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): 170 total
• Cancer dependency (DepMap): dependent in 86.7% of screened cell lines
• MANE Select transcript: NM_001812

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: 10 — 4 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay

ENST00000273853, ENST00000506410, ENST00000506882, ENST00000507196, ENST00000510189, ENST00000513216, ENST00000515140, ENST00000910804, ENST00000929364, ENST00000960630

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.

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

157 total, 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

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 86.7% of screened cell lines.

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

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): Q03188, H0Y8J2, H0Y9W1

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	RmlC-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.

PDB	Method	Resolution (Å)
7R5R	ELECTRON MICROSCOPY	2.44
7PII	ELECTRON MICROSCOPY	2.68
28OP	ELECTRON MICROSCOPY	2.7
5LSJ	X-RAY DIFFRACTION	3.25
7XHO	ELECTRON MICROSCOPY	3.29
6MUP	ELECTRON MICROSCOPY	3.5
6SE6	ELECTRON MICROSCOPY	3.5
5LSK	X-RAY DIFFRACTION	3.5
9TAW	ELECTRON MICROSCOPY	3.54
6MUO	ELECTRON MICROSCOPY	3.6
6SEF	ELECTRON MICROSCOPY	3.7
7XHN	ELECTRON MICROSCOPY	3.71
6SEE	ELECTRON MICROSCOPY	4.2
9TAX	ELECTRON MICROSCOPY	4.5
7QOO	ELECTRON MICROSCOPY	4.6
7YYH	ELECTRON MICROSCOPY	8.9
7YWX	ELECTRON MICROSCOPY	12

Predicted structure (AlphaFold)

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

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): 73, 96, 130, 146, 183, 189, 225, 261, 316, 333, 376, 397, 439, 528, 538, 684, 709, 710, 734, 763 …

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: 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 (11): kinetochore (GO:0000776), condensed chromosome, centromeric region (GO:0000779), inner kinetochore (GO:0000939), nucleus (GO:0005634), nucleoplasm (GO:0005654), pericentric heterochromatin (GO:0005721), cytosol (GO:0005829), nuclear body (GO:0016604), midbody (GO:0030496), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694)

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
intracellular membraneless organelle	3
cellular anatomical structure	3
chromosome, centromeric region	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
kinetochore	1
protein-containing complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
heterochromatin	1
cytoplasm	1
nucleoplasm	1
chromosomal region	1

Protein interactions and networks

STRING

904 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CENPC	CENPA	P49450	999
CENPC	CENPH	Q9H3R5	995
CENPC	CENPB	P07199	993
CENPC	CENPT	Q96BT3	993
CENPC	CENPS	Q8N2Z9	986
CENPC	CENPN	Q96H22	986
CENPC	DNMT3B	Q9UBC3	978
CENPC	CENPU	Q71F23	970
CENPC	CENPI	Q92674	966
CENPC	CENPM	Q9NSP4	939
CENPC	CENPW	Q5EE01	935
CENPC	CENPL	Q8N0S6	928
CENPC	CENPO	Q9BU64	922
CENPC	CENPK	Q9BS16	917
CENPC	CENPP	Q6IPU0	915

IntAct

136 interactions, top by confidence:

A	B	Type	Score
NPM1	NVL	psi-mi:“MI:0914”(association)	0.610
CENPC	H1-5	psi-mi:“MI:0915”(physical association)	0.560
MIS12	SPC24	psi-mi:“MI:0914”(association)	0.530
RBM34	NVL	psi-mi:“MI:0914”(association)	0.530
RRP8	NVL	psi-mi:“MI:0914”(association)	0.530
RPL18	NOP56	psi-mi:“MI:0914”(association)	0.530
CENPC	NDC80	psi-mi:“MI:0914”(association)	0.530
MACROH2A2	PPM1G	psi-mi:“MI:0914”(association)	0.530
N	RBM47	psi-mi:“MI:0914”(association)	0.530
RBM4	NVL	psi-mi:“MI:0914”(association)	0.530
NIFK	RSL1D1	psi-mi:“MI:0914”(association)	0.530
ABT1	ZNF316	psi-mi:“MI:0914”(association)	0.530
CENPH	PSMD11	psi-mi:“MI:0914”(association)	0.530
MAGEB2	GTPBP10	psi-mi:“MI:0914”(association)	0.530
RPL13	RRP8	psi-mi:“MI:0914”(association)	0.530
CENPC	CENPC	psi-mi:“MI:0915”(physical association)	0.520
CENPC	CENPA	psi-mi:“MI:0915”(physical association)	0.510
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
CENPC	DAXX	psi-mi:“MI:0915”(physical association)	0.440

BioGRID (146): CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Proximity Label-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Affinity Capture-MS), CENPC (Proximity Label-MS), CENPC (Affinity Capture-MS), MIS12 (Affinity Capture-MS), DSN1 (Affinity Capture-MS)

ESM2 similar proteins: A1L2H3, A2AKX3, A5D8S0, B0S6S9, D3Z987, E1BC15, O43303, O60673, O95405, P56715, Q03188, Q2M2Z5, Q3MHH3, Q3V089, Q569L8, Q5BQN8, Q5CZC0, Q5DTT3, Q5R9I1, Q5VWN6, Q61493, Q641I1, Q6NS59, Q6NSW3, Q6ZP01, Q6ZU52, Q7TSH4, Q7Z333, Q7Z3T8, Q80U44, Q80U59, Q86UW6, Q86WS4, Q86XD8, Q8IXS0, Q8MJ03, Q8MJ04, Q8MJ06, Q8N1H7, Q8N7Z5

Diamond homologs: P49452, P49453, Q03188

SIGNOR signaling

2 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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
Nucleosome assembly	6	33.6×	3e-07
Amplification of signal from the kinetochores	10	23.2×	3e-10
Peptide chain elongation	13	19.4×	6e-12
Viral mRNA Translation	13	19.4×	6e-12
PELO:HBS1L and ABCE1 dissociate a ribosome on a non-stop mRNA	13	19.2×	6e-12
Mitotic Spindle Checkpoint	10	18.7×	2e-09
Formation of a pool of free 40S subunits	14	18.4×	4e-12
Selenocysteine synthesis	13	18.4×	9e-12

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	14	22.0×	2e-12
ribosomal large subunit biogenesis	5	18.8×	5e-04
chromosome segregation	12	17.7×	1e-09
ribosomal small subunit biogenesis	7	13.5×	1e-04
negative regulation of translation	7	11.6×	2e-04
mitotic spindle organization	5	11.5×	4e-03
rRNA processing	9	10.8×	2e-05
translation	12	10.4×	4e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	129
Likely benign	12
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2894 predictions. Top by Δscore:

Variant	Effect	Δscore
4:67472579:A:AC	donor_gain	1.0000
4:67472580:C:CC	donor_gain	1.0000
4:67472639:T:A	donor_gain	1.0000
4:67489959:GTACT:G	donor_loss	1.0000
4:67489961:ACTC:A	donor_loss	1.0000
4:67489963:TCACC:T	donor_loss	1.0000
4:67489964:CACCA:C	donor_loss	1.0000
4:67489965:A:AC	donor_gain	1.0000
4:67489966:C:CA	donor_gain	1.0000
4:67489966:CCA:C	donor_gain	1.0000
4:67490122:C:CC	acceptor_gain	1.0000
4:67492847:A:AC	donor_gain	1.0000
4:67492868:C:CC	donor_gain	1.0000
4:67492892:AT:A	donor_gain	1.0000
4:67492893:T:TA	donor_gain	1.0000
4:67492944:T:TA	donor_gain	1.0000
4:67492999:T:A	acceptor_loss	1.0000
4:67493878:TTTTA:T	donor_loss	1.0000
4:67493879:TTTA:T	donor_loss	1.0000
4:67493880:TTAC:T	donor_loss	1.0000
4:67493881:TA:T	donor_loss	1.0000
4:67493882:A:T	donor_loss	1.0000
4:67493883:C:A	donor_loss	1.0000
4:67493894:T:A	donor_gain	1.0000
4:67493984:CAATA:C	acceptor_gain	1.0000
4:67493985:AATA:A	acceptor_gain	1.0000
4:67493986:ATA:A	acceptor_gain	1.0000
4:67493987:TA:T	acceptor_gain	1.0000
4:67493989:C:CC	acceptor_gain	1.0000
4:67495153:TCTTA:T	donor_loss	1.0000

AlphaMissense

6236 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:67472623:A:C	F938L	0.998
4:67472623:A:T	F938L	0.998
4:67472625:A:G	F938L	0.998
4:67472624:A:G	F938S	0.997
4:67472671:G:C	N922K	0.997
4:67472671:G:T	N922K	0.997
4:67474896:A:T	V918D	0.997
4:67490022:A:G	L872S	0.997
4:67490029:C:A	G870W	0.997
4:67472630:A:G	L936P	0.996
4:67472653:A:C	N928K	0.996
4:67472653:A:T	N928K	0.996
4:67474973:A:C	F892L	0.996
4:67474973:A:T	F892L	0.996
4:67474975:A:G	F892L	0.996
4:67474902:A:G	F916S	0.995
4:67489997:C:A	K880N	0.995
4:67489997:C:G	K880N	0.995
4:67489999:T:G	K880Q	0.995
4:67490028:C:T	G870E	0.995
4:67472611:T:A	K942N	0.994
4:67472611:T:G	K942N	0.994
4:67472635:A:C	S934R	0.994
4:67472635:A:T	S934R	0.994
4:67472637:T:G	S934R	0.994
4:67474948:A:G	C901R	0.994
4:67474953:A:G	L899P	0.994
4:67472630:A:T	L936H	0.993
4:67490028:C:A	G870V	0.993
4:67474901:G:C	F916L	0.992

dbSNP variants (sampled 300 via entrez): RS1000000868 (4:67531786 G>A,C), RS1000007497 (4:67469031 CAT>C), RS1000197376 (4:67484457 T>C), RS1000204883 (4:67529277 G>A), RS1000224111 (4:67491912 G>T), RS1000228827 (4:67525444 C>A,T), RS10002575 (4:67483283 G>A,C), RS10003115 (4:67520510 C>G,T), RS1000311832 (4:67469031 C>A,T), RS1000327847 (4:67541713 G>A), RS10003368 (4:67521343 T>C), RS1000368394 (4:67475439 C>A,T), RS1000427653 (4:67491725 A>G), RS1000436744 (4:67531537 T>C), RS1000506300 (4:67536859 T>C)

Disease associations

OMIM: gene MIM:117141 | 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
GCST000266_10	Multiple sclerosis (severity)	4.000000e-06
GCST002826_10	Urate levels (BMI interaction)	2.000000e-06
GCST006921_13	Regular attendance at a pub or social club	7.000000e-09
GCST008476_34	Emphysema annual change measurement in smokers (percent low attenuation area)	9.000000e-06
GCST009028_15	Adverse response to drug	5.000000e-07
GCST010988_217	Adult body size	4.000000e-08
GCST011122_51	Walking pace	4.000000e-08

EFO canonical traits (5, from GWAS)

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 (VIP=true, CPIC=false)

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	3
perfluorooctane sulfonic acid	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
Air Pollutants	decreases expression, increases abundance	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
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)

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