CENPA

Summary

CENPA (centromere protein A, HGNC:1851) is a protein-coding gene on chromosome 2p23.3, encoding Histone H3-like centromeric protein A (P49450). Histone H3-like nucleosomal protein that is specifically found in centromeric nucleosomes. It is a common-essential gene (DepMap: required in 93.5% of cancer cell lines).

Centromeres are the differentiated chromosomal domains that specify the mitotic behavior of chromosomes. This gene encodes a centromere protein which contains a histone H3 related histone fold domain that is required for targeting to the centromere. Centromere protein A is proposed to be a component of a modified nucleosome or nucleosome-like structure in which it replaces 1 or both copies of conventional histone H3 in the (H3-H4)2 tetrameric core of the nucleosome particle. The protein is a replication-independent histone that is a member of the histone H3 family. Alternative splicing results in multiple transcript variants encoding distinct isoforms.

Source: NCBI Gene 1058 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 15 total
• Cancer dependency (DepMap): dependent in 93.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_001809

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1851
Approved symbol	CENPA
Name	centromere protein A
Location	2p23.3
Locus type	gene with protein product
Status	Approved
Aliases	CENP-A, CenH3
Ensembl gene	ENSG00000115163
Ensembl biotype	protein_coding
OMIM	117139
Entrez	1058

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 3 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000233505, ENST00000335756, ENST00000419525, ENST00000460030, ENST00000472719, ENST00000475662, ENST00000916420

RefSeq mRNA: 2 — MANE Select: NM_001809 NM_001042426, NM_001809

CCDS: CCDS1729, CCDS42662

Canonical transcript exons

ENST00000335756 — 5 exons

Exon	Start	End
ENSE00001358334	26793812	26794589
ENSE00001358353	26786056	26786296
ENSE00003563717	26792756	26792833
ENSE00003577712	26793145	26793326
ENSE00003601718	26792131	26792240

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 98.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 31.8077 / max 242.4479, expressed in 1462 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
19276	46.3871	1817
19279	31.5342	1460
19280	0.2735	133

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	98.05	gold quality
secondary oocyte	CL:0000655	96.59	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.72	gold quality
ventricular zone	UBERON:0003053	91.91	gold quality
endometrium epithelium	UBERON:0004811	90.56	gold quality
buccal mucosa cell	CL:0002336	86.96	silver quality
ganglionic eminence	UBERON:0004023	85.14	gold quality
embryo	UBERON:0000922	84.92	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.92	gold quality
thymus	UBERON:0002370	82.30	gold quality
trabecular bone tissue	UBERON:0002483	80.31	gold quality
bone marrow	UBERON:0002371	79.65	gold quality
stromal cell of endometrium	CL:0002255	77.89	gold quality
mucosa of transverse colon	UBERON:0004991	77.23	gold quality
esophagus squamous epithelium	UBERON:0006920	77.00	gold quality
ileal mucosa	UBERON:0000331	76.78	gold quality
lower esophagus mucosa	UBERON:0035834	76.53	gold quality
oral cavity	UBERON:0000167	73.87	gold quality
rectum	UBERON:0001052	73.75	gold quality
vermiform appendix	UBERON:0001154	73.59	gold quality
esophagus mucosa	UBERON:0002469	73.52	gold quality
epithelium of esophagus	UBERON:0001976	73.10	gold quality
gingival epithelium	UBERON:0001949	72.89	gold quality
pancreatic ductal cell	CL:0002079	72.74	silver quality
lymph node	UBERON:0000029	72.61	gold quality
bone marrow cell	CL:0002092	72.12	gold quality
squamous epithelium	UBERON:0006914	71.67	gold quality
gingiva	UBERON:0001828	71.15	gold quality
jejunal mucosa	UBERON:0000399	70.43	gold quality
caecum	UBERON:0001153	70.14	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6108	yes	259.39
E-MTAB-9689	no	182.51
E-MTAB-6524	no	177.38
E-ANND-3	no	2.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXM1

miRNA regulators (miRDB)

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

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-219A-5P	99.91	73.36	735
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-4782-3P	99.88	73.31	735
HSA-MIR-6766-3P	99.88	73.38	732
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-3660	99.68	67.33	1149
HSA-MIR-4526	99.68	67.07	1136
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-3120-3P	99.54	70.28	2669

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 93.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• CENP-A, -B, and -C chromatin complex that contains the I-type alpha-satellite array constitutes the prekinetochore in HeLa cells (PMID:11884609)
• Overexpression of this protein plays an important role for aneuploidy in colorectal cancers. (PMID:12839935)
• phosphorylation of CENP-A on Ser-7 by Aurora-A in prophase is essential for kinetochore function. (PMID:14667408)
• the centromere-targeting domain of CENP-A confers a unique structural rigidity to the nucleosomes into which it assembles, and it is likely to have a role in maintaining centromere identity (PMID:15282608)
• Results suggest a role for increased CENP-A incorporation in the faithful segregation of larger chromosomes & facilitate assembly of larger kinetochore structures. (PMID:15702419)
• The CENP-A nucleosome associated complex (NAC) is essential, as disruption of the complex causes errors of chromosome alignment and segregation. (PMID:16622419)
• The CENP-H-I complex may function, in part, as a marker directing CENP-A deposition to centromeres. (PMID:16622420)
• Three human proteins essential for centromere/kinetochore structure and function, hMis18alpha, hMis18beta, and M18BP1, the complex of which is accumulated specifically at the telophase-G1 centromere, are identified. (PMID:17199038)
• depletion of CENP-A is lethal, but recruitment of normal levels of kinetochore proteins, centromere-generated mitotic checkpoint signaling, chromosome segregation, and viability can be rescued by histone H3 carrying the CENP-A targeting domain (PMID:17244537)
• CENP-A bound to a mature centromere is quantitatively and equally partitioned to sister centromeres generated during S phase, thereby remaining stably associated through multiple cell divisions. (PMID:17339380)
• Centromeric chromatin consists of several CENP-A subdomains. (PMID:17651496)
• Results suggest that the cooperative action of CENP-A NAC/CAD subunits and the KMN network drives efficient chromosome segregation and bipolar spindle assembly during mitosis. (PMID:18007590)
• data support the view that two CENP-A molecules are packed with H4, but not with H3, in a single centromeric nucleosome (PMID:18072184)
• HJURP is a possible cell-cycle-regulated CENP-A-specific histone chaperone required for centromeric chromatin assembly (PMID:19410544)
• HJURP is a key factor for CENP-A deposition and maintenance at centromeres (PMID:19410545)
• Acceptor-bleaching FRET indicates that CENP-T directly associates with CENP-A and CENP-B. (PMID:19412974)
• Data suggest that CENP-N interprets the information encoded within CENP-A nucleosomes and recruits other proteins to centromeric chromatin that are required for centromere function and propagation. (PMID:19543270)
• CENP-H-containing complex facilitates deposition of newly synthesized CENP-A into centromeric chromatin in cooperation with FACT and CHD1. (PMID:19625449)
• The centromere-targeting domain of CENP-A is both necessary and sufficient for recruitment to double-strand breaks. CENP-A accumulation at DNA breaks is enhanced by active non-homologous end-joining but does not require DNA-PKcs or Ligase IV. (PMID:19717431)
• findings indicate a novel aspect of pRb acute loss that promotes aneuploidy mainly by inducing CENPA overexpression (PMID:20003272)
• found that HJURP, a member of the complex, was required for cell cycle specific targeting of CENP-A to centromeres. (PMID:20080577)
• p53-dependent senescence that arises from CENP-A reduction acts as a “self-defense mechanism” to prevent centromere-defective cells from undergoing mitotic proliferation that potentially leads to massive generation of aneuploid cells. (PMID:20160010)
• Studies indicate that CENP-A is strongly favored as the epigenetic mark that specifies centromere identity. (PMID:20206496)
• On chromosomes 1 and 19, which are more affected by the above evolutionary mechanisms than are chromosomes 21 and 5, CENP-A associated repeats were also recovered from a second homogeneous array present on each chromosome. (PMID:20331851)
• CENP-C binds directly to CENP-A chromatin and, together with CENP-N, provides the foundation upon which other centromere and kinetochore proteins are assembled. (PMID:20566683)
• Using autoantibodies from systemic sclerosis (SSc) patients, two anti-CENP-A-specific motifs were defined in its immunodominant epitope Ap17-30. One of these motifs matched residues 53-62 of FOXE3, a protein not previously implicated in SSc. (PMID:20630806)
• results show pluripotent stem cells have mechanism to maintain genomic integrity by possessing flexibility to reduce CENPA required to maintain functional centromere under self-renewing conditions and maintaining reserve CENPA mRNA to rebuild centromere (PMID:20650959)
• crystal structure of a subnucleosomal heterotetramer, (CENP-A-H4)(2); results indicate that CENP-A marks centromere location by restructuring the nucleosome from within its folded histone core (PMID:20739937)
• CENP-A nucleosomes are organized as asymmetric heterotypic tetramers rather than canonical octamers, forming a chromatin fiber with distinct folding characteristics (PMID:21059934)
• Results report that the level of CENP-A, a protein required for cell division, declines precipitously with age in an islet-specific manner. (PMID:21068465)
• UNG2 colocalizes with CENP-A and H2AX phosphorylation at centromeres in normally cycling cells. (PMID:21399697)
• Overexpression of CENP-A is frequently observed in hepatocellular carcinoma. (PMID:21423629)
• The crystal structure of an HJURP-CENP-A-histone H4 complex shows that HJURP binds a CENP-A-H4 heterodimer (PMID:21478274)
• crystal structure of the human centromeric nucleosome containing CENP-A; CENP-A loop 1 may function in stabilizing the centromeric chromatin containing CENP-A, possibly by providing a binding site for trans-acting factors (PMID:21743476)
• The data suggest that the role of the Mis18 complex in CENP-A deposition is to recruit HJURP and that the CENP-A nucleosome assembly activity of HJURP is responsible for centromeric chromatin assembly to maintain the epigenetic mark. (PMID:21768289)
• Two neocentromeres formed in chromosome 8q21 with a unique DNA and CENP-A chromatin configuration. (PMID:21826412)
• overexpression of CENP-A is closely associated with hepatitis B virus x protein COOH mutation in hepatocellular carcinoma (PMID:21956590)
• structural comparison between CENP-A and H3 in nucleosomes (PMID:22127263)
• CENP-A and/or B status is predictive of the extent of skin involvement over time in systemic sclerosis. (PMID:22467948)
• The authors report that de novo CENP-A assembly and kinetochore formation on human centromeric alphoid DNA arrays is regulated by a histone H3K9 acetyl/methyl balance. (PMID:22473132)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	selenoh	ENSDARG00000093022
mus_musculus	Cenpa	ENSMUSG00000029177
rattus_norvegicus		ENSRNOG00000071944
caenorhabditis_elegans		WBGENE00001831
caenorhabditis_elegans		WBGENE00010036

Paralogs (20): H3-3B (ENSG00000132475), H3-3A (ENSG00000163041), H3-4 (ENSG00000168148), H3C13 (ENSG00000183598), H3-5 (ENSG00000188375), H3C12 (ENSG00000197153), H3C4 (ENSG00000197409), H3C14 (ENSG00000203811), H3C15 (ENSG00000203852), H3Y2 (ENSG00000268799), H3Y1 (ENSG00000269466), H3-7 (ENSG00000273213), H3C8 (ENSG00000273983), H3C6 (ENSG00000274750), H3C11 (ENSG00000275379), H3C1 (ENSG00000275714), H3C7 (ENSG00000277775), H3C10 (ENSG00000278828), H3C2 (ENSG00000286522), H3C3 (ENSG00000287080)

Protein

Protein identifiers

Histone H3-like centromeric protein A — P49450 (reviewed: P49450)

Alternative names: Centromere autoantigen A, Centromere protein A

All UniProt accessions (2): P49450, F8WD88

UniProt curated annotations — full annotation on UniProt →

Function. Histone H3-like nucleosomal protein that is specifically found in centromeric nucleosomes. Replaces conventional H3 in the nucleosome core of centromeric chromatin that serves as an assembly site for the inner kinetochore. The presence of CENPA subtly modifies the nucleosome structure and the way DNA is wrapped around the nucleosome and gives rise to protruding DNA ends that are less well-ordered and rigid compared to nucleosomes containing histone H3. May serve as an epigenetic mark that propagates centromere identity through replication and cell division. Required for recruitment and assembly of kinetochore proteins, and as a consequence required for progress through mitosis, chromosome segregation and cytokinesis.

Subunit / interactions. Component of centromeric nucleosomes, where DNA is wrapped around a histone octamer core. The octamer contains two molecules each of H2A, H2B, CENPA and H4 assembled in one CENPA-H4 heterotetramer and two H2A-H2B heterodimers. CENPA modulates the DNA-binding characteristics of nucleosomes so that protruding DNA ends have higher flexibility than in nucleosomes containing conventional histone H3. Inhibits binding of histone H1 to nucleosomes, since histone H1 binds preferentially to rigid DNA linkers that protrude from nucleosomes. Nucleosomes containing CENPA also contain histone H2A variants such as MACROH2A and H2A.Z/H2AZ1. The CENPA-H4 heterotetramer is more compact and structurally more rigid than corresponding H3-H4 heterotetramers. Can assemble into nucleosomes that contain both CENPA and histone H3.3; these nucleosomes interact with a single CENPC chain. Heterotrimer composed of HJURP, CENPA and histone H4, where HJURP interacts with the dimer formed by CENPA and histone H4 and prevents tetramerization of CENPA and H4. Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. Interacts (via CATD domain) with HJURP; the interaction is direct and is required for its localization to centromeres. Interacts with CENPC, CENPN and CENPT; interaction is direct. Part of a centromere complex consisting of CENPA, CENPT and CENPW. Identified in centromere complexes containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1. Can self-associate. The CENPA-H4 heterotetramer can bind DNA by itself (in vitro). Interacts with CDK1, PPP1CA and RBBP7. (Microbial infection) Interacts directly with herpes virus HHV-1 protein ICP0.

Subcellular location. Nucleus. Chromosome. Centromere.

Post-translational modifications. Ubiquitinated. Interaction with herpes virus HSV-1 ICP0 protein, leads to its degradation by the proteasome pathway. Trimethylated by NTMT1 at the N-terminal glycine after cleavage of Met-1. Methylation is low before incorporation into nucleosomes and increases with cell cycle progression, with the highest levels in mitotic nucleosomes. Phosphorylated by CDK1 at Ser-68 during early mitosis; this abolishes association with chromatin and centromeres, prevents interaction with HJURP and thereby prevents premature assembly of CENPA into centromeres. Dephosphorylated at Ser-68 by PPP1CA during late mitosis. Phosphorylation of Ser-7 by AURKA and AURKB during prophase is required for localization of AURKA and AURKB at inner centromere and is essential for normal cytokinesis. Initial phosphorylation during prophase is mediated by AURKA and is maintained by AURKB. Poly-ADP-ribosylated by PARP1.

Domain organisation. The CATD (CENPA targeting domain) region is responsible for the more compact structure of nucleosomes containing CENPA. It is necessary and sufficient to mediate the localization into centromeres.

Miscellaneous. Antibodies against CENPA are present in sera from patients with autoimmune diseases that developed autoantibodies against centrosomal proteins.

Similarity. Belongs to the histone H3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49450-1	1	yes
P49450-2	2

RefSeq proteins (2): NP_001035891, NP_001800* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000164	Histone_H3/CENP-A	Family
IPR007125	H2A/H2B/H3	Domain
IPR009072	Histone-fold	Homologous_superfamily

Pfam: PF00125

UniProt features (29 total): mutagenesis site 8, modified residue 6, helix 4, region of interest 3, strand 3, initiator methionine 1, chain 1, splice variant 1, turn 1, compositionally biased region 1

Structure

Experimental structures (PDB)

36 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
5CVD	X-RAY DIFFRACTION	1.3
6KDQ	X-RAY DIFFRACTION	1.5
6KDS	X-RAY DIFFRACTION	1.84
3NQJ	X-RAY DIFFRACTION	2.1
7R5R	ELECTRON MICROSCOPY	2.44
3NQU	X-RAY DIFFRACTION	2.5
5ZBX	X-RAY DIFFRACTION	2.58
3R45	X-RAY DIFFRACTION	2.6
6E0P	ELECTRON MICROSCOPY	2.6
6E0C	ELECTRON MICROSCOPY	2.63
3WTP	X-RAY DIFFRACTION	2.67
7PII	ELECTRON MICROSCOPY	2.68
7U46	ELECTRON MICROSCOPY	2.68
5Z23	X-RAY DIFFRACTION	2.73
7D20	ELECTRON MICROSCOPY	3
6SEG	ELECTRON MICROSCOPY	3.1
6O1D	ELECTRON MICROSCOPY	3.4
6MUP	ELECTRON MICROSCOPY	3.5
6SE6	ELECTRON MICROSCOPY	3.5
3AN2	X-RAY DIFFRACTION	3.6
6MUO	ELECTRON MICROSCOPY	3.6
9K9L	ELECTRON MICROSCOPY	3.66
6SEF	ELECTRON MICROSCOPY	3.7
6SE0	ELECTRON MICROSCOPY	3.8
6TEM	ELECTRON MICROSCOPY	3.9
6BUZ	ELECTRON MICROSCOPY	3.92
6C0W	ELECTRON MICROSCOPY	4
9GXA	ELECTRON MICROSCOPY	4.01
6SEE	ELECTRON MICROSCOPY	4.2
9TAX	ELECTRON MICROSCOPY	4.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49450-F1	81.96	0.62

Antibody-complex structures (SAbDab): 2 — 6E0C, 6E0P

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 (6): 27, 68, 2, 7, 17, 19

Mutagenesis-validated functional residues (8):

Position	Phenotype
7	induces a delay at the terminal stage of cytokinesis and chromosome misalignment during mitosis due to a defect in kinet
17	impaired mitotic chromosome congression and chromosome segregation; when associated with a-19.
19	impaired mitotic chromosome congression and chromosome segregation; when associated with a-17.
68	no effect on interaction with hjurp. impairs localization at centromeres.
68	impairs interaction with hjurp, association with chromatin and localization at centromeres.
80–81	impairs retention at centromeres, but not targeting to centromeres.
104	reduces location at centromeres. abolishes location at centromeres; when associated with c-112.
112	no effect on location at centromeres. abolishes location at centromeres; when associated with g-104.

Function

Pathways and Gene Ontology

Reactome pathways

21 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-606279	Deposition of new CENPA-containing nucleosomes at the centromere
R-HSA-68877	Mitotic Prometaphase
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-141424	Amplification of signal from the kinetochores
R-HSA-162582	Signal Transduction
R-HSA-1640170	Cell Cycle
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195258	RHO GTPase Effectors
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-68882	Mitotic Anaphase
R-HSA-68886	M Phase
R-HSA-69278	Cell Cycle, Mitotic
R-HSA-69618	Mitotic Spindle Checkpoint
R-HSA-69620	Cell Cycle Checkpoints
R-HSA-73886	Chromosome Maintenance
R-HSA-774815	Nucleosome assembly
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 427 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_UP, GOBP_MITOTIC_CYTOKINESIS, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, MODULE_52, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, MODULE_451, KANG_DOXORUBICIN_RESISTANCE_UP, SHIPP_DLBCL_VS_FOLLICULAR_LYMPHOMA_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, CROONQUIST_NRAS_SIGNALING_DN, GOBP_SPINDLE_LOCALIZATION, OHASHI_AURKB_TARGETS, GOBP_CHROMOSOME_LOCALIZATION

GO Biological Process (7): establishment of mitotic spindle orientation (GO:0000132), mitotic cytokinesis (GO:0000281), CENP-A containing chromatin assembly (GO:0034080), kinetochore assembly (GO:0051382), protein localization to CENP-A containing chromatin (GO:0061644), protein localization to chromosome, centromeric region (GO:0071459), cell division (GO:0051301)

GO Molecular Function (5): DNA binding (GO:0003677), chromatin binding (GO:0003682), structural constituent of chromatin (GO:0030527), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515)

GO Cellular Component (10): chromosome, centromeric region (GO:0000775), condensed chromosome, centromeric region (GO:0000779), nucleosome (GO:0000786), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), cytosol (GO:0005829), CENP-A containing nucleosome (GO:0043505), chromosome (GO:0005694), CENP-A containing chromatin (GO:0061638)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Cell Cycle	3
Mitotic Prometaphase	2
M Phase	2
Amplification of signal from the kinetochores	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
Nucleosome assembly	1
Mitotic Spindle Checkpoint	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Mitotic Metaphase and Anaphase	1
Cell Cycle, Mitotic	1
Cell Cycle Checkpoints	1
Chromosome Maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
chromatin	3
mitotic cell cycle	2
binding	2
chromosome, centromeric region	2
cellular anatomical structure	2
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
chromatin organization	1
kinetochore assembly	1
protein localization to CENP-A containing chromatin	1
kinetochore organization	1
protein-containing complex assembly	1
membraneless organelle assembly	1
protein localization to chromatin	1
protein localization to chromosome, centromeric region	1
protein localization to chromosome	1
cellular process	1
nucleic acid binding	1
structural molecule activity	1
protein dimerization activity	1
chromosomal region	1
condensed chromosome	1
protein-DNA complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
heterochromatin	1
cytoplasm	1
nucleosome	1
CENP-A containing chromatin	1
intracellular membraneless organelle	1
chromosome, centromeric core domain	1

Protein interactions and networks

STRING

3812 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CENPA	CENPC	Q03188	999
CENPA	CENPB	P07199	990
CENPA	CENPH	Q9H3R5	989
CENPA	CENPI	Q92674	988
CENPA	CENPN	Q96H22	982
CENPA	HJURP	Q8NCD3	970
CENPA	CENPE	Q02224	968
CENPA	CENPK	Q9BS16	960
CENPA	CENPM	Q9NSP4	956
CENPA	H2AC20	Q16777	956
CENPA	H2AC19	P20670	956
CENPA	CENPU	Q71F23	948
CENPA	H4C16	P02304	945
CENPA	CENPT	Q96BT3	940
CENPA	CENPS	Q8N2Z9	938

IntAct

40 interactions, top by confidence:

A	B	Type	Score
HJURP	CENPA	psi-mi:“MI:0914”(association)	0.930
HJURP	CENPA	psi-mi:“MI:0915”(physical association)	0.930
CENPA	HJURP	psi-mi:“MI:0915”(physical association)	0.930
HJURP	CENPA	psi-mi:“MI:0403”(colocalization)	0.930
CENPA	HJURP	psi-mi:“MI:0914”(association)	0.930
H4C16	CENPA	psi-mi:“MI:0407”(direct interaction)	0.790
CENPA	H4C16	psi-mi:“MI:0915”(physical association)	0.790
CENPA	H4C16	psi-mi:“MI:0407”(direct interaction)	0.790
CENPA	NPM1	psi-mi:“MI:0914”(association)	0.600
CENPA	NPM1	psi-mi:“MI:0403”(colocalization)	0.600
CENPA	MCM2	psi-mi:“MI:0915”(physical association)	0.580
MCM2	CENPA	psi-mi:“MI:0914”(association)	0.580
MCM2	CENPA	psi-mi:“MI:0915”(physical association)	0.580
CENPA	OPTN	psi-mi:“MI:0915”(physical association)	0.560
CENPC	CENPA	psi-mi:“MI:0915”(physical association)	0.510
HJURP	CENPA	psi-mi:“MI:0915”(physical association)	0.500
CENPA	SIRT6	psi-mi:“MI:0915”(physical association)	0.400
CENPA	ABL1	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (445): CENPA (Synthetic Growth Defect), COPS8 (Affinity Capture-Western), HJURP (Affinity Capture-Western), CENPA (Reconstituted Complex), CENPA (Biochemical Activity), CDK9 (Affinity Capture-MS), PGK1 (Affinity Capture-MS), MRPL19 (Affinity Capture-MS), ATP5H (Affinity Capture-MS), MRPL3 (Affinity Capture-MS), MRPS27 (Affinity Capture-MS), TMCO1 (Affinity Capture-MS), NOL8 (Affinity Capture-MS), HJURP (Affinity Capture-MS), TBC1D14 (Affinity Capture-MS)

ESM2 similar proteins: A0A1W2PP81, A0A1W2PPE2, A0A1W2PPH5, A0A1W2PPL8, A0A1W2PR64, A0A1W2PRV1, A0A3B3IU63, A4QVR2, A5DQL2, A9UMV8, F4HR03, O35216, P06898, P0C1H6, P0C5Y9, P0C5Z0, P0DW11, P0DW12, P0DW13, P0DW14, P0DW85, P35061, P48003, P49450, Q00728, Q3SZB8, Q3ZBX9, Q4IMD1, Q5M8Q2, Q5TKR9, Q64522, Q64598, Q7Z2G1, Q803H4, Q873G4, Q8BRB7, Q8BZ21, Q8CGP5, Q8IUE6, Q8R1M2

Diamond homologs: A2XHJ3, A2Y533, C0HL66, C0HL67, O15819, O35216, P02299, P02302, P06352, P08437, P08898, P08903, P22843, P49449, P49450, P50564, P59169, P59226, P68427, P68428, P68429, P68430, P68431, P68432, P68433, P69071, P69072, P69073, P69074, P69075, P69076, P69077, P69078, P69079, P69149, P69150, P69244, P69245, P69246, P69248

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
AURKB	unknown	CENPA	phosphorylation
HJURP	“up-regulates activity”	CENPA	binding
NPM1	“up-regulates activity”	CENPA	binding
CDK1	“down-regulates quantity by destabilization”	CENPA	phosphorylation
CENPA	“form complex”	“CENP-A nucleosome”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 16 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
Deposition of new CENPA-containing nucleosomes at the centromere	6	68.0×	4e-08
Cell Cycle, Mitotic	5	17.2×	4e-04
Cell Cycle	6	15.4×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	12
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1565 predictions. Top by Δscore:

Variant	Effect	Δscore
2:26764422:GCAAA:G	donor_gain	1.0000
2:26764423:CAAAG:C	donor_loss	1.0000
2:26764424:AAAGT:A	donor_loss	1.0000
2:26764426:AG:A	donor_loss	1.0000
2:26764427:G:GG	donor_gain	1.0000
2:26774249:AGAT:A	acceptor_gain	1.0000
2:26774250:GATG:G	acceptor_gain	1.0000
2:26775459:CCTA:C	acceptor_loss	1.0000
2:26775461:TA:T	acceptor_loss	1.0000
2:26775462:A:AG	acceptor_gain	1.0000
2:26775463:G:GT	acceptor_gain	1.0000
2:26775463:GC:G	acceptor_gain	1.0000
2:26775463:GCT:G	acceptor_gain	1.0000
2:26775463:GCTC:G	acceptor_gain	1.0000
2:26775463:GCTCT:G	acceptor_gain	1.0000
2:26775664:G:GT	donor_gain	1.0000
2:26775672:CACAG:C	donor_loss	1.0000
2:26775673:ACAGG:A	donor_loss	1.0000
2:26775674:CAGG:C	donor_loss	1.0000
2:26775675:AGGT:A	donor_loss	1.0000
2:26775677:GTGC:G	donor_loss	1.0000
2:26776367:CACAG:C	acceptor_loss	1.0000
2:26776368:ACAG:A	acceptor_gain	1.0000
2:26776368:ACAGG:A	acceptor_gain	1.0000
2:26776369:C:G	acceptor_gain	1.0000
2:26776369:CA:C	acceptor_loss	1.0000
2:26776370:A:AG	acceptor_gain	1.0000
2:26776370:AG:A	acceptor_gain	1.0000
2:26776370:AGG:A	acceptor_gain	1.0000
2:26776370:AGGG:A	acceptor_gain	1.0000

AlphaMissense

886 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:26793148:G:C	A98P	0.994
2:26792229:T:C	F67L	0.993
2:26792231:C:A	F67L	0.993
2:26792231:C:G	F67L	0.993
2:26793157:T:C	F101L	0.992
2:26793159:T:A	F101L	0.992
2:26793159:T:G	F101L	0.992
2:26792801:T:A	W86R	0.991
2:26792801:T:C	W86R	0.991
2:26793181:G:C	A109P	0.989
2:26793153:A:C	E99D	0.988
2:26793153:A:T	E99D	0.988
2:26793229:G:C	D125H	0.988
2:26793230:A:C	D125A	0.987
2:26792803:G:C	W86C	0.985
2:26792803:G:T	W86C	0.985
2:26793218:T:A	L121H	0.985
2:26793230:A:T	D125V	0.984
2:26792195:G:C	Q55H	0.983
2:26792195:G:T	Q55H	0.983
2:26793154:G:C	A100P	0.983
2:26793145:G:C	A97P	0.982
2:26793231:T:A	D125E	0.982
2:26793231:T:G	D125E	0.982
2:26793152:A:T	E99V	0.981
2:26793230:A:G	D125G	0.981
2:26792230:T:C	F67S	0.980
2:26792802:G:C	W86S	0.980
2:26793178:G:C	D108H	0.979
2:26793199:C:G	H115D	0.979

dbSNP variants (sampled 300 via entrez): RS1000190001 (2:26787838 C>G,T), RS1000201191 (2:26787511 G>A,T), RS1000754062 (2:26788441 C>A), RS1000849399 (2:26789725 A>G), RS1000956442 (2:26787967 T>G), RS1001378982 (2:26792907 G>A,C,T), RS1001516069 (2:26794223 G>C), RS1001568258 (2:26793851 A>G), RS1002224140 (2:26786616 G>T), RS1002422304 (2:26786885 G>A), RS1002538568 (2:26792651 A>C), RS1002559764 (2:26785144 A>C), RS1002700769 (2:26786081 G>A,T), RS1003138401 (2:26785830 G>C,T), RS1003380860 (2:26789837 G>C)

Disease associations

OMIM: gene MIM:117139 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST010697_14	Cortical surface area (min-P)	2.000000e-09
GCST010698_75	Subcortical volume (min-P)	2.000000e-13
GCST010699_41	Brain morphology (min-P)	2.000000e-08
GCST010700_38	Cortical thickness (MOSTest)	3.000000e-08
GCST010701_56	Cortical surface area (MOSTest)	4.000000e-16
GCST010702_20	Subcortical volume (MOSTest)	2.000000e-64
GCST010703_76	Brain morphology (MOSTest)	1.000000e-16

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation	4
Estradiol	increases expression, decreases reaction	4
sodium arsenite	increases expression, decreases expression, decreases methylation	3
Cisplatin	affects cotreatment, decreases expression	3
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment	3
bisphenol A	decreases expression, increases expression	2
arsenite	increases reaction, decreases expression, affects binding	2
cobaltous chloride	decreases expression	2
Fulvestrant	decreases expression, decreases reaction, increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Cadmium	decreases reaction, decreases expression	2
Doxorubicin	affects response to substance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
methyleugenol	decreases expression	1
propionaldehyde	decreases expression	1
methylselenic acid	affects expression	1
pyrazolo(3,4-d)pyrimidine	affects expression	1
afimoxifene	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
cupric oxide	decreases expression	1
hydroquinone	decreases expression	1
isobutyl alcohol	decreases expression, increases abundance, affects cotreatment	1
indeno(1,2,3-cd)pyrene	decreases expression	1
diallyl trisulfide	decreases expression	1
beta-methylcholine	affects expression	1

Clinical trials (associated diseases)

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