MIS18A

Summary

MIS18A (MIS18 kinetochore protein A, HGNC:1286) is a protein-coding gene on chromosome 21q22.11, encoding Protein Mis18-alpha (Q9NYP9). Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis. It is a common-essential gene (DepMap: required in 94.0% of cancer cell lines).

Enables identical protein binding activity. Predicted to be involved in CENP-A containing chromatin assembly and chromosome segregation. Predicted to act upstream of or within pericentric heterochromatin organization and protein localization to chromosome, centromeric region. Located in cytosol and nucleoplasm.

Source: NCBI Gene 54069 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 40 total
• Cancer dependency (DepMap): dependent in 94.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_018944

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1286
Approved symbol	MIS18A
Name	MIS18 kinetochore protein A
Location	21q22.11
Locus type	gene with protein product
Status	Approved
Aliases	B28, FASP1, hMis18alpha
Ensembl gene	ENSG00000159055
Ensembl biotype	protein_coding
OMIM	618137
Entrez	54069

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000290130, ENST00000486363, ENST00000926599, ENST00000956396

RefSeq mRNA: 1 — MANE Select: NM_018944 NM_018944

CCDS: CCDS13611

Canonical transcript exons

ENST00000290130 — 5 exons

Exon	Start	End
ENSE00001042846	32268228	32269117
ENSE00001042848	32274830	32274896
ENSE00001042850	32278681	32279049
ENSE00001042851	32269707	32269803
ENSE00001042852	32270407	32270529

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.69.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.5714 / max 132.9588, expressed in 1632 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190178	8.5714	1632

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	99.69	gold quality
secondary oocyte	CL:0000655	99.67	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.26	gold quality
ventricular zone	UBERON:0003053	88.07	gold quality
ganglionic eminence	UBERON:0004023	87.61	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	87.10	gold quality
embryo	UBERON:0000922	87.07	gold quality
right testis	UBERON:0004534	86.97	gold quality
testis	UBERON:0000473	86.59	gold quality
left testis	UBERON:0004533	86.28	gold quality
buccal mucosa cell	CL:0002336	85.76	gold quality
mucosa of sigmoid colon	UBERON:0004993	83.83	gold quality
sperm	CL:0000019	83.82	gold quality
male germ cell	CL:0000015	83.07	gold quality
mucosa of transverse colon	UBERON:0004991	82.58	gold quality
trabecular bone tissue	UBERON:0002483	82.17	gold quality
esophagus squamous epithelium	UBERON:0006920	82.15	gold quality
bone marrow	UBERON:0002371	81.93	gold quality
rectum	UBERON:0001052	81.90	gold quality
colonic mucosa	UBERON:0000317	81.17	gold quality
endometrium	UBERON:0001295	81.05	gold quality
ovary	UBERON:0000992	80.54	gold quality
epithelium of esophagus	UBERON:0001976	80.29	gold quality
esophagus mucosa	UBERON:0002469	80.20	gold quality
left ovary	UBERON:0002119	79.62	gold quality
adrenal tissue	UBERON:0018303	79.41	gold quality
amniotic fluid	UBERON:0000173	79.03	gold quality
calcaneal tendon	UBERON:0003701	79.01	gold quality
lower esophagus mucosa	UBERON:0035834	78.79	gold quality
right ovary	UBERON:0002118	78.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.42

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

45 targeting MIS18A, 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-9-5P	100.00	72.28	2361
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6515-3P	99.82	68.19	1933
HSA-MIR-4729	99.69	72.18	4233
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-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-766-5P	99.47	67.91	2225
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-382-3P	98.83	67.10	1074

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 94.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 8)

• it is suggested that pp5644 physically bind to FASP1 (PMID:15881666)
• 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.[Mis18alpha, Mis18beta, M18BP1] (PMID:17199038)
• Stable binding of Mis18alpha-Mis18beta heterotetramer to centromeres in telophase licenses them for CENP-A deposition. (PMID:26942680)
• the Mis18 complex contains dual CENP-C recognition motifs that are combinatorially required to generate robust centromeric localization that leads to CENP-A deposition (PMID:27239045)
• Mis18alpha is important for epidermal cell proliferation and stratification, because it is required for the deposition of CENP-A at the centromeric nucleosomes. (PMID:27670610)
• The authors demonstrate that CDK1 controls Mis18 complex recruitment to centromeres by regulating oligomerization of M18BP1 through the Mis18alpha:Mis18beta scaffold. (PMID:28059702)
• Data show that the MIS18 kinetochore protein A (Mis18alpha) N-terminal region modulates Holliday junction recognition protein (HJURP) binding. (PMID:31492860)
• Nuclear translocation of ATG5 induces DNA mismatch repair deficiency (MMR-D)/microsatellite instability (MSI) via interacting with Mis18alpha in colorectal cancer. (PMID:33645631)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	mis18a	ENSDARG00000035333
mus_musculus	Mis18a	ENSMUSG00000022978
rattus_norvegicus	Mis18a	ENSRNOG00000021555

Paralogs (1): OIP5 (ENSG00000104147)

Protein

Protein identifiers

Protein Mis18-alpha — Q9NYP9 (reviewed: Q9NYP9)

Alternative names: FAPP1-associated protein 1

All UniProt accessions (1): Q9NYP9

UniProt curated annotations — full annotation on UniProt →

Function. Required for recruitment of CENPA to centromeres and normal chromosome segregation during mitosis.

Subunit / interactions. Homodimer, and heterodimer with OIP5/MIS18B. Identified in a complex containing MIS18A, OIP5/MIS18B, MIS18BP1, RBBP7 and RBBP4.

Subcellular location. Nucleus. Chromosome. Centromere.

Tissue specificity. Detected in testis.

Similarity. Belongs to the mis18 family.

RefSeq proteins (1): NP_061817* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004910	Yippee/Mis18/Cereblon	Domain
IPR034752	Mis18	Domain

Pfam: PF03226

UniProt features (33 total): strand 9, mutagenesis site 7, binding site 4, modified residue 4, turn 3, helix 3, chain 1, domain 1, cross-link 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
8S30	X-RAY DIFFRACTION	1.94
7SFY	X-RAY DIFFRACTION	2.5
7SFZ	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYP9-F1	79.84	0.48

Functional residue map

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

Ligand- & substrate-binding residues (4): 85; 88; 141; 144

Post-translational modifications (5): 162, 36, 39, 40, 233

Mutagenesis-validated functional residues (7):

Position	Phenotype
82	abolishes interaction with oip5; when associated with d-176.
85	abolishes location at the centromere.
88	abolishes location at the centromere.
134	no effect.
141	abolishes location at the centromere.
144	abolishes location at the centromere.
176	abolishes interaction with oip5; when associated with e-82.

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-606279	Deposition of new CENPA-containing nucleosomes at the centromere
R-HSA-1640170	Cell Cycle
R-HSA-73886	Chromosome Maintenance
R-HSA-774815	Nucleosome assembly

MSigDB gene sets: 186 (showing top): GOBP_CHROMOSOME_ORGANIZATION, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, PATIL_LIVER_CANCER, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME_CENTROMERIC_REGION, MODULE_256, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, MODULE_480, GOBP_ORGANELLE_ASSEMBLY, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, DOUGLAS_BMI1_TARGETS_DN, DODD_NASOPHARYNGEAL_CARCINOMA_UP

GO Biological Process (6): chromosome segregation (GO:0007059), CENP-A containing chromatin assembly (GO:0034080), cell division (GO:0051301), protein localization to chromosome, centromeric region (GO:0071459), obsolete pericentric heterochromatin organization (GO:0140462), heterochromatin formation (GO:0031507)

GO Molecular Function (4): protein-macromolecule adaptor activity (GO:0030674), identical protein binding (GO:0042802), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): chromosome, centromeric region (GO:0000775), chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), CENP-A recruiting complex (GO:0098654), chromosome (GO:0005694)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Nucleosome assembly	1
Cell Cycle	1
Chromosome Maintenance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein binding	2
cell cycle process	1
chromatin organization	1
kinetochore assembly	1
protein localization to CENP-A containing chromatin	1
cellular process	1
protein localization to chromosome	1
cellular component assembly	1
heterochromatin boundary formation	1
negative regulation of gene expression, epigenetic	1
heterochromatin organization	1
molecular adaptor activity	1
cation binding	1
binding	1
chromosomal region	1
chromosome	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1
nuclear protein-containing complex	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIS18A	MIS18BP1	Q6P0N0	998
MIS18A	OIP5	O43482	996
MIS18A	DNMT3A	Q9Y6K1	816
MIS18A	CENPC	Q03188	785
MIS18A	HJURP	Q8NCD3	720
MIS18A	DNMT3B	Q9UBC3	714
MIS18A	CENPA	P49450	694
MIS18A	CENPT	Q96BT3	604
MIS18A	CENPQ	Q7L2Z9	587
MIS18A	CENPI	Q92674	582
MIS18A	ITGB3BP	Q13352	574
MIS18A	CENPK	Q9BS16	557
MIS18A	CENPS	Q8N2Z9	556
MIS18A	CENPH	Q9H3R5	541
MIS18A	RBBP7	Q16576	527

IntAct

186 interactions, top by confidence:

A	B	Type	Score
OIP5	MIS18A	psi-mi:“MI:0915”(physical association)	0.950
MIS18A	OIP5	psi-mi:“MI:0915”(physical association)	0.950
MIS18A	OIP5	psi-mi:“MI:0914”(association)	0.950
MIS18BP1	OIP5	psi-mi:“MI:0915”(physical association)	0.770
TXLNA	MIS18A	psi-mi:“MI:0915”(physical association)	0.740
NDEL1	MIS18A	psi-mi:“MI:0915”(physical association)	0.740
AIMP2	MIS18A	psi-mi:“MI:0915”(physical association)	0.720
MIS18A	AIMP2	psi-mi:“MI:0915”(physical association)	0.720
NUP58	MIS18A	psi-mi:“MI:0915”(physical association)	0.720
MIS18A	NUP58	psi-mi:“MI:0915”(physical association)	0.720
HLA-A	TAPBP	psi-mi:“MI:0915”(physical association)	0.690
MIS18A	DCTN6	psi-mi:“MI:0914”(association)	0.640

BioGRID (165): MIS18A (Two-hybrid), MIS18A (Two-hybrid), MIS18A (Two-hybrid), MIS18A (Two-hybrid), ZNF471 (Two-hybrid), MIS18A (Affinity Capture-MS), MIS18A (Affinity Capture-MS), MIS18A (Affinity Capture-MS), MIS18A (Affinity Capture-MS), MIS18A (Synthetic Lethality), MIS18A (Proximity Label-MS), MIS18A (Proximity Label-MS), MIS18A (Proximity Label-MS), MIS18A (Proximity Label-MS), MIS18A (Proximity Label-MS)

ESM2 similar proteins: A0A8M9QN10, A2AQ14, A2ARM1, A2CI97, A2CI98, A2CJ06, A5D7N9, B1MT51, B2RZC4, B5SNH4, O43147, O43482, O70173, P0C6P5, P59729, P70371, P97433, Q3UHA3, Q5BIW4, Q5BK24, Q5EB20, Q5I0F1, Q5PQS0, Q5SSH7, Q5U3H9, Q68UT5, Q6GR31, Q6IRN0, Q6NV72, Q6P4K6, Q6ZUJ8, Q7TSI1, Q7Z2Z1, Q7Z4M0, Q80VA5, Q8BPZ8, Q8BQ33, Q8IUY3, Q8ND61, Q8WYP3

Diamond homologs: A5D7N9, B1MT51, B2RZC4, B5SNH4, Q68UT5, Q9CZJ6, Q9NYP9

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
MIS18A	“form complex”	“CENP-A recruiting complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 98 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
Loss of Nlp from mitotic centrosomes	5	12.0×	5e-03
Loss of proteins required for interphase microtubule organization from the centrosome	5	12.0×	5e-03
Anchoring of the basal body to the plasma membrane	7	12.0×	7e-04
AURKA Activation by TPX2	5	11.5×	5e-03
Recruitment of NuMA to mitotic centrosomes	6	10.6×	3e-03
Recruitment of mitotic centrosome proteins and complexes	5	10.3×	7e-03
Regulation of PLK1 Activity at G2/M Transition	5	9.6×	8e-03
RHO GTPases Activate Formins	6	7.1×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	29
Likely benign	4
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

600 predictions. Top by Δscore:

Variant	Effect	Δscore
21:32269127:T:TC	acceptor_gain	1.0000
21:32270402:CTTA:C	donor_loss	1.0000
21:32270403:TTAC:T	donor_loss	1.0000
21:32270404:TACCT:T	donor_loss	1.0000
21:32270405:A:AC	donor_gain	1.0000
21:32270405:AC:A	donor_gain	1.0000
21:32270406:C:CC	donor_gain	1.0000
21:32270406:CC:C	donor_gain	1.0000
21:32270406:CCTTT:C	donor_gain	1.0000
21:32270525:GGACG:G	acceptor_gain	1.0000
21:32270526:GACG:G	acceptor_gain	1.0000
21:32270527:ACG:A	acceptor_gain	1.0000
21:32270528:CG:C	acceptor_gain	1.0000
21:32270528:CGC:C	acceptor_gain	1.0000
21:32270529:GC:G	acceptor_loss	1.0000
21:32270530:C:CC	acceptor_gain	1.0000
21:32270535:A:AC	acceptor_gain	1.0000
21:32274822:TTACT:T	donor_loss	1.0000
21:32274824:ACT:A	donor_loss	1.0000
21:32274826:TCA:T	donor_loss	1.0000
21:32274827:CACC:C	donor_loss	1.0000
21:32274828:A:AC	donor_gain	1.0000
21:32274828:A:AT	donor_loss	1.0000
21:32274828:AC:A	donor_gain	1.0000
21:32274829:C:CA	donor_gain	1.0000
21:32274829:CC:C	donor_gain	1.0000
21:32274829:CCA:C	donor_gain	1.0000
21:32274829:CCAA:C	donor_gain	1.0000
21:32274892:AACAC:A	acceptor_gain	1.0000
21:32274893:ACAC:A	acceptor_gain	1.0000

AlphaMissense

1527 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:32278767:A:G	F83S	0.994
21:32270433:A:C	F166L	0.993
21:32270433:A:T	F166L	0.993
21:32270435:A:G	F166L	0.993
21:32270445:C:A	K162N	0.992
21:32270445:C:G	K162N	0.992
21:32274881:A:T	V117D	0.992
21:32278762:A:G	C85R	0.989
21:32278766:G:C	F83L	0.989
21:32278766:G:T	F83L	0.989
21:32278768:A:G	F83L	0.989
21:32270477:A:C	Y152D	0.988
21:32270486:C:G	G149R	0.988
21:32278737:C:T	G93D	0.988
21:32270485:C:T	G149D	0.987
21:32278735:C:G	D94H	0.987
21:32278752:C:G	C88S	0.987
21:32278753:A:T	C88S	0.987
21:32278734:T:G	D94A	0.986
21:32278733:G:C	D94E	0.985
21:32278733:G:T	D94E	0.985
21:32278734:T:A	D94V	0.985
21:32278753:A:G	C88R	0.985
21:32278767:A:C	F83C	0.985
21:32270485:C:A	G149V	0.984
21:32270510:A:G	C141R	0.984
21:32278686:A:G	L110P	0.984
21:32278732:A:G	S95P	0.984
21:32278761:C:G	C85S	0.984
21:32278762:A:T	C85S	0.984

dbSNP variants (sampled 300 via entrez): RS1000043346 (21:32269536 T>A), RS1000051510 (21:32259038 T>G), RS1000080561 (21:32258761 G>C), RS1000083552 (21:32171031 A>T), RS1000144956 (21:32264410 C>T), RS1000146369 (21:32212925 C>G), RS1000158760 (21:32236170 C>A,T), RS1000172863 (21:32199793 G>A,C), RS1000176924 (21:32157711 C>G), RS1000179401 (21:32275233 T>C,G), RS1000187715 (21:32197125 A>C), RS1000198339 (21:32185266 C>A), RS1000201039 (21:32238314 C>T), RS1000263071 (21:32264706 T>G), RS1000317846 (21:32206389 C>T)

Disease associations

OMIM: gene MIM:618137 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001531_3	Temperament	4.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004825	temperament and character inventory

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	3
Cyclosporine	decreases expression	3
bisphenol A	affects expression, decreases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Cisplatin	increases reaction, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
FR900359	decreases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
arsenite	affects binding, increases reaction	1
4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone	increases expression	1
sodium arsenite	increases abundance, increases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
entinostat	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Dasatinib	decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Arsenic	increases abundance, increases expression	1
Azathioprine	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1

Clinical trials (associated diseases)

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