Bos taurus	Q32KX7	99.1%	Diamond
Xenopus tropicalis	Q28H21	98.1%	Diamond
Xenopus laevis	Q4QR06	98.1%	Diamond
Gallus gallus	Q5SDR3	88.3%	Diamond
Arabidopsis thaliana	Q94AY3	67.1%	Diamond
Caenorhabditis elegans	Q19336	44.7%	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
PDCD11	protein-coding	22984
CALHM2	protein-coding	51063
TAF5	protein-coding	6877
ATP5MK	protein-coding	84833
MIR1307	ncRNA	100302174
RPEL1	protein-coding	729020
INA	protein-coding	9118
NT5C2	protein-coding	22978

Protein

Protein identifiers

Polycomb group RING finger protein 6 — Q9BYE7 (reviewed: Q9BYE7)

Alternative names: Mel18 and Bmi1-like RING finger, RING finger protein 134

All UniProt accessions (2): A0A3B3ISZ4, Q9BYE7

UniProt curated annotations — full annotation on UniProt →

Function. Transcriptional repressor. May modulate the levels of histone H3K4Me3 by activating KDM5D histone demethylase. Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development. PcG PRC1 complex acts via chromatin remodeling and modification of histones; it mediates monoubiquitination of histone H2A ‘Lys-119’, rendering chromatin heritably changed in its expressibility. Within the PRC1-like complex, regulates RNF2 ubiquitin ligase activity.

Subunit / interactions. Component of a PRC1-like complex. Interacts with BMI1/PCGF4, RING1 and RNF2. Interacts with KDM5D. Interacts with CBX4, CBX6, CBX7 and CBX8.

Subcellular location. Nucleus.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated during mitosis. Phosphorylated on Ser-30 by CDK7 in vitro.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BYE7-1	1	yes
Q9BYE7-3	3

RefSeq proteins (2): NP_001011663, NP_115530 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001841	Znf_RING	Domain
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017907	Znf_RING_CS	Conserved_site
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR032443	RAWUL	Domain
IPR046979	PCGF6_RAWUL	Domain
IPR051507	PCGF	Family

Pfam: PF13923, PF16207

UniProt features (26 total): mutagenesis site 4, compositionally biased region 4, cross-link 2, splice variant 2, sequence conflict 2, helix 2, turn 2, modified residue 2, chain 1, zinc finger region 1, sequence variant 1, region of interest 1, strand 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
2DJB	Solution structure of the RING domain of the human Polycomb group RING finger protein 6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BYE7-F1	73.32	0.40

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Functional residue map

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

Post-translational modifications (4)

Type	Positions
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	223, 234
Phosphoserine	30, 115

Mutagenesis-validated functional residues (4)

Position	Phenotype
30	abolishes phosphorylation.
57	does not abolish phosphorylation.
59	does not abolish phosphorylation.
69	does not abolish phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 4; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

4 pathways:

ID	Pathway	Evidence
R-HSA-8953750	Transcriptional Regulation by E2F6	curated
R-HSA-74160	Gene expression (Transcription)	—
R-HSA-212436	Generic Transcription Pathway	—
R-HSA-73857	RNA Polymerase II Transcription	—

MSigDB gene sets: 111 (showing top): TGCGCANK_UNKNOWN, AACYNNNNTTCCS_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, WANG_LMO4_TARGETS_DN, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM1, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOCC_NUCLEAR_UBIQUITIN_LIGASE_COMPLEX, AML1_01, GOBP_CHROMATIN_REMODELING, GOBP_HETEROCHROMATIN_ORGANIZATION, GOBP_EPIGENETIC_REGULATION_OF_GENE_EXPRESSION, GOCC_TRANSFERASE_COMPLEX, GOCC_PCG_PROTEIN_COMPLEX, LIU_SOX4_TARGETS_DN, GOCC_PRC1_COMPLEX

GO Biological Process (6): negative regulation of transcription by RNA polymerase II (GO:0000122), chromatin remodeling (GO:0006338), DNA-templated transcription (GO:0006351), regulation of transcription by RNA polymerase II (GO:0006357), heterochromatin formation (GO:0031507), negative regulation of DNA-templated transcription (GO:0045892)

GO Molecular Function (3): zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102)

Reactome top-level categories

3 top-level categories:

Category	Pathways
Generic Transcription Pathway	1
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

23 GO namespaces:

Category	Terms
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
chromatin organization	1
gene expression	1
RNA biosynthetic process	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
transition metal ion binding	1
binding	1
cation binding	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1
PcG protein complex	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 5 of 14 annotations. The rest are phylogenetic / computational / electronic (IEA).

5 experimentally-supported GO terms:

GO term	NS	Evidence
chromatin remodeling	BP	mutant phenotype
negative regulation of DNA-templated transcription	BP	direct assay
PRC1 complex	CC	direct assay
PcG protein complex	CC	direct assay
nucleus	CC	direct assay

Protein interactions and networks

STRING

showing 15 of 977 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCGF6	RNF2	Q99496	896
PCGF6	RING1	Q06587	890
PCGF6	L3MBTL2	Q969R5	755
PCGF6	RYBP	Q8N488	733
PCGF6	YAF2	Q8IY57	726
PCGF6	E2F6	O75461	630
PCGF6	CBX2	Q14781	623
PCGF6	PHC1	P78364	606
PCGF6	CBX7	O95931	599
PCGF6	KDM2B	Q8NHM5	593
PCGF6	CBX6	O95503	584
PCGF6	CBX4	O00257	577
PCGF6	CBX8	Q9HC52	549
PCGF6	PHC2	Q8IXK0	531
PCGF6	AUTS2	Q8WXX7	493

IntAct

Human interaction partners of PCGF6 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

18 partners by confidence:

Partner	Interaction type	MIscore	Records
RNF2	physical association	0.880	1
CBX7	direct interaction	0.780	1
CBX8	direct interaction	0.780	1
RING1	physical association	0.740	1
CBX4	association	0.640	3
E2F6	association	0.640	1
CBX6	direct interaction	0.440	1
HSP90AB1	physical association	0.400	1
CDC42	physical association	0.370	1
PEX10	physical association	0.370	1
PNMA1	physical association	0.370	1
RAD18	physical association	0.370	1
SS18L1	physical association	0.370	1
UBE2U	physical association	0.370	1
TIMM8A	association	0.350	1
UBA6	association	0.350	1
PRKAB1	physical association	0.000	1
TULP3	physical association	0.000	1

BioGRID (338 interactions; top human partners by supporting records): RNF2 (Affinity Capture-MS; 18 records), L3MBTL2 (Affinity Capture-MS; 10 records), RYBP (Affinity Capture-MS; 10 records), E2F6 (Affinity Capture-MS; 9 records), MAX (Affinity Capture-MS; 9 records), RING1 (Affinity Capture-MS; 9 records), CBX3 (Affinity Capture-MS; 8 records), MYC (Affinity Capture-MS; 8 records), WDR5 (Affinity Capture-MS; 8 records), YAF2 (Affinity Capture-MS; 8 records), CBX7 (Affinity Capture-MS; 7 records), CBX1 (Affinity Capture-MS; 6 records), CBX8 (Affinity Capture-MS; 6 records), MGA (Affinity Capture-MS; 6 records), TFDP1 (Affinity Capture-MS; 6 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
Ub:E2	“up-regulates activity”	PCGF6	ubiquitination
CDK7	unknown	PCGF6	phosphorylation

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
★ PRC1.6a complex	13	RYBP, TFDP1, HDAC1, MAX, MGA, PCGF6, WDR5, CBX3, E2F6, HDAC2, L3MBTL2, RING1, RNF2
★ PRC1.6b complex	13	CBX3, HDAC1, L3MBTL2, MGA, PCGF6, RING1, WDR5, E2F6, HDAC2, MAX, RNF2, TFDP1, YAF2
E2F-6 complex	12	E2F6, EHMT2, GJB3, L3MBTL2, TFDP1, EHMT1, MAX, MGA, PCGF6, RING1, RNF2, YAF2
PCGF6-RING1A complex	2	PCGF6, RING1
PCGF6-RING1B complex	2	PCGF6, RNF2

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 18 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
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	5	93.9×	2e-07
Regulation of PTEN gene transcription	5	55.8×	1e-06
Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)	5	45.8×	2e-06
Oxidative Stress Induced Senescence	5	28.3×	1e-05

Disease & clinical

Genetic variants

Variant evidence for PCGF6: 60 ClinVar records (0 pathogenic / likely pathogenic); 6 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	48
Likely benign	1
Benign	1

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 35 predictions of 656):

Position(s)	Effect	Δscore	Sites
10:103314184–103314185	donor_loss	1.0000	5
10:103326532–103326533	donor_loss	1.0000	5
10:103326633–103326634	acceptor_loss	1.0000	3
10:103326637	acceptor_gain	1.0000
10:103345133–103345134	acceptor_loss	1.0000	4
10:103345137	acceptor_gain	1.0000
10:103347236–103347237	donor_loss	1.0000	5
10:103347298–103347299	acceptor_loss	1.0000	6
10:103347397	donor_gain	1.0000
10:103348714–103348715	donor_loss	1.0000	4

AlphaMissense

921 missense substitutions predicted likely pathogenic (of 2,267 scored), across 188 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
D188	8	1.000	1.000
H152	8	0.999	1.000
H177	8	0.998	1.000
F154	8	0.991	1.000
F163	8	0.991	0.999
D193	8	0.991	0.998
D143	8	0.979	0.998
F213	8	0.971	1.000
H287	8	0.958	0.994
D305	8	0.944	0.975
D333	8	0.917	0.981
N184	8	0.914	0.999
S157	8	0.913	0.998
F245	8	0.911	0.989
D252	8	0.897	0.956
C134	7	1.000	1.000
C137	7	1.000	1.000
C150	7	1.000	1.000
C155	7	1.000	1.000
C158	7	1.000	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

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

2 prognostic cancer types:

Cancer	Prognostic	p-value
Pancreatic Adenocarcinoma (validation)	unfavorable	0.000376
Glioblastoma Multiforme (validation)	favorable	0.000989

Disease associations

OMIM: gene MIM:607816 | disease phenotypes:

GWAS associations

6 associations:

Study	Trait	p-value
GCST002539_77	Schizophrenia	6e-19
GCST006803_98	Schizophrenia	7e-18
GCST004521_123	Autism spectrum disorder or schizophrenia	4e-14
GCST002149_2	Schizophrenia	4e-13
GCST010703_273	Brain morphology (MOSTest)	5e-13
GCST008361_2	Response to cognitive-behavioural therapy in major depressive disorder	2e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0007820	cognitive behavioural therapy
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

16 total (human), top 16 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
FR900359	increases phosphorylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	increases expression	1
NSC668394	increases expression	1
Arbutin	increases expression	1
Cisplatin	increases expression	1
Gold	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Quercetin	increases phosphorylation	1
Silicon Dioxide	increases expression	1
Tretinoin	decreases expression	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E2GB	HAP1 PCGF6 (-) 1	Cancer cell line	Male
CVCL_E2GC	HAP1 PCGF6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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