CBX2

Summary

CBX2 (chromobox 2, HGNC:1552) is a protein-coding gene on chromosome 17q25.3, encoding Chromobox protein homolog 2 (Q14781). 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.

This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 84733 — RefSeq curated summary.

At a glance

• Gene–disease (curated): 46,XY complete gonadal dysgenesis (Supportive, GenCC) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 202 total — 2 pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_005189

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1552
Approved symbol	CBX2
Name	chromobox 2
Location	17q25.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC10561, M33
Ensembl gene	ENSG00000173894
Ensembl biotype	protein_coding
OMIM	602770
Entrez	84733

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000269399, ENST00000310942, ENST00000571484

RefSeq mRNA: 2 — MANE Select: NM_005189 NM_005189, NM_032647

CCDS: CCDS11764, CCDS32757

Canonical transcript exons

ENST00000310942 — 5 exons

Exon	Start	End
ENSE00000949912	79779362	79779427
ENSE00001193142	79783732	79787983
ENSE00001465034	79781696	79781801
ENSE00002654435	79778148	79778307
ENSE00003627649	79778384	79778427

Expression profiles

Bgee: expression breadth ubiquitous, 178 present calls, max score 91.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.9300 / max 94.0980, expressed in 1065 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
163186	6.9300	1065

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	91.03	gold quality
oocyte	CL:0000023	89.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.22	gold quality
ganglionic eminence	UBERON:0004023	86.96	gold quality
ventricular zone	UBERON:0003053	85.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	82.07	gold quality
right testis	UBERON:0004534	80.86	gold quality
apex of heart	UBERON:0002098	80.72	gold quality
left testis	UBERON:0004533	80.67	gold quality
sperm	CL:0000019	79.98	silver quality
male germ cell	CL:0000015	79.50	silver quality
testis	UBERON:0000473	79.35	gold quality
embryo	UBERON:0000922	77.67	gold quality
parotid gland	UBERON:0001831	74.47	gold quality
nasal cavity epithelium	UBERON:0005384	74.24	gold quality
olfactory bulb	UBERON:0002264	72.89	gold quality
type B pancreatic cell	CL:0000169	72.83	gold quality
epithelium of nasopharynx	UBERON:0001951	72.55	gold quality
cortical plate	UBERON:0005343	72.42	gold quality
stromal cell of endometrium	CL:0002255	72.14	gold quality
endothelial cell	CL:0000115	71.61	silver quality
esophagus mucosa	UBERON:0002469	71.07	gold quality
lower esophagus mucosa	UBERON:0035834	70.54	gold quality
gingival epithelium	UBERON:0001949	70.47	silver quality
heart left ventricle	UBERON:0002084	69.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	69.39	gold quality
cardiac ventricle	UBERON:0002082	69.26	gold quality
sural nerve	UBERON:0015488	68.95	gold quality
vastus lateralis	UBERON:0001379	68.15	gold quality
gingiva	UBERON:0001828	67.98	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.26
E-MTAB-6678	no	2.42

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EZH2, HOXA10, MTF2, RNF2, RUNX1

miRNA regulators (miRDB)

15 targeting CBX2, 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-4779	99.86	66.50	1583
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-330-3P	99.41	69.95	2521
HSA-MIR-12116	97.94	68.91	595
HSA-MIR-6787-5P	97.54	63.85	457
HSA-MIR-6748-3P	97.20	65.66	836
HSA-MIR-4701-5P	96.45	68.41	1121
HSA-MIR-588	96.45	68.36	1127
HSA-MIR-8081	96.42	67.75	738
HSA-MIR-3943	95.87	64.57	523

Literature-anchored findings (GeneRIF, showing 31)

• hPc2 serves as a SUMO E3 ligase for cystathionine beta-synthase, increasing the efficiency of sumoylation. (PMID:19107218)
• CDYL functions as a molecular bridge between PRC2 and the repressive chromatin mark H3K27me3, forming a positive feedback loop to facilitate the establishment and propagation of H3K27me3 modifications along the chromatin (PMID:22009739)
• Two distinct mechanisms are involved in CBX2-mediated gene silencing. The short CBX2-2 isoform would repress the transcription in a PRC1-independent fashion, whereas gene repression by the long CBX2-1 isoform is mediated by the PRC1 protein complex. (PMID:22419124)
• This study does not support CBX2 gene disruption as a common cause of gonadal gonadal disorders of sex development. (PMID:23219007)
• CBX2 upregulation and amplification significantly correlated with metastatic progression and lower overall survival in many cancer types, particularly those of the breast (PMID:25225902)
• CBX2 role in the sex development cascade is to stimulate the male pathway and concurrently inhibit the female pathway. (PMID:25569159)
• Data show that basal-like subgroup was enriched for aggressive tumors and somatic mutations in trithorax-group genes and it overexpressed polycomb genes EZH2 and CBX2. (PMID:26431491)
• up-regulated in metastatic castration-resistant prostate cancer and elevated expression correlates with poor clinical outcome (PMID:26877821)
• These results suggest that CBX2’s phosphorylation is critical for its transcriptional repression of target genes. (PMID:28992316)
• study indicates a distinct function of the shorter form of CBX2 and by identifying several of its unique targets, can advance our understanding of DSD pathogenesis and ultimately DSD diagnosis and management. (PMID:29998616)
• CBX2 overexpression in breast tumours was associated with the upregulation of genes involved in cell cycle progression. The predicted function of CBX2 was confirmed in vitro, providing the first experimental evidence that CBX2 promotes breast cancer cell growth. (PMID:30820027)
• CBX2-dependent transcriptional landscape: implications for human sex development and its defects. (PMID:31719618)
• The transcriptional regulator CBX2 and ovarian function: A whole genome and whole transcriptome approach. (PMID:31745224)
• CASC9 Facilitates Cell Proliferation in Bladder Cancer by Regulating CBX2 Expression. (PMID:32570259)
• Chromobox 2 Expression Predicts Prognosis After Curative Resection of Oesophageal Squamous Cell Carcinoma. (PMID:32576584)
• CBX2 depletion inhibits the proliferation, invasion and migration of gastric cancer cells by inactivating the YAP/beta-catenin pathway. (PMID:33313949)
• Multiomics integrative analysis reveals antagonistic roles of CBX2 and CBX7 in metabolic reprogramming of breast cancer. (PMID:33400401)
• M33 condenses chromatin through nuclear body formation and methylation of both histone H3 lysine 9 and lysine 27. (PMID:34274396)
• CBX2 Expression in Colorectal Mucosa-adenoma-adenocarcinoma Sequence. (PMID:34500520)
• CBX2 Induces Glioma Cell Proliferation and Invasion Through the Akt/PI3K Pathway. (PMID:34709960)
• CBX2 in DSD: The Quirky Kid on the Block. (PMID:35263754)
• Developmental maturation of the hematopoietic system controlled by a Lin28b-let-7-Cbx2 axis. (PMID:35385744)
• CBX2 shapes chromatin accessibility promoting AML via p38 MAPK signaling pathway. (PMID:35681235)
• Loss of CBX2 causes genomic instability and Wnt activation in high grade serous ovarian carcinoma cells. (PMID:36621979)
• MiR-30a-5p inhibits cell behaviors in esophageal cancer via modulating CBX2. (PMID:37196609)
• Subcellular expression pattern and clinical significance of CBX2 and CBX7 in breast cancer subtypes. (PMID:37553450)
• Prognostic hub gene CBX2 drives a cancer stem cell-like phenotype in HCC revealed by multi-omics and multi-cohorts. (PMID:37980163)
• Phosphorylation of USP27X by GSK3beta maintains the stability and oncogenic functions of CBX2. (PMID:38030604)
• Cuproptosis-related ceRNA axis triggers cell proliferation and cell cycle through CBX2 in lung adenocarcinoma. (PMID:38355480)
• Bioinformatics analysis reveals that CBX2 promotes enzalutamide resistance in prostate cancer. (PMID:39175037)
• USP33 facilitates the ovarian cancer progression via deubiquitinating and stabilizing CBX2. (PMID:39256572)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cbx2	ENSDARG00000044938
mus_musculus	Cbx2	ENSMUSG00000025577
rattus_norvegicus	Cbx2	ENSRNOG00000049215
caenorhabditis_elegans		WBGENE00001995
caenorhabditis_elegans		WBGENE00007615

Paralogs (8): CBX5 (ENSG00000094916), CBX7 (ENSG00000100307), CBX1 (ENSG00000108468), CBX3 (ENSG00000122565), CBX8 (ENSG00000141570), CBX4 (ENSG00000141582), CBX6 (ENSG00000183741), NPTXR (ENSG00000221890)

Protein

Protein identifiers

Chromobox protein homolog 2 — Q14781 (reviewed: Q14781)

All UniProt accessions (1): Q14781

UniProt curated annotations — full annotation on UniProt →

Function. 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. Binds to histone H3 trimethylated at ‘Lys-9’ (H3K9me3) or at ‘Lys-27’ (H3K27me3). Plays a role in the lineage differentiation of the germ layers in embryonic development. Involved in sexual development, acting as activator of NR5A1 expression.

Subunit / interactions. Component of a PRC1-like complex. The composition of the PRC1 complex may differ between the PRC1 complex in pluripotent embryonic stem cells containing RNF2, CBX7 and PCGF2, and the PRC1 complex in differentiating cells containing RNF2, CBX2, CBX4 and BMI1. May interact with H3C15, H3C1 and RNF2. Interacts (via chromodomain) with histone H3K9Me3 and H3K27me3.

Subcellular location. Nucleus. Chromosome.

Disease relevance. 46,XY sex reversal 5 (SRXY5) [MIM:613080] A disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. The human orthologuous proteins of Drosophila Polycomb group protein Pc, CBX2, CBX4, CBX6, CBX7 and CBX8, show distinct nuclear localizations, contribute differently to transcriptional repression, and appear to be part of distinct PRC1-like protein complexes. The hPRC-H complex purification reported by PubMed:12167701 probably presents a mixture of different complexes.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14781-1	1	yes
Q14781-2	2

RefSeq proteins (2): NP_005180, NP_116036 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000953	Chromo/chromo_shadow_dom	Domain
IPR016197	Chromo-like_dom_sf	Homologous_superfamily
IPR023779	Chromodomain_CS	Conserved_site
IPR023780	Chromo_domain	Domain
IPR033773	CBX7_C	Conserved_site
IPR042796	CBX2	Family

Pfam: PF00385, PF17218

UniProt features (30 total): compositionally biased region 6, region of interest 4, modified residue 3, strand 3, helix 3, cross-link 2, splice variant 2, sequence variant 2, chain 1, domain 1, DNA-binding region 1, mutagenesis site 1, short sequence motif 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3H91	X-RAY DIFFRACTION	1.5
5EPK	X-RAY DIFFRACTION	1.8
2D9U	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14781-F1	57.29	0.14

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 (5): 247, 247, 302, 146, 153

Mutagenesis-validated functional residues (1):

Position	Phenotype
17	reduced interaction with h3c15 and h3c1.

Function

Pathways and Gene Ontology

Reactome pathways

24 pathways

ID	Pathway
R-HSA-2559580	Oxidative Stress Induced Senescence
R-HSA-3108214	SUMOylation of DNA damage response and repair proteins
R-HSA-3899300	SUMOylation of transcription cofactors
R-HSA-4551638	SUMOylation of chromatin organization proteins
R-HSA-4570464	SUMOylation of RNA binding proteins
R-HSA-4655427	SUMOylation of DNA methylation proteins
R-HSA-8939243	RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known
R-HSA-8943724	Regulation of PTEN gene transcription
R-HSA-9976102	Differentiation of naive CD4+ T cells to T helper 2 cells (Th2 cells)
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-162582	Signal Transduction
R-HSA-212436	Generic Transcription Pathway
R-HSA-2262752	Cellular responses to stress
R-HSA-2559583	Cellular Senescence
R-HSA-2990846	SUMOylation
R-HSA-3108232	SUMO E3 ligases SUMOylate target proteins
R-HSA-392499	Metabolism of proteins
R-HSA-597592	Post-translational protein modification
R-HSA-6807070	PTEN Regulation
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8878171	Transcriptional regulation by RUNX1
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9006925	Intracellular signaling by second messengers

MSigDB gene sets: 238 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, FOXO4_01, KONG_E2F3_TARGETS, AAAYRNCTG_UNKNOWN, GTGCCTT_MIR506, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, JAZAG_TGFB1_SIGNALING_VIA_SMAD4_UP, LIAO_METASTASIS, GARCIA_TARGETS_OF_FLI1_AND_DAX1_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GOBP_SEX_DIFFERENTIATION, TGGNNNNNNKCCAR_UNKNOWN, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), cell differentiation (GO:0030154), development of primary sexual characteristics (GO:0045137), chromatin organization (GO:0006325), sex differentiation (GO:0007548)

GO Molecular Function (4): DNA binding (GO:0003677), chromatin binding (GO:0003682), histone H3K9me2/3 reader activity (GO:0062072), protein binding (GO:0005515)

GO Cellular Component (7): euchromatin (GO:0000791), heterochromatin (GO:0000792), nucleus (GO:0005634), nucleoplasm (GO:0005654), PcG protein complex (GO:0031519), PRC1 complex (GO:0035102), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
SUMO E3 ligases SUMOylate target proteins	5
Cellular Senescence	1
Transcriptional regulation by RUNX1	1
PTEN Regulation	1
Differentiation of T cells	1
Intracellular signaling by second messengers	1
RNA Polymerase II Transcription	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Post-translational protein modification	1
SUMOylation	1
Metabolism of proteins	1
PIP3 activates AKT signaling	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
developmental process involved in reproduction	2
binding	2
chromatin	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
cellular developmental process	1
multicellular organism development	1
sex differentiation	1
cellular component organization	1
nucleic acid binding	1
histone H3 reader activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cellular anatomical structure	1
nuclear protein-containing complex	1
nuclear ubiquitin ligase complex	1
PcG protein complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1279 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CBX2	RING1	Q06587	998
CBX2	PHC1	P78364	997
CBX2	BMI1	P35226	995
CBX2	RNF2	Q99496	995
CBX2	R4GMX3	R4GMX3	995
CBX2	PCGF2	P35227	990
CBX2	CBX8	Q9HC52	980
CBX2	PHC2	Q8IXK0	963
CBX2	CBX4	O00257	951
CBX2	RYBP	Q8N488	930
CBX2	PCGF1	Q9BSM1	914
CBX2	PHC3	Q8NDX5	903
CBX2	YAF2	Q8IY57	883
CBX2	SLC25A3	Q00325	876
CBX2	CBX7	O95931	865

IntAct

106 interactions, top by confidence:

A	B	Type	Score
BMI1	CBX4	psi-mi:“MI:0914”(association)	0.900
PCGF2	CBX4	psi-mi:“MI:0914”(association)	0.840
PHC1	CBX4	psi-mi:“MI:0914”(association)	0.790
RING1	CBX4	psi-mi:“MI:0914”(association)	0.730
RNF2	E2F6	psi-mi:“MI:0914”(association)	0.730
CSNK2B	NMT2	psi-mi:“MI:0914”(association)	0.660
RNF2	CBX4	psi-mi:“MI:0914”(association)	0.660
CSNK2B	RPS6KA4	psi-mi:“MI:0914”(association)	0.640
RPL10A	RRP8	psi-mi:“MI:0914”(association)	0.640
CBX2	MDFI	psi-mi:“MI:0915”(physical association)	0.620
MDFI	CBX2	psi-mi:“MI:0915”(physical association)	0.620
	CBX2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP2-3	CBX2	psi-mi:“MI:0915”(physical association)	0.560
RBMY1A1	CBX2	psi-mi:“MI:0915”(physical association)	0.560
KRTAP10-7	CBX2	psi-mi:“MI:0915”(physical association)	0.560
CBX2	KRTAP10-9	psi-mi:“MI:0915”(physical association)	0.560
RBMY1F	CBX2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (224): CBX2 (Two-hybrid), KRTAP2-4 (Two-hybrid), DHX57 (Two-hybrid), RBMY1F (Two-hybrid), KRTAP10-7 (Two-hybrid), KRTAP10-9 (Two-hybrid), KRTAP10-1 (Two-hybrid), KRTAP10-3 (Two-hybrid), CBX2 (Protein-peptide), CBX2 (Affinity Capture-MS), CBX2 (Affinity Capture-MS), CBX2 (Affinity Capture-MS), CBX2 (Two-hybrid), CBX2 (Two-hybrid), CBX2 (Proximity Label-MS)

ESM2 similar proteins: A2VDR9, A5PKG8, A6NMT0, A7MB40, A8MUI8, E2R9X2, O00257, O15353, O43151, O55187, P19419, P30658, P48382, P52950, P59598, Q03989, Q0GGX2, Q13029, Q14781, Q28BT7, Q2MHN3, Q32MQ0, Q32N19, Q3SWY1, Q3TEI4, Q3U108, Q3UHR0, Q497V6, Q568E2, Q571I4, Q5JPB2, Q5NSW5, Q5TGY3, Q61818, Q6PAL7, Q6ZRI6, Q7TSH3, Q7Z5J4, Q811R2, Q86YN6

Diamond homologs: A0A0P0VUY4, G3V8T1, O60016, O95931, P05205, P23198, P29227, P30658, P45968, P45973, P60889, P83916, P83917, Q10103, Q13185, Q14781, Q3TYA6, Q5F3W5, Q5KQL9, Q5R6X7, Q61686, Q6AYK9, Q8N8U2, Q8VDS3, Q94F87, Q99549, Q9AXT8, Q9D5D8, Q9WTK2, Q9Y232, Q9Y6F7, Q9Y6F8, G5EDE2, G5EET5, O00257, O43463, O54864, O55187, O95503, P26017

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CBX2	“form complex”	“Polycomb repressive complex 1”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 97 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
SUMOylation of DNA methylation proteins	9	90.2×	5e-14
RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known	10	44.9×	2e-12
SUMOylation of transcription cofactors	10	36.3×	1e-11
SUMOylation of RNA binding proteins	10	35.5×	1e-11
Transcriptional Regulation by E2F6	7	30.6×	1e-07
Regulation of PTEN gene transcription	9	24.0×	6e-09
SUMOylation of DNA damage response and repair proteins	10	21.9×	2e-09
SUMOylation of chromatin organization proteins	9	21.3×	2e-08

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	6	12.9×	2e-03
nucleosome assembly	6	9.8×	5e-03
chromatin remodeling	9	7.6×	1e-03
RNA splicing	7	7.2×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	129
Likely benign	41
Benign	16

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
6826	NM_005189.3(CBX2):c.293C>T (p.Pro98Leu)	Pathogenic
6827	NM_005189.3(CBX2):c.1328G>C (p.Arg443Pro)	Pathogenic

SpliceAI

637 predictions. Top by Δscore:

Variant	Effect	Δscore
17:79778305:AAGGT:A	donor_loss	1.0000
17:79778308:G:GA	donor_loss	1.0000
17:79778309:T:A	donor_loss	1.0000
17:79778425:CAAGT:C	donor_loss	1.0000
17:79778426:AAGT:A	donor_loss	1.0000
17:79778428:G:GG	donor_gain	1.0000
17:79778428:GT:G	donor_loss	1.0000
17:79778429:TGAGT:T	donor_loss	1.0000
17:79779360:A:AG	acceptor_gain	1.0000
17:79779361:G:GA	acceptor_gain	1.0000
17:79779361:GA:G	acceptor_gain	1.0000
17:79779361:GAC:G	acceptor_gain	1.0000
17:79779425:G:GT	donor_gain	1.0000
17:79779425:GAA:G	donor_gain	1.0000
17:79779428:G:GG	donor_gain	1.0000
17:79779433:G:GT	donor_gain	1.0000
17:79778403:TC:T	donor_gain	0.9900
17:79778423:TCCAA:T	donor_gain	0.9900
17:79778425:CAA:C	donor_gain	0.9900
17:79778426:AA:A	donor_gain	0.9900
17:79778430:GAGTC:G	donor_loss	0.9900
17:79779357:TGCA:T	acceptor_loss	0.9900
17:79779358:GCAG:G	acceptor_loss	0.9900
17:79779359:CAG:C	acceptor_loss	0.9900
17:79779361:GACA:G	acceptor_gain	0.9900
17:79779361:GACAT:G	acceptor_gain	0.9900
17:79778308:G:GG	donor_gain	0.9800
17:79778382:AG:A	acceptor_gain	0.9800
17:79778383:GG:G	acceptor_gain	0.9800
17:79779424:AGAAG:A	donor_loss	0.9800

AlphaMissense

3463 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:79778269:T:C	F12L	1.000
17:79778270:T:C	F12S	1.000
17:79778270:T:G	F12C	1.000
17:79778271:C:A	F12L	1.000
17:79778271:C:G	F12L	1.000
17:79778276:C:A	A14D	1.000
17:79778285:T:A	I17N	1.000
17:79778285:T:C	I17T	1.000
17:79778285:T:G	I17S	1.000
17:79778288:T:C	L18P	1.000
17:79778396:T:G	Y29D	1.000
17:79778400:T:C	L30P	1.000
17:79778403:T:A	V31D	1.000
17:79778407:G:C	K32N	1.000
17:79778407:G:T	K32N	1.000
17:79778408:T:A	W33R	1.000
17:79778408:T:C	W33R	1.000
17:79778409:G:C	W33S	1.000
17:79778410:G:C	W33C	1.000
17:79778410:G:T	W33C	1.000
17:79778414:G:C	G35R	1.000
17:79778417:T:A	W36R	1.000
17:79778417:T:C	W36R	1.000
17:79778418:G:C	W36S	1.000
17:79778419:G:C	W36C	1.000
17:79778419:G:T	W36C	1.000
17:79779368:C:A	N41K	1.000
17:79779368:C:G	N41K	1.000
17:79779369:A:C	S42R	1.000
17:79779371:C:A	S42R	1.000

dbSNP variants (sampled 300 via entrez): RS1000019274 (17:79785428 G>A,C), RS1000165054 (17:79785864 C>G), RS1000337948 (17:79778934 C>T), RS1001467738 (17:79779119 C>T), RS1002107162 (17:79778982 C>T), RS1002126642 (17:79782910 G>A), RS1002413780 (17:79782776 T>C,G), RS1002468712 (17:79780181 C>G,T), RS1002915283 (17:79787708 G>A), RS1003107086 (17:79779875 G>A,C), RS1003533417 (17:79783951 C>G), RS1004460877 (17:79777395 G>C), RS1004655255 (17:79786275 G>A), RS1004803922 (17:79786165 C>T), RS1004896028 (17:79777565 T>C)

Disease associations

OMIM: gene MIM:602770 | disease phenotypes: MIM:400044, MIM:613080

GenCC curated gene-disease

Disease	Classification	Inheritance
46,XY complete gonadal dysgenesis	Supportive	Autosomal dominant
46,XY sex reversal 5	Limited	Semidominant

Mondo (3): disorder of sexual differentiation (MONDO:0002145), 46,XY complete gonadal dysgenesis (MONDO:0010765), 46,XY sex reversal 5 (MONDO:0013120)

Orphanet (2): Difference of sex development (Orphanet:90771), 46,XY complete gonadal dysgenesis (Orphanet:242)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000037	Male pseudohermaphroditism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000055	Abnormal female external genitalia morphology
HP:0000147	Polycystic ovaries
HP:0003577	Congenital onset
HP:0008232	Elevated circulating follicle stimulating hormone level
HP:0008733	Dysplastic testis
HP:0011731	Abnormality of circulating cortisol level
HP:0012245	Sex reversal
HP:0030345	Abnormal circulating luteinizing hormone concentration

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST010703_16	Brain morphology (MOSTest)	1.000000e-09

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D012734	Disorders of Sex Development	C12.050.351.875.253; C12.200.706.316; C12.800.316; C16.131.939.316; C19.391.119
D006061	Gonadal Dysgenesis, 46,XY	C12.050.351.875.253.096.687; C12.050.351.875.253.309.388; C12.200.706.316.096.687; C12.200.706.316.309.388; C12.800.316.096.687; C12.800.316.309.388; C16.131.939.316.096.687; C16.131.939.316.309.388; C19.391.119.096.687; C19.391.119.309.388
C567766	46, XY Sex Reversal 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3779761 (SINGLE PROTEIN)

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

ChEMBL bioactivities

13 potent at pChembl≥5 of 15 total, top 12 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.10	Kd	80	nM	CHEMBL5723325
6.96	Kd	110	nM	CHEMBL5723325
6.52	Kd	300	nM	CHEMBL3780251
6.41	Kd	390	nM	CHEMBL4635096
5.96	Kd	1100	nM	CHEMBL4646516
5.82	Kd	1500	nM	CHEMBL4640223
5.80	Kd	1600	nM	CHEMBL3780712
5.76	Kd	1750	nM	CHEMBL5715919
5.75	Kd	1800	nM	CHEMBL3939958
5.51	Kd	3100	nM	CHEMBL4637043
5.34	Kd	4600	nM	CHEMBL5715922
5.00	Kd	1e+04	nM	CHEMBL4643012

PubChem BioAssay actives

8 with measured affinity, of 14 total; 8 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
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxohexyl]-trimethylazanium	1288271: Binding affinity to N-terminal His6-tagged human CBX2 (8 to 62) expressed in Escherichia coli BL21 using FITC-peptide-3 as competitive binding probe by fluorescence polarization assay	kd	0.3000	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-2-cyclopentylacetyl]amino]-6-oxohexyl]-trimethylazanium	1650075: Binding affinity to CBX2 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	0.3900	uM
[(5S)-6-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[3-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]propanoylamino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-oxohexyl]-trimethylazanium	1650075: Binding affinity to CBX2 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	1.1000	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-3-phenylpropanoyl]amino]-6-oxohexyl]-trimethylazanium	1650075: Binding affinity to CBX2 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	1.5000	uM
[(5S)-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-bromobenzoyl)amino]-3-phenylpropanoyl]amino]butanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-oxohexyl]-trimethylazanium	1288271: Binding affinity to N-terminal His6-tagged human CBX2 (8 to 62) expressed in Escherichia coli BL21 using FITC-peptide-3 as competitive binding probe by fluorescence polarization assay	kd	1.6000	uM
methyl (2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[(4-tert-butylbenzoyl)amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-(diethylamino)hexanoyl]amino]-3-hydroxypropanoate	1319530: Binding affinity to human N-terminal his-tagged CBX2 chromodomain (9 to 66 residues) expressed in Escherichia coli Rosetta BL21(DE3)pLysS by ITC method	kd	1.8000	uM
[(5S)-6-[[(2S)-1-amino-3-hydroxy-1-oxopropan-2-yl]amino]-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[3-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]propanoylamino]-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]propanoyl]amino]-4-methylpentanoyl]amino]-6-oxohexyl]-trimethylazanium	1650075: Binding affinity to CBX2 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	3.1000	uM
[(5S)-5-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-acetamido-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]butanoyl]amino]-2-cyclopentylacetyl]amino]-6-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-6-[[3-carboxy-4-(3-hydroxy-6-oxoxanthen-9-yl)phenyl]carbamothioylamino]-1-oxohexan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-6-oxohexyl]-trimethylazanium	1650075: Binding affinity to CBX2 (unknown origin) assessed as dissociation constant by fluorescence polarization analysis	kd	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases methylation, affects cotreatment	6
trichostatin A	affects cotreatment, decreases expression, affects expression	4
bisphenol A	affects expression, increases expression	2
sodium arsenite	decreases expression	2
Benzo(a)pyrene	increases methylation, increases expression	2
Calcitriol	affects cotreatment, decreases expression	2
Estradiol	affects cotreatment, increases expression	2
Nickel	increases expression	2
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
beta-lapachone	decreases expression	1
nickel sulfate	increases expression	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	decreases expression, increases response to substance	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
Temozolomide	increases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Copper	affects binding, decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Lead	affects expression	1

ChEMBL screening assays

12 unique, capped per target: 11 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3782542	Binding	Binding affinity to N-terminal His6-tagged human CBX2 (8 to 62) expressed in Escherichia coli BL21 using FITC-peptide-3 as competitive binding probe by fluorescence polarization assay	Selective Inhibition of CBX6: A Methyllysine Reader Protein in the Polycomb Family. — ACS Med Chem Lett
CHEMBL5723287	Functional	Affinity Biochemical interaction: (Fluorescence polarisation (fluorescein conjugated)) EUB0002728a CBX2	Affinity Biochemical Literature for EUbOPEN Chemogenomic Library

Cellosaurus cell lines

3 cell lines: 3 embryonic stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_A0L0	SEES3-1V human CBX2, clone1	Embryonic stem cell	Male
CVCL_A0L1	SEES3-1V human CBX2, clone2	Embryonic stem cell	Male
CVCL_A0L2	SEES3-1V human CBX2, clone3	Embryonic stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03718234	PHASE1	COMPLETED	Subcutaneous Hydrocortisone Children With Congenital Adrenal Hyperplasia
NCT00485186	Not specified	WITHDRAWN	Gene Polymorphisms Influencing Steroid Synthesis and Action
NCT01875640	Not specified	COMPLETED	Decision Support for Parents Receiving Information About Child’s Rare Disease
NCT02784184	Not specified	UNKNOWN	COPENHAGEN Minipuberty Study
NCT03102554	Not specified	ENROLLING_BY_INVITATION	Genetics of Differences of Sex Development and Hypospadias
NCT03283852	Not specified	RECRUITING	Identifying New Genetic Causes to Development Disorders
NCT04195490	Not specified	UNKNOWN	Evaluation of Outcomes of Feminizing Genitoplasty in Children With Disorders of Sex Development
NCT04463316	Not specified	RECRUITING	GROWing Up With Rare GENEtic Syndromes
NCT04717349	Not specified	RECRUITING	Data Collection Study of Pediatric and Adolescent Gynecology Conditions
NCT05058781	Not specified	RECRUITING	Minipuberty in Infants Born With Potential Hypogonadism Hypogonadotrope
NCT06692049	Not specified	RECRUITING	Gonadal Tissue Cryopreservation for Fertility Preservation in Children with a Disorder of Sex Development
NCT06989593	Not specified	RECRUITING	Breaking Silence Through Story: A Narrative Medicine Intervention for Parents of Children With Urogenital Conditions