CENPC

Summary

CENPC (centromere protein C, HGNC:1854) is a protein-coding gene on chromosome 4q13.2, encoding Centromere protein C (Q03188). Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. It is a selective cancer dependency (DepMap: 86.7% of cell lines).

Centromere protein C 1 is a centromere autoantigen and a component of the inner kinetochore plate. The protein is required for maintaining proper kinetochore size and a timely transition to anaphase. A putative pseudogene exists on chromosome 12.

Source: NCBI Gene 1060 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 171 total
• GTEx eGene: eQTL in 44 tissues, sQTL in 3 (q < 0.05)
• Cancer dependency (DepMap): dependent in 86.7% of screened cell lines
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.89 (unconstrained)
• MANE Select transcript: NM_001812
• Notable: 171 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1854
Approved symbol	CENPC
Name	centromere protein C
Location	4q13.2
Locus type	gene with protein product
Status	Approved
Aliases	CENP-C, hcp-4, MIF2
Ensembl gene	ENSG00000145241
Ensembl biotype	protein_coding
OMIM	117141
Entrez	1060

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 8 protein_coding, 8 nonsense_mediated_decay, 3 retained_intron

MANE Select: ENST00000273853

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

ENST00000273853, ENST00000506410, ENST00000506882, ENST00000507196, ENST00000510189, ENST00000513216, ENST00000515140, ENST00000910804, ENST00000929364, ENST00000960630, ENST00000978464, ENST00001031336, ENST00001081194, ENST00001081195, ENST00001104480, ENST00001105505, ENST00001115209, ENST00001115210, ENST00001133243

RefSeq mRNA: 2 — MANE Select: NM_001812 NM_001362481, NM_001812

CCDS: CCDS47063

Canonical transcript exons

ENST00000273853 — 19 exons

Exon	Start	End
ENSE00001156505	67468762	67472675
ENSE00002036687	67545338	67545503
ENSE00003481382	67519217	67519502
ENSE00003489010	67506788	67506934
ENSE00003497249	67518156	67518368
ENSE00003497771	67530815	67530914
ENSE00003505673	67512402	67512569
ENSE00003510849	67495159	67495212
ENSE00003544191	67508814	67509105
ENSE00003549647	67539840	67539934
ENSE00003556321	67493884	67493988
ENSE00003570959	67514074	67514687
ENSE00003591694	67540980	67541050
ENSE00003595330	67489967	67490121
ENSE00003603092	67505205	67505284
ENSE00003604070	67474888	67474978
ENSE00003608882	67492869	67492997
ENSE00003641200	67544149	67544195
ENSE00003691778	67492180	67492275

Expression profiles

Bgee: expression breadth ubiquitous, 146 present calls, max score 96.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.1847 / max 108.5483, expressed in 1117 samples.

Highest expression (Bgee): calcaneal tendon, sural nerve, corpus callosum, bone marrow cell, bone marrow.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CENPC is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 44 tissues and its splicing (sQTL) in 3 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 47 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Nerve Tibial	eqtl	7.5e-56	+0.58	4:67538729:G:A
Whole Blood	eqtl	4.7e-42	-0.50	4:67511596:G:T
Adipose Subcutaneous	eqtl	8.7e-38	-0.62	4:67545510:C:T
Skin Sun Exposed Lower leg	eqtl	1.3e-32	-0.61	4:67545510:C:T
Skin Not Sun Exposed Suprapubic	eqtl	7.2e-30	-0.55	4:67545510:C:T
Cells Cultured fibroblasts	eqtl	6.6e-27	-0.20	4:67457912:A:G
Esophagus Mucosa	eqtl	2.6e-20	-0.43	4:67511596:G:T
Artery Tibial	eqtl	1.5e-16	+0.28	4:67518539:C:T
Testis	eqtl	4.1e-16	+0.34	4:67530454:T:C
Cells EBV-transformed lymphocytes	eqtl	1.2e-15	+0.41	4:67435210:C:A
Thyroid	eqtl	1.9e-15	-0.43	4:67545510:C:T
Spleen	eqtl	2.3e-15	-0.77	4:67511596:G:T
Esophagus Muscularis	eqtl	2.5e-15	+0.34	4:67478263:C:G
Breast Mammary Tissue	eqtl	4.8e-12	-0.38	4:67545510:C:T
Brain Spinal cord cervical c-1	eqtl	1.0e-10	-0.32	4:67420908:A:G
Brain Cerebellum	eqtl	1.1e-10	+0.53	4:67403763:G:C
Lung	eqtl	1.2e-10	-0.37	4:67511596:G:T
Colon Transverse	eqtl	2.7e-10	-0.48	4:67511596:G:T
Artery Aorta	eqtl	1.5e-09	-0.26	4:67441530:C:T
Esophagus Gastroesophageal Junction	eqtl	6.4e-09	+0.29	4:67518539:C:T

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
52309	16.0948	1707
52308	7.8926	1586
52310	2.3479	957
52311	0.8367	451

Top tissues by expression

showing 100 of 157 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	96.48	gold quality
sural nerve	UBERON:0015488	94.07	gold quality
corpus callosum	UBERON:0002336	92.50	gold quality
bone marrow cell	CL:0002092	92.27	gold quality
bone marrow	UBERON:0002371	92.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	91.26	gold quality
tonsil	UBERON:0002372	90.59	gold quality
body of pancreas	UBERON:0001150	88.98	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.58	gold quality
ventricular zone	UBERON:0003053	88.01	gold quality
adrenal tissue	UBERON:0018303	87.29	gold quality
lymph node	UBERON:0000029	86.33	gold quality
left ovary	UBERON:0002119	86.33	gold quality
colonic epithelium	UBERON:0000397	86.32	gold quality
pancreas	UBERON:0001264	86.08	gold quality
ovary	UBERON:0000992	85.84	gold quality
endometrium	UBERON:0001295	85.71	gold quality
tibial nerve	UBERON:0001323	84.56	gold quality
uterine cervix	UBERON:0000002	84.48	gold quality
rectum	UBERON:0001052	84.10	gold quality
vagina	UBERON:0000996	84.07	gold quality
right ovary	UBERON:0002118	83.94	gold quality
minor salivary gland	UBERON:0001830	83.81	gold quality
saliva-secreting gland	UBERON:0001044	83.80	gold quality
thoracic mammary gland	UBERON:0005200	83.67	gold quality
gall bladder	UBERON:0002110	83.60	gold quality
uterus	UBERON:0000995	83.50	gold quality
thyroid gland	UBERON:0002046	83.40	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	83.36	gold quality
duodenum	UBERON:0002114	83.05	gold quality
omental fat pad	UBERON:0010414	83.04	gold quality
vermiform appendix	UBERON:0001154	83.00	gold quality
embryo	UBERON:0000922	82.93	gold quality
ganglionic eminence	UBERON:0004023	82.93	gold quality
esophagus mucosa	UBERON:0002469	82.92	gold quality
right lung	UBERON:0002167	82.78	gold quality
left lobe of thyroid gland	UBERON:0001120	82.75	gold quality
adipose tissue	UBERON:0001013	82.69	gold quality
endocervix	UBERON:0000458	82.64	gold quality
spleen	UBERON:0002106	82.54	gold quality
urinary bladder	UBERON:0001255	82.52	gold quality
stomach	UBERON:0000945	82.48	gold quality
descending thoracic aorta	UBERON:0002345	82.48	gold quality
smooth muscle tissue	UBERON:0001135	82.46	gold quality
subcutaneous adipose tissue	UBERON:0002190	82.41	gold quality
body of uterus	UBERON:0009853	82.22	gold quality
leukocyte	CL:0000738	82.21	gold quality
ectocervix	UBERON:0012249	82.18	gold quality
popliteal artery	UBERON:0002250	82.16	gold quality
tibial artery	UBERON:0007610	82.15	gold quality
monocyte	CL:0000576	82.11	gold quality
esophagus	UBERON:0001043	82.11	gold quality
adrenal gland	UBERON:0002369	82.11	gold quality
prostate gland	UBERON:0002367	82.01	gold quality
body of stomach	UBERON:0001161	81.97	gold quality
right adrenal gland cortex	UBERON:0035827	81.97	gold quality
fundus of stomach	UBERON:0001160	81.93	gold quality
skin of abdomen	UBERON:0001416	81.91	gold quality
small intestine	UBERON:0002108	81.83	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.69	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	81.68	gold quality
right lobe of thyroid gland	UBERON:0001119	81.60	gold quality
intestine	UBERON:0000160	81.57	gold quality
zone of skin	UBERON:0000014	81.56	gold quality
ascending aorta	UBERON:0001496	81.43	gold quality
thoracic aorta	UBERON:0001515	81.39	gold quality
myometrium	UBERON:0001296	81.35	gold quality
pituitary gland	UBERON:0000007	81.30	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.28	gold quality
testis	UBERON:0000473	81.27	gold quality
sigmoid colon	UBERON:0001159	81.26	gold quality
metanephros cortex	UBERON:0010533	81.22	gold quality
mucosa of stomach	UBERON:0001199	81.17	gold quality
colon	UBERON:0001155	81.15	gold quality
skin of leg	UBERON:0001511	81.14	gold quality
liver	UBERON:0002107	81.10	gold quality
islet of Langerhans	UBERON:0000006	81.08	gold quality
left adrenal gland	UBERON:0001234	81.05	gold quality
right adrenal gland	UBERON:0001233	81.02	gold quality
cortex of kidney	UBERON:0001225	81.01	gold quality
left adrenal gland cortex	UBERON:0035825	80.96	gold quality
lower esophagus muscularis layer	UBERON:0035833	80.86	gold quality
adenohypophysis	UBERON:0002196	80.85	gold quality
lower esophagus	UBERON:0013473	80.83	gold quality
lung	UBERON:0002048	80.80	gold quality
left coronary artery	UBERON:0001626	80.53	gold quality
transverse colon	UBERON:0001157	80.41	gold quality
granulocyte	CL:0000094	80.38	gold quality
right lobe of liver	UBERON:0001114	80.35	gold quality
material anatomical entity	UBERON:0000465	80.32	gold quality
anatomical system	UBERON:0000467	80.32	gold quality
multicellular organism	UBERON:0000468	80.32	gold quality
right coronary artery	UBERON:0001625	80.08	gold quality
left testis	UBERON:0004533	79.90	gold quality
right uterine tube	UBERON:0001302	79.74	gold quality
upper lobe of left lung	UBERON:0008952	79.54	gold quality
stromal cell of endometrium	CL:0002255	79.34	gold quality
kidney	UBERON:0002113	79.34	gold quality
right testis	UBERON:0004534	79.32	gold quality
fallopian tube	UBERON:0003889	79.27	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.35

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Cerebellum	tissue	19.3
Corpus callosum	tissue	19.3
Pons	tissue	17.9
Olfactory bulb	tissue	17.8
Spinal cord	tissue	17.7
Midbrain	tissue	17.6
Septum	tissue	17.5
Putamen	tissue	17.3
Superior colliculi	tissue	17.3
Thalamus	tissue	17.2
Ventral forebrain	tissue	17.0
Substantia nigra	tissue	16.6
Hippocampal formation	tissue	16.4
Entorhinal cortex	tissue	16.1
Medulla oblongata	tissue	15.6
Prefrontal cortex	tissue	15.5
Cerebral cortex	tissue	15.5
Motor cortex	tissue	15.5
Hypothalamus	tissue	15.5
Periaqueductal gray	tissue	15.2
Retrosplenial and cingulate cortex	tissue	15.0
Somatosensory cortex	tissue	15.0
Occipital cortex	tissue	14.8
Basal ganglia	tissue	14.7
Amygdala	tissue	14.7
Retrosplenial cortex	tissue	14.3
Temporal cortex	tissue	14.1
Insular cortex	tissue	13.5
Nucleus accumbens	tissue	12.7
Frontal cortex	tissue	9.6
Caudate putamen	tissue	9.2
Postcentral gyrus	tissue	9.1
Locus coeruleus	tissue	8.2
Hippocampus	tissue	7.5
Choroid plexus	tissue	6.2
Ovary	tissue	3.7
Bone marrow	tissue	3.3
Breast	tissue	3.1
Endometrium 1	tissue	2.9
Thyroid gland	tissue	2.9
Prostate	tissue	2.7
Pituitary gland	tissue	2.5
Retina	tissue	2.5
Pancreas	tissue	2.4
Skin 1	tissue	2.2
Vagina	tissue	2.2
Epididymis	tissue	2.1
Fallopian tube	tissue	2.1
Spleen	tissue	1.9
Kidney	tissue	1.9
Cervix	tissue	1.8
Salivary gland	tissue	1.8
Thymus	tissue	1.8
Lymph node	tissue	1.7
Stomach 1	tissue	1.7
Testis	tissue	1.6
Seminal vesicle	tissue	1.5
Parathyroid gland	tissue	1.4
Smooth muscle	tissue	1.4
Lung	tissue	1.4

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — White matter (19.3), Cerebellar cortex (17.8), Dorsal spinal cord (17.7), Flocculonodular lobe (17.2), Dorsal hippocampus (16.4).

Regulation

Is transcription factor: no

Functional genomics

gnomAD constraint: pLI 2.58e-05, LOEUF 0.886, missense Z 0.489 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000273853 — one region, missense o/e 0.91. DepMap (CRISPR cell-line fitness): dependent in 86.7% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Caki-2 (-1.961), HCC1187 (-1.944), NCI-H747 (-1.626), AsPC-1 (-1.529), C2BBe1 (-1.524), DB (-1.478), UACC-62 (-1.456), S-117 (-1.41), RERF-GC-1B (-1.379), OS-RC-2 (-1.337), NCI-H209 (-1.327), SK-ES-1 (-1.282), HT-1080 (-1.279), HPAF-II (-1.261), KP-3 (-1.257).

Literature-anchored findings (GeneRIF, showing 29)

• CENP-C may target the centromere by establishing multiple contacts with both the DNA and protein constituents of the kinetochore (PMID:12490152)
• the interaction between CENP-B and CENP-C may be involved in the correct assembly of CENP-C on alphoid DNA (PMID:14612452)
• CENPC target sites that can be sumoylated by SUMO-2 were shown to be equally susceptible to SUMO-1 attachments which include specific sites on SUMO-2 itself, Ubc9, and the recombinant CENP-C fragments (PMID:15272016)
• a functional interplay between the chromosomal passenger complex and CENP-C. (PMID:17287400)
• Using protein truncation and in vitro mutagenesis, we have identified the nucleolar localization sequences on CENPC1,and evidence shows that CENPC1 is an RNA-associating protein that binds alpha-satellite RNA by an in vitro binding assay. (PMID:17623812)
• CENP-C and CENP-H co-localize to the CENP-A chromatin domain. (PMID:17651496)
• DNMT3B interacts with CENP-C to modulate DNA methylation and the histone code at centromere. (PMID:19482874)
• C-terminal domain of CENP-C displays multiple and critical functions for mammalian centromere formation (PMID:19503796)
• Direct binding of Cenp-C to the Mis12 complex joins the inner and outer kinetochore. (PMID:21353556)
• CENP-C works as an important factor for centromeric M18BP1 recruitment (PMID:22540025)
• The CENP-A/histone H3.3 nucleosome forms an unexpectedly stable structure and allows the binding of the essential centromeric protein, CENP-C, which is ectopically mislocalized in the chromosomes of CENP-A overexpressing tumor cells. (PMID:25408271)
• CENP-C recruits the Ndc80 complex through its interactions with KNL1 and the Mis12 complex at kinetochores during chromosome segregation. (PMID:25660545)
• We used a synthetic system to dissect how CenH3(CENP-A) contributes to the accumulation of CENP-C and CENP-T, two key components that are necessary for the formation of functional kinetochores (PMID:25843710)
• CENP-B directly binds both CENP-A’s amino-terminal tail and CENP-C, a key nucleator of kinetochore assembly (PMID:25942623)
• CENP-C affects nucleosome shape and dynamics in a manner analogous to allosteric regulation of enzymes. CENP-C depletion leads to rapid removal of CENP-A from centromeres, indicating their collaboration in maintaining centromere identity. (PMID:25954010)
• HPV18 E7 inhibited the binding of CENP-C to alpha-satellite DNAs. (PMID:25997930)
• CENP-C, a CCAN subunit, is crucial for kinetochore assembly because it links centromeres with the microtubule-binding interface of kinetochores. (PMID:26124289)
• CENP-C and CENP-I are key factors connecting kinetochore to CENP-A assembly. (PMID:26527398)
• A nonhistone centromere protein, CENP-C, binds and reshapes the nucleosome, sliding the DNA gyres back to positions similar to those in canonical nucleosomes containing conventional histone H3. (PMID:26878239)
• Upon cross-linking, the entire CENPA/CENPB/CENPC/CENPT complex is nuclease-protected over an alpha-satellite dimer that comprises the fundamental unit of centromeric chromatin. We conclude that CENPA/CENPC and CENPT pathways for kinetochore assembly are physically integrated over young alpha-satellite dimers. (PMID:27384170)
• Whereas CENP-C recruits a single MIS12:NDC80 complex, the authors show here that CENP-T binds one MIS12:NDC80 and two NDC80 complexes upon phosphorylation by the mitotic CDK1:Cyclin B complex at three distinct CENP-T sites. (PMID:28012276)
• Levels of centromere aberrations increase upon depletion of CENP-A, CENP-C, and CENP-T/W, during replicative senescence, and in cancer cells. (PMID:28167779)
• CENP-C specifically binds alpha satellite non-coding RNAs. (PMID:28787590)
• Collectively, these studies clarify how CENP-N and CENP-C decode and stabilize the non-canonical CENP-A nucleosome to enforce epigenetic centromere specification and kinetochore assembly. (PMID:29280735)
• CENP-N stabilizes CENP-A nucleosomes alone and additively with CENP-C in vitro. However, removal of CENP-C and CENP-N from cells, or mutating CENP-A so that it no longer interacts with CENP-C or CENP-N, had no effect on centromeric CENP-A stability in vivo. Thus, the stability of CENP-A nucleosomes in chromatin does not arise solely from its interactions with CENP-C or CENP-N. (PMID:29343552)
• two key conformational changes within the CENP-A nucleosome upon CENP-C binding, are reported. (PMID:31475439)
• CDK1-mediated CENP-C phosphorylation modulates CENP-A binding and mitotic kinetochore localization (PMID:31676716)
• A genetic memory initiates the epigenetic loop necessary to preserve centromere position. (PMID:32945564)
• The Elusive Structure of Centro-Chromatin: Molecular Order or Dynamic Heterogenetity? (PMID:33065112)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-161h7.4	ENSDARG00000087238
mus_musculus	Cenpc1	ENSMUSG00000029253
rattus_norvegicus	Cenpc	ENSRNOG00000021776

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:99700) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 5 distinct phenotype terms.

Mouse phenotype (MP)	Records
abnormal chromosome morphology	1
embryonic growth retardation	1
abnormal mitosis	1
embryonic lethality, complete penetrance	1
abnormal cell nucleus size	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
Ovis aries	P49453	62.0%	Diamond

Genomic neighbors (locus context)

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

Symbol	Type	Entrez
STAP1	protein-coding	26228
UBA6-DT	ncRNA	550112
UBA6	protein-coding	55236

Protein

Protein identifiers

Centromere protein C — Q03188 (reviewed: Q03188)

Alternative names: Centromere autoantigen C, Centromere protein C 1, Interphase centromere complex protein 7

All UniProt accessions (3): H0Y8J2, H0Y9W1, Q03188

UniProt curated annotations — full annotation on UniProt →

Function. Component of the CENPA-NAC (nucleosome-associated) complex, a complex that plays a central role in assembly of kinetochore proteins, mitotic progression and chromosome segregation. The CENPA-NAC complex recruits the CENPA-CAD (nucleosome distal) complex and may be involved in incorporation of newly synthesized CENPA into centromeres. CENPC recruits DNA methylation and DNMT3B to both centromeric and pericentromeric satellite repeats and regulates the histone code in these regions.

Subunit / interactions. Oligomer. Component of the CENPA-NAC complex, at least composed of CENPA, CENPC, CENPH, CENPM, CENPN, CENPT and CENPU. The CENPA-NAC complex interacts with the CENPA-CAD complex, composed of CENPI, CENPK, CENPL, CENPO, CENPP, CENPQ, CENPR and CENPS. Binds to DAXX. Interacts with DNMT3B. Interacts directly with CENPA. Identified in a centromere complex containing histones H2A, H2B and H4, and at least CENPA, CENPB, CENPC, CENPT, CENPN, HJURP, SUPT16H, SSRP1 and RSF1. Interacts with MEIKIN.

Subcellular location. Nucleus. Chromosome. Centromere. Kinetochore.

Domain organisation. The MIF2 homology domain II targets centromeres and binds the alpha satellite DNA in vivo. The MIF2 homology domain III can induce CENPC dimerization/oligomerization.

Similarity. Belongs to the CENP-C/MIF2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q03188-1	1	yes
Q03188-2	2

RefSeq proteins (2): NP_001349410, NP_001803* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011051	RmlC_Cupin_sf	Homologous_superfamily
IPR014710	PpnP-like_jellyroll	Homologous_superfamily
IPR025974	Mif2/CENP-C_cupin	Domain
IPR028052	CENP-C_N_dom	Domain
IPR028386	CENP-C/Mif2/cnp3	Family
IPR028931	CENP-C_mid	Domain

Pfam: PF11699, PF15620, PF15622

UniProt features (65 total): modified residue 21, cross-link 16, region of interest 8, compositionally biased region 7, short sequence motif 4, splice variant 2, sequence variant 2, strand 2, chain 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

17 structures by resolution:

PDB	Title	Method	Resolution (Å)
7R5R	Structure of the human CCAN CENP-A alpha-satellite complex	ELECTRON MICROSCOPY	2.44
7PII	Structure of the human CCAN CENP-A alpha-satellite complex	ELECTRON MICROSCOPY	2.68
28OP	Structure of the human inner kinetochore CCAN and CENP-C bound to DNA	ELECTRON MICROSCOPY	2.7
5LSJ	CRYSTAL STRUCTURE OF THE HUMAN KINETOCHORE MIS12-CENP-C delta-HEAD2 COMPLEX	X-RAY DIFFRACTION	3.25
7XHO	Structure of human inner kinetochore CCAN complex	ELECTRON MICROSCOPY	3.29
6MUP	CENP-A nucleosome bound by two copies of CENP-C(CD) and two copies CENP-N(NT)	ELECTRON MICROSCOPY	3.5
6SE6	Class2 : CENP-A nucleosome in complex with CENP-C central region	ELECTRON MICROSCOPY	3.5
5LSK	CRYSTAL STRUCTURE OF THE HUMAN KINETOCHORE MIS12-CENP-C COMPLEX	X-RAY DIFFRACTION	3.5
9TAW	Structure of the human inner kinetochore CCAN bound to DNA	ELECTRON MICROSCOPY	3.54
6MUO	CENP-A nucleosome bound by two copies of CENP-C(CD) and one copy CENP-N(NT)	ELECTRON MICROSCOPY	3.6
6SEF	Class2C : CENP-A nucleosome in complex with CENP-C central region	ELECTRON MICROSCOPY	3.7
7XHN	Structure of human inner kinetochore CCAN-DNA complex	ELECTRON MICROSCOPY	3.71
6SEE	Class2A : CENP-A nucleosome in complex with CENP-C central region	ELECTRON MICROSCOPY	4.2
9TAX	Structure of the human inner kinetochore CCAN bound to a mono-CENP-A nucleosome	ELECTRON MICROSCOPY	4.5
7QOO	Structure of the human inner kinetochore CCAN complex	ELECTRON MICROSCOPY	4.6
7YYH	Structure of the human CCANdeltaT CENP-A alpha-satellite complex	ELECTRON MICROSCOPY	8.9
7YWX	Structure of the human CCAN CENP-A alpha-satellite complex	ELECTRON MICROSCOPY	12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q03188-F1	48.33	0.08

Human Protein Atlas

Protein class: Predicted intracellular proteins, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): kinetochore; nuclear bodies; midbody; nucleoplasm

Antibody reliability (HPA): IF supported

Functional residue map

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

Post-translational modifications (37)

Type	Positions
Phosphoserine	73, 96, 146, 189, 225, 261, 316, 333, 376, 397, 439, 528, 538, 684, 709, 710, 763, 773
Phosphothreonine	130, 183, 734
Glycyl lysine isopeptide (lys-gly) (interchain with g-cter in sumo2)	45, 119, 134, 180, 212, 217, 238, 260, 271, 273, 297, 440, 534, 677, 727, 807

Function

Pathways and Gene Ontology

Reactome pathways

7 curated (TAS) of 21; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

21 pathways:

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

MSigDB gene sets: 182 (showing top): GSE45365_NK_CELL_VS_CD8_TCELL_DN, GOBP_MEIOTIC_CHROMOSOME_SEGREGATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, DACOSTA_UV_RESPONSE_VIA_ERCC3_XPCS_DN, GOBP_CHROMOSOME_LOCALIZATION, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_DN, DARWICHE_SQUAMOUS_CELL_CARCINOMA_DN, chr4q13, PUJANA_CHEK2_PCC_NETWORK, GOBP_ORGANELLE_FISSION, GOBP_MITOTIC_NUCLEAR_DIVISION, GOBP_ORGANELLE_ASSEMBLY

GO Biological Process (6): mitotic cell cycle (GO:0000278), chromosome segregation (GO:0007059), cell division (GO:0051301), attachment of mitotic spindle microtubules to kinetochore (GO:0051315), kinetochore assembly (GO:0051382), spindle attachment to meiosis I kinetochore (GO:0051455)

GO Molecular Function (4): DNA binding (GO:0003677), centromeric DNA binding (GO:0019237), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (8): kinetochore (GO:0000776), condensed chromosome, centromeric region (GO:0000779), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), cytosol (GO:0005829), nuclear body (GO:0016604), chromosome, centromeric region (GO:0000775)

Reactome top-level categories

14 top-level categories:

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

28 GO namespaces:

Category	Terms
intracellular membraneless organelle	2
chromosome, centromeric region	2
cellular anatomical structure	2
cell cycle	1
mitotic nuclear division	1
cell cycle process	1
cellular process	1
mitotic metaphase chromosome alignment	1
attachment of spindle microtubules to kinetochore	1
mitotic cell cycle process	1
kinetochore organization	1
protein-containing complex assembly	1
membraneless organelle assembly	1
meiotic metaphase I homologous chromosome alignment	1
attachment of meiotic spindle microtubules to kinetochore	1
nucleic acid binding	1
sequence-specific double-stranded DNA binding	1
protein binding	1
binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
condensed chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
heterochromatin	1
cytoplasm	1
nucleoplasm	1
chromosomal region	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 9 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

9 experimentally-supported GO terms:

GO term	NS	Evidence
chromosome segregation	BP	mutant phenotype
kinetochore assembly	BP	mutant phenotype
mitotic cell cycle	BP	mutant phenotype
condensed chromosome, centromeric region	CC	direct assay
kinetochore	CC	direct assay
nuclear body	CC	direct assay
nucleoplasm	CC	direct assay
pericentric heterochromatin	CC	direct assay
identical protein binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,016 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CENPC	CENPA	P49450	976
CENPC	CENPT	Q96BT3	951
CENPC	CENPB	P07199	948
CENPC	CENPH	Q9H3R5	934
CENPC	CENPN	Q96H22	916
CENPC	CENPS	Q8N2Z9	903
CENPC	CENPI	Q92674	899
CENPC	CENPE	Q02224	876
CENPC	CENPU	Q71F23	875
CENPC	CENPM	Q9NSP4	849
CENPC	CENPL	Q8N0S6	821
CENPC	CENPO	Q9BU64	818
CENPC	NDC80	O14777	807
CENPC	CENPK	Q9BS16	780
CENPC	CENPQ	Q7L2Z9	778

IntAct

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

15 partners by confidence:

Partner	Interaction type	MIscore	Records
H1-5	physical association	0.560	1
NDC80	association	0.530	3
CENPA	physical association	0.510	4
DAXX	physical association	0.440	2
CHTOP	physical association	0.400	1
NS	physical association	0.370	5
CDC42	physical association	0.370	2
NS1	physical association	0.370	2
ELOC	physical association	0.370	1
MEIKIN	physical association	0.370	1
AURKB	colocalization	0.270	1
POGZ	colocalization	0.270	1
RAD21	colocalization	0.270	1
SGO1	colocalization	0.270	1
MAPK14	physical association	0.000	1

BioGRID (145 interactions; top human partners by supporting records): MIS12 (Affinity Capture-MS; 4 records), NIFK (Affinity Capture-MS; 4 records), PTEN (Affinity Capture-Western; 4 records), CENPA (Proximity Label-MS; 3 records), FGL1 (Affinity Capture-MS; 3 records), MYC (Affinity Capture-MS; 3 records), NPM1 (Affinity Capture-MS; 3 records), PMF1 (Affinity Capture-MS; 3 records), ACTA2 (Affinity Capture-MS; 2 records), CENPU (Affinity Capture-MS; 2 records), CHTOP (Cross-Linking-MS (XL-MS); 2 records), CIAO1 (Proximity Label-MS; 2 records), DGCR8 (Affinity Capture-MS; 2 records), DSN1 (Affinity Capture-MS; 2 records), H2AFY2 (Affinity Capture-MS; 2 records)

SIGNOR signaling

2 signaling interactions:

A	Effect	B	Mechanism
CENPC	“up-regulates activity”	“CENP-A nucleosome”	binding
CENPC	“form complex”	“CCAN complex”	binding

Protein complexes (CORUM) (4)

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

4 complexes by size:

Complex	Subunits	Members
CEN complex	37	SUPT16H, BMI1, CENPC, CENPU, FBL, RNF2, COBLL1, CUL4A, DDB1, HSPA5, NUP93, KIF23, ZFP91, CENPI, CENPK, RACGAP1, SSRP1, ZC3H13, CENPH, CENPM, HSPA8, VIRMA, CBX3, CENPB, SMARCA5, SRRT, CBX8, CENPA, CENPO, PLPPR3, RSF1, WDR11, WTAP, CENPL, DHX38, RING1, SHCBP1
CENP-A nucleosomal complex	15	CENPA, CENPH, CENPT, RSF1, CENPB, CENPL, CENPN, H2AC1, HJURP, SSRP1, SUPT16H, CENPC, CENPI, H4C1, H2BC3
CENP-A NAC-CAD complex	14	CENPB, CENPM, CENPN, CENPO, CENPQ, CENPS, CENPT, CENPC, CENPH, CENPK, CENPL, CENPP, CENPU, ITGB3BP
CENP-A NAC complex	7	CENPU, CENPB, CENPC, CENPH, CENPM, CENPN, CENPT

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 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
Resolution of Sister Chromatid Cohesion	5	39.3×	8e-06
RHO GTPase Effectors	6	37.1×	8e-07
RHO GTPases Activate Formins	5	35.3×	9e-06
Separation of Sister Chromatids	5	27.6×	1e-05
Signaling by Rho GTPases	6	18.6×	9e-06
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	6	18.3×	9e-06

Disease & clinical

Genetic variants

Variant evidence for CENPC: 171 ClinVar records (0 pathogenic / likely pathogenic); 7 GWAS associations.

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	130
Likely benign	12
Benign	0

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 27 predictions of 1,737):

Position(s)	Effect	Δscore	Sites
4:67472639	donor_gain	1.0000
4:67489965–67489966	donor_loss	1.0000	4
4:67492851	donor_gain	1.0000
4:67492944	donor_gain	1.0000
4:67492998–67492999	acceptor_loss	1.0000	5
4:67493882–67493883	donor_loss	1.0000	4
4:67493894	donor_gain	1.0000
4:67495157–67495158	donor_loss	1.0000	4
4:67495213–67495214	acceptor_loss	1.0000	5
4:67495220	acceptor_gain	1.0000

AlphaMissense

667 missense substitutions predicted likely pathogenic (of 6,236 scored), across 166 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
N928	8	0.972	0.996
F938	8	0.966	0.998
D888	8	0.957	0.986
N922	8	0.954	0.997
F916	8	0.944	0.995
F892	8	0.934	0.996
F867	8	0.919	0.988
H904	8	0.873	0.977
W751	7	0.975	0.991
K880	7	0.968	0.995
Q940	7	0.927	0.988
Q883	7	0.913	0.987
C901	7	0.905	0.994
F303	7	0.899	0.982
R739	7	0.883	0.986
E754	7	0.870	0.945
F17	7	0.867	0.976
F849	7	0.840	0.966
D863	7	0.821	0.873
D914	7	0.808	0.901

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
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	2.62e-05
Kidney Renal Clear Cell Carcinoma (validation)	favorable	8.88e-05

Disease associations

OMIM: gene MIM:117141 | disease phenotypes:

GWAS associations

7 associations:

Study	Trait	p-value
GCST006921_5	Regular attendance at a pub or social club	7e-9
GCST010988_371	Adult body size	4e-8
GCST011122_26	Walking pace	4e-8
GCST009028_4	Adverse response to drug	5e-7
GCST002826_9	Urate levels (BMI interaction)	2e-6
GCST000266_10	Multiple sclerosis (severity)	4e-6
GCST008476_34	Emphysema annual change measurement in smokers (percent low attenuation area)	9e-6

EFO canonical traits (from GWAS)

5 canonical traits:

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004531	urate measurement
EFO:0009592	social interaction measurement
EFO:0007626	emphysema imaging measurement
EFO:0009658	adverse effect

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, decreases methylation, affects expression	3
perfluorooctane sulfonic acid	decreases expression	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression, increases abundance	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
16-hydroxycleroda-3,13(14)-dien-15,16-olide	decreases expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Leflunomide	decreases expression	1
Arsenic	decreases expression, increases abundance	1
Caffeine	increases phosphorylation	1
Clorgyline	increases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Ozone	increases abundance, increases expression	1
Quercetin	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1
Aflatoxin B1	decreases methylation	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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