MCM3AP

Summary

MCM3AP (minichromosome maintenance complex component 3 associated protein, HGNC:6946) is a protein-coding gene on chromosome 21q22.3, encoding Germinal-center associated nuclear protein (O60318). As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores. It is a common-essential gene (DepMap: required in 97.8% of cancer cell lines).

The minichromosome maintenance protein 3 (MCM3) is one of the MCM proteins essential for the initiation of DNA replication. The protein encoded by this gene is a MCM3 binding protein. It was reported to have phosphorylation-dependent DNA-primase activity, which was up-regulated in antigen immunization induced germinal center. This protein was demonstrated to be an acetyltransferase that acetylates MCM3 and plays a role in DNA replication. The mutagenesis of a nuclear localization signal of MCM3 affects the binding of this protein with MCM3, suggesting that this protein may also facilitate MCM3 nuclear localization. This gene is expressed in the brain or in neuronal tissue. An allelic variant encoding amino acid Lys at 915, instead of conserved Glu, has been identified in patients with mild intellectual disability.

Source: NCBI Gene 8888 — RefSeq curated summary.

At a glance

• Gene–disease (curated): peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (Definitive, ClinGen)
• GWAS associations: 5
• Clinical variants (ClinVar): 1,648 total — 84 pathogenic, 23 likely-pathogenic
• Phenotypes (HPO): 34
• Cancer dependency (DepMap): dependent in 97.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_003906

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6946
Approved symbol	MCM3AP
Name	minichromosome maintenance complex component 3 associated protein
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	Map80, KIAA0572, GANP, SAC3
Ensembl gene	ENSG00000160294
Ensembl biotype	protein_coding
OMIM	603294
Entrez	8888

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 4 protein_coding_CDS_not_defined, 3 protein_coding, 3 retained_intron

ENST00000291688, ENST00000397708, ENST00000426537, ENST00000467026, ENST00000479557, ENST00000481113, ENST00000486937, ENST00000494755, ENST00000495475, ENST00000496607

RefSeq mRNA: 1 — MANE Select: NM_003906 NM_003906

CCDS: CCDS13734

Canonical transcript exons

ENST00000291688 — 28 exons

Exon	Start	End
ENSE00003463408	46236829	46236979
ENSE00003482097	46243465	46243722
ENSE00003484738	46254392	46254526
ENSE00003500518	46244807	46245197
ENSE00003526095	46246628	46246886
ENSE00003533166	46240811	46241017
ENSE00003561146	46265925	46266166
ENSE00003581188	46251529	46251682
ENSE00003597990	46246307	46246404
ENSE00003603723	46242802	46242931
ENSE00003620264	46264117	46264217
ENSE00003633023	46235133	46235426
ENSE00003634959	46265321	46265523
ENSE00003643410	46256789	46256986
ENSE00003647431	46261280	46261411
ENSE00003667275	46260793	46260906
ENSE00003673707	46258939	46259091
ENSE00003688476	46254776	46254844
ENSE00003847161	46284068	46285611
ENSE00003889626	46280497	46280575
ENSE00003889786	46277527	46277717
ENSE00003890013	46273388	46273585
ENSE00003890398	46270401	46270563
ENSE00003890417	46283615	46283838
ENSE00003891802	46275186	46275325
ENSE00003892257	46279993	46280137
ENSE00003894261	46272561	46272829
ENSE00003895239	46266982	46267142

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 95.07.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.9597 / max 366.6815, expressed in 1824 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
190927	37.6197	1821
190928	3.0275	1509
190926	2.4842	1361
190925	0.6253	331
190929	0.1339	48
190923	0.0503	7
190924	0.0187	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tendon of biceps brachii	UBERON:0008188	95.07	gold quality
tibial nerve	UBERON:0001323	94.93	gold quality
right uterine tube	UBERON:0001302	94.89	gold quality
gastrocnemius	UBERON:0001388	94.51	gold quality
body of uterus	UBERON:0009853	94.47	gold quality
mucosa of stomach	UBERON:0001199	94.41	gold quality
right lobe of thyroid gland	UBERON:0001119	94.37	gold quality
right ovary	UBERON:0002118	94.37	gold quality
cerebellar hemisphere	UBERON:0002245	94.35	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.30	gold quality
granulocyte	CL:0000094	94.27	gold quality
cerebellar cortex	UBERON:0002129	94.27	gold quality
left ovary	UBERON:0002119	94.15	gold quality
muscle of leg	UBERON:0001383	94.04	gold quality
left lobe of thyroid gland	UBERON:0001120	94.02	gold quality
left uterine tube	UBERON:0001303	93.92	gold quality
endocervix	UBERON:0000458	93.85	gold quality
adenohypophysis	UBERON:0002196	93.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	93.70	gold quality
skin of leg	UBERON:0001511	93.67	gold quality
spleen	UBERON:0002106	93.62	gold quality
thyroid gland	UBERON:0002046	93.60	gold quality
metanephros cortex	UBERON:0010533	93.59	gold quality
ventricular zone	UBERON:0003053	93.54	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.51	gold quality
ectocervix	UBERON:0012249	93.50	gold quality
lower esophagus	UBERON:0013473	93.49	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.49	gold quality
cerebellum	UBERON:0002037	93.46	gold quality
sural nerve	UBERON:0015488	93.45	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	7.62
E-MTAB-7606	no	1264.44
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOXO1, NFKB, SPI1

miRNA regulators (miRDB)

17 targeting MCM3AP, 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-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-6797-3P	99.17	66.94	668
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-6076	98.61	65.69	637
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-4513	95.04	67.06	727
HSA-MIR-6855-3P	95.04	66.57	725

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 26)

• inhibits initiation of DNA replication via binding to MCM3 (PMID:12226073)
• plays a certain important role in the maturation of immunoglobulin or selection of B cells in germinal centers during the immune response to TD-Ag. A selective function of GANP molecule on B cell proliferation and differentiation might exist. (PMID:12885157)
• abnormal over-expression of GANP together with AID might be associated with rigorous DNA damage, potentially causing the malignant development of Cholangiocarcinoma (CCAs) during long-term inflammation. (PMID:19578742)
• GANP protects cells from cellular senescence caused by DNA damage and that a significant decrease in GANP expression leads to malignancy by generating hyperploidy and chromosomal instability (CIN). (PMID:19686285)
• GANP depletion inhibits mRNA export, with retention of mRNPs and NXF1 in punctate foci within the nucleus. (PMID:20005110)
• Data show that human germinal center-associated nuclear protein (GANP) is critically involved in cell proliferation at the mitotic phase through its selective support of shugoshin-1 mRNA export. (PMID:20384790)
• GANP may serve as an essential link required to transport AID to B-cell nuclei and to target AID to actively transcribed IgV regions (PMID:20507984)
• HBV DNA integration sites into human genome were random, and MCM3AP was a new site. (PMID:20714864)
• MCM3AP and GANP are different proteins, occupying different locations in the cell and transcribed from different promoters (PMID:21195085)
• GANP, a homologue of yeast Sac3 that is involved in mRNA export, is indispensable for ensuring the stability of human genomic DNA and GANP knockdown causes apoptosis and necrosis of p53-insufficient cancer cells. (PMID:22395445)
• GANP transgene may play a critical role in Lyn tyrosine-protein kinase-mediated signaling during selection of high-affinity B cells in peripheral lymphoid organs. (PMID:22942428)
• The cellular protein MCM3AP is required for inhibition of cellular DNA synthesis by the IE86 protein of human cytomegalovirus. (PMID:23094019)
• GANP-mediated chromatin modification promotes transcription complex recruitment and positioning at immunoglobulin variable loci to favour AID targeting. (PMID:23652018)
• A homozygous potentially pathogenic variant (c.2743G>A) was identified, which encodes amino acid Lys, instead of conserved Glu, at the position 915, in patients with mild intellectual disability. (PMID:24123876)
• GANP is induced in activated T4 cells & physically interacts with A3G. GANP is encapsidated in HIV-1 virions & modulates A3G packaging into the cores. Upregulation increases A3G-catalyzed viral G–>A hypermutation, suppressing infectivity. (PMID:24198285)
• MCM3AP and POMP Mutations Cause a DNA-Repair and DNA-Damage-Signaling Defect in an Immunodeficient Child (PMID:26615982)
• These results indicated that the GANP protein is associated with breast cancer resistance. (PMID:26749495)
• The identification of MCM3AP variants in affected individuals from multiple centres establishes it as a disease gene for childhood-onset recessively inherited Charcot-Marie-Tooth neuropathy with intellectual disability. (PMID:28633435)
• Circular RNA MCM3AP-AS1 directly bound to miR-194-5p and acted as competing endogenous RNA while subsequently facilitating miR-194-5p target gene FOXA1 expression in hepatocellular carcinoma cells. (PMID:30782188)
• The G allele of rs2839178 at the GANP locus was significantly associated with reduced breast cancer risk and longer disease-free survival in breast cancer patients, showing a consistent direction in the association between susceptibility and clinical outcome. (PMID:30810967)
• MCM3AP encodes germinal center-associated nuclear protein (GANP), a protein involved in the export of certain messenger RNAs from the nucleus to the cytoplasm (PMID:31241196)
• Distinct effects on mRNA export factor GANP underlie neurological disease phenotypes and alter gene expression depending on intron content. (PMID:32202298)
• Genetic spectrum of MCM3AP and its relationship with phenotype of Charcot-Marie-Tooth disease. (PMID:32319184)
• The critical role of germinal center-associated nuclear protein in cell biology, immunohematology, and hematolymphoid oncogenesis. (PMID:32827560)
• Long noncoding RNA MCM3AP antisense RNA 1 is downregulated in chronic obstructive pulmonary disease and regulates human bronchial smooth muscle cell proliferation. (PMID:32940099)
• Two Cases of Periodic Paralysis Associated With MCM3AP Variants. (PMID:37611268)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mcm3ap	ENSDARG00000021402
mus_musculus	Mcm3ap	ENSMUSG00000001150
rattus_norvegicus	Mcm3ap	ENSRNOG00000001272
caenorhabditis_elegans		WBGENE00017642

Paralogs (2): LENG8 (ENSG00000167615), SAC3D1 (ENSG00000168061)

Protein

Protein identifiers

Germinal-center associated nuclear protein — O60318 (reviewed: O60318)

Alternative names: 80 kDa MCM3-associated protein, MCM3 acetylating protein, MCM3 acetyltransferase

All UniProt accessions (2): O60318, A0A0A0MSZ7

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the TREX-2 complex, involved in the export of mRNAs to the cytoplasm through the nuclear pores. Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations. Binds to and acetylates the replication protein MCM3. Plays a role in the initiation of DNA replication and participates in controls that ensure that DNA replication initiates only once per cell cycle. Through the acetylation of histones, affects the assembly of nucleosomes at immunoglobulin variable region genes and promotes the recruitment and positioning of transcription complex to favor DNA cytosine deaminase AICDA/AID targeting, hence promoting somatic hypermutations.

Subunit / interactions. Isoform GANP: Component of the nuclear pore complex (NPC)-associated TREX-2 complex (transcription and export complex 2), composed of at least GANP, 2 copies of ENY2, PCID2, SEM1/DSS1, and either centrin CETN2 or centrin CETN3. The TREX-2 complex also associates with ALYREF/ALY. Interacts with RNA polymerase II subunit POLR2A and with the transcription elongation factor SUPT5H/SPT5. Interacts (via FG-repeats) with NXF1; this interaction is not mediated by RNA. Isoform GANP interacts with nuclear envelope proteins NUP62, NUP153 and RANBP2/NUP358; interaction with NUP153 is required for full localization at the nuclear pore complex. Interacts with several RNA helicases, including DHX9, DDX21, and DDX39A/DDX39, and with DNA topoisomerase TOP2A. Directly interacts with AICDA/AID. Interacts with the glucocorticoid receptor NR3C1. Isoform MCM3AP: Interacts with the glucocorticoid receptor NR3C1. Interacts with MCM3; this interaction leads to MCM3 acetylation.

Subcellular location. Nucleus envelope. Nucleus. Nuclear pore complex. Nucleoplasm. Chromosome Cytoplasm.

Tissue specificity. Widely expressed. Up-regulated in germinal center B-cells in tonsils (at protein level).

Disease relevance. Peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (PNRIID) [MIM:618124] An autosomal recessive disorder characterized by early childhood-onset of peripheral sensorimotor neuropathy, progressive distal muscle weakness, atrophy in hands and feet, and gait difficulties, often with loss of ambulation. Most affected individuals also have impaired intellectual development, although some have normal cognition. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis. The disease is caused by variants affecting distinct genetic loci, including the gene represented in this entry.

Miscellaneous. Produced via an alternative promoter within an intron of GANP. MCM3AP promoter elements are poorly conserved in mice, suggesting that the regulation of MCM3AP may be human specific.

Similarity. Belongs to the SAC3 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O60318-1	GANP	yes
O60318-2	MCM3AP, 80 kDa MCM3-associated protein

RefSeq proteins (1): NP_003897* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000717	PCI_dom	Domain
IPR005062	SAC3/GANP/THP3_conserved	Domain
IPR031907	MCM3AP_GANP	Domain
IPR031908	NupH_GANP	Domain
IPR031910	GANP_CID_dom	Domain
IPR034265	MCM3AP_RRM	Domain
IPR035979	RBD_domain_sf	Homologous_superfamily
IPR045107	SAC3/GANP/THP3	Family

Pfam: PF03399, PF16766, PF16768, PF16769

Catalyzed reactions (Rhea), 1 shown:

• L-lysyl-[histone] + acetyl-CoA = N(6)-acetyl-L-lysyl-[histone] + CoA + H(+) (RHEA:21992)

UniProt features (57 total): sequence variant 25, region of interest 12, modified residue 7, compositionally biased region 6, mutagenesis site 2, chain 1, domain 1, coiled-coil region 1, splice variant 1, helix 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
4DHX	X-RAY DIFFRACTION	2.1
9DLP	ELECTRON MICROSCOPY	2.79
9T6N	ELECTRON MICROSCOPY	3
9UPC	ELECTRON MICROSCOPY	3.14
9UPB	ELECTRON MICROSCOPY	3.41
8R7J	ELECTRON MICROSCOPY	3.5
8R7K	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60318-F1	65.83	0.25

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 (7): 32, 430, 489, 490, 508, 538, 557

Mutagenesis-validated functional residues (2):

Position	Phenotype
1496–1501	loss of i nteraction with mcm3, loss of nuclear localization, loss of chromatin-binding.
1730–1733	severely decreased acetylase activity, loss of dna replication inhibition. does not affect chromatin-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 199 (showing top): GOBP_NUCLEAR_TRANSPORT, ONKEN_UVEAL_MELANOMA_UP, GOBP_IMMUNOGLOBULIN_PRODUCTION, HESS_TARGETS_OF_HOXA9_AND_MEIS1_UP, GOBP_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_SOMATIC_DIVERSIFICATION_OF_IMMUNE_RECEPTORS, BYSTRYKH_HEMATOPOIESIS_STEM_CELL_AND_BRAIN_QTL_TRANS, MORF_PML, HOEBEKE_LYMPHOID_STEM_CELL_UP, LEE_LIVER_CANCER_ACOX1_DN, GOBP_SOMATIC_DIVERSIFICATION_OF_IMMUNE_RECEPTORS_VIA_SOMATIC_MUTATION, MORF_IKBKG, GOBP_PROTEIN_DNA_COMPLEX_ORGANIZATION, GOBP_NUCLEAR_EXPORT, GOBP_CHROMATIN_REMODELING

GO Biological Process (7): mRNA export from nucleus (GO:0006406), protein transport (GO:0015031), somatic hypermutation of immunoglobulin genes (GO:0016446), poly(A)+ mRNA export from nucleus (GO:0016973), nucleosome organization (GO:0034728), immune system process (GO:0002376), mRNA transport (GO:0051028)

GO Molecular Function (8): nucleic acid binding (GO:0003676), chromatin binding (GO:0003682), histone acetyltransferase activity (GO:0004402), histone H3 acetyltransferase activity (GO:0010484), histone binding (GO:0042393), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (11): nucleus (GO:0005634), nucleoplasm (GO:0005654), chromosome (GO:0005694), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear membrane (GO:0031965), nuclear pore nuclear basket (GO:0044615), transcription export complex 2 (GO:0070390), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
nuclear protein-containing complex	3
nucleus	2
nuclear envelope	2
RNA export from nucleus	1
gene expression	1
mRNA transport	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
somatic diversification of immune receptors via somatic mutation	1
somatic diversification of immunoglobulins	1
mRNA export from nucleus	1
chromatin remodeling	1
protein-DNA complex organization	1
biological_process	1
RNA transport	1
protein-lysine-acetyltransferase activity	1
histone modifying activity	1
histone acetyltransferase activity	1
protein binding	1
catalytic activity	1
transferase activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
cytoplasm	1
organelle membrane	1
nuclear pore	1
endomembrane system	1
organelle envelope	1
cellular_component	1

Protein interactions and networks

STRING

2112 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MCM3AP	PCID2	Q5JVF3	994
MCM3AP	CETN2	P41208	981
MCM3AP	ENY2	Q9NPA8	980
MCM3AP	MCM3	P25205	971
MCM3AP	SEM1	Q6ZVN7	947
MCM3AP	CETN3	O15182	899
MCM3AP	NXF1	Q9UBU9	850
MCM3AP	ALYREF	Q86V81	759
MCM3AP	DDX39B	Q13838	711
MCM3AP	NUP153	P49790	651
MCM3AP	CD38	P28907	649
MCM3AP	SARNP	P82979	640
MCM3AP	FYTTD1	Q96QD9	632
MCM3AP	RGPD1	P0C839	612
MCM3AP	RAE1	P78406	601

IntAct

120 interactions, top by confidence:

A	B	Type	Score
CETN1	SFI1	psi-mi:“MI:0914”(association)	0.640
RPL28	MAGEB2	psi-mi:“MI:0914”(association)	0.560
MCM3AP	SEM1	psi-mi:“MI:0914”(association)	0.530
IER2	KPNA3	psi-mi:“MI:0914”(association)	0.530
TIMP3	ZZEF1	psi-mi:“MI:0914”(association)	0.530
CLEC11A	VWA8	psi-mi:“MI:0914”(association)	0.530
PIP	TBKBP1	psi-mi:“MI:0914”(association)	0.530
NS1	PIK3R2	psi-mi:“MI:0914”(association)	0.530
POC1A	TXNDC9	psi-mi:“MI:0914”(association)	0.480
PLEC	MCM3AP	psi-mi:“MI:0915”(physical association)	0.400
MCM3AP	PCNA	psi-mi:“MI:0915”(physical association)	0.370
CELSR3	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
CLSTN1	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	CDC25A	psi-mi:“MI:0915”(physical association)	0.370
POLR2G	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	EP300	psi-mi:“MI:0915”(physical association)	0.370
CDC73	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	FAM118B	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	SMAD3	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	SMAD9	psi-mi:“MI:0915”(physical association)	0.370
SUV39H2	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
MCM3AP	TAF1D	psi-mi:“MI:0915”(physical association)	0.370
TSC22D1	MCM3AP	psi-mi:“MI:0915”(physical association)	0.370
Nme7	MCM3AP	psi-mi:“MI:0914”(association)	0.350
Spcs2	SEC11A	psi-mi:“MI:0914”(association)	0.350

BioGRID (154): MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Proximity Label-MS), MCM3AP (Proximity Label-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS), MCM3AP (Affinity Capture-MS)

ESM2 similar proteins: E9Q3G8, O08587, O15117, O15504, O35601, O60318, O60934, P32499, P33215, P35658, P42566, P42567, P49790, P49791, Q15054, Q3B7M6, Q3MHS2, Q4ADK7, Q4R4T9, Q5EAW4, Q5FVW4, Q5R4Y2, Q5RB98, Q5VT52, Q5XGN1, Q5ZI22, Q5ZK28, Q640Z6, Q6P0U9, Q6PFD9, Q6PFK1, Q6XV80, Q75UQ2, Q7K0D8, Q80U93, Q8CIC2, Q8HXY9, Q8NHV4, Q8R1N0, Q9C829

Diamond homologs: A6H687, A6NKF1, O60318, Q9USI4, Q9WUU9, F4JAU2, P46674, Q67XV2, O74889, Q9U3V9, Q1MTP1

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CDK2	“up-regulates activity”	MCM3AP	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

1648 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	84
Likely pathogenic	23
Uncertain significance	720
Likely benign	652
Benign	91

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1061288	NM_003906.5(MCM3AP):c.4830_4837del (p.Leu1611fs)	Pathogenic
1378815	NM_003906.5(MCM3AP):c.3421del (p.Glu1141fs)	Pathogenic
1393589	NM_003906.5(MCM3AP):c.4297del (p.His1433fs)	Pathogenic
1410879	NC_000021.8:g.(?47676683)(47676920_?)del	Pathogenic
1423443	NM_003906.5(MCM3AP):c.1273_1274insC (p.Ser425fs)	Pathogenic
1437387	NM_003906.5(MCM3AP):c.2592C>G (p.Tyr864Ter)	Pathogenic
1441403	NM_003906.5(MCM3AP):c.1747G>T (p.Glu583Ter)	Pathogenic
1441725	NM_003906.5(MCM3AP):c.3799_3808del (p.Pro1267fs)	Pathogenic
1451462	NM_003906.5(MCM3AP):c.3476_3477del (p.Gln1159fs)	Pathogenic
1453302	NM_003906.5(MCM3AP):c.3503_3507dup (p.Gln1170Ter)	Pathogenic
1455754	NC_000021.8:g.(?47401765)(47705200_?)del	Pathogenic
1456374	NM_003906.5(MCM3AP):c.1106_1107del (p.Ser369fs)	Pathogenic
1686886	NM_003906.5(MCM3AP):c.4290+3G>T	Pathogenic
1806138	NM_003906.5(MCM3AP):c.584del (p.Pro195fs)	Pathogenic
1897225	NM_003906.5(MCM3AP):c.1256_1257del (p.Arg419fs)	Pathogenic
1911604	NM_003906.5(MCM3AP):c.121C>T (p.Gln41Ter)	Pathogenic
1932011	NM_003906.5(MCM3AP):c.613del (p.Ser205fs)	Pathogenic
1959085	NM_003906.5(MCM3AP):c.1541_1542insA (p.Phe514fs)	Pathogenic
1965162	NM_003906.5(MCM3AP):c.2667C>G (p.Tyr889Ter)	Pathogenic
1978760	NM_003906.5(MCM3AP):c.5366_5369del (p.Pro1789fs)	Pathogenic
2024232	NM_003906.5(MCM3AP):c.4715_4716dup (p.Ile1573fs)	Pathogenic
2028549	NM_003906.5(MCM3AP):c.539_540del (p.His180fs)	Pathogenic
2085245	NM_003906.5(MCM3AP):c.1010dup (p.Leu337fs)	Pathogenic
2098588	NM_003906.5(MCM3AP):c.1730C>G (p.Ser577Ter)	Pathogenic
2109072	NM_003906.5(MCM3AP):c.819dup (p.Cys274fs)	Pathogenic
2113664	NM_003906.5(MCM3AP):c.3935T>G (p.Leu1312Ter)	Pathogenic
2113669	NM_003906.5(MCM3AP):c.1098dup (p.Val367fs)	Pathogenic
2113674	NM_003906.5(MCM3AP):c.4015del (p.Ala1339fs)	Pathogenic
2114782	NM_003906.5(MCM3AP):c.2830G>T (p.Gly944Ter)	Pathogenic
2119864	NM_003906.5(MCM3AP):c.4570del (p.Val1524fs)	Pathogenic

SpliceAI

5040 predictions. Top by Δscore:

Variant	Effect	Δscore
21:46235427:C:CC	acceptor_gain	1.0000
21:46240982:T:TC	acceptor_gain	1.0000
21:46244805:ACCC:A	donor_gain	1.0000
21:46244806:CCCC:C	donor_gain	1.0000
21:46246302:CTTA:C	donor_loss	1.0000
21:46246303:TTACC:T	donor_loss	1.0000
21:46246304:TACCT:T	donor_loss	1.0000
21:46246305:A:AC	donor_gain	1.0000
21:46246306:C:CC	donor_gain	1.0000
21:46246306:C:CG	donor_loss	1.0000
21:46246405:C:CG	acceptor_loss	1.0000
21:46246616:T:TA	donor_gain	1.0000
21:46246639:T:TA	donor_gain	1.0000
21:46246710:AGC:A	donor_gain	1.0000
21:46246711:G:C	donor_gain	1.0000
21:46254843:ACC:A	acceptor_loss	1.0000
21:46254844:CCTG:C	acceptor_loss	1.0000
21:46254845:C:CA	acceptor_loss	1.0000
21:46254846:T:G	acceptor_loss	1.0000
21:46256784:CTGA:C	donor_loss	1.0000
21:46256785:TGACC:T	donor_loss	1.0000
21:46256786:GACCT:G	donor_loss	1.0000
21:46256787:ACCT:A	donor_loss	1.0000
21:46256788:C:A	donor_loss	1.0000
21:46256812:C:CA	donor_gain	1.0000
21:46256994:CA:C	acceptor_gain	1.0000
21:46258933:ACT:A	donor_loss	1.0000
21:46258934:CT:C	donor_loss	1.0000
21:46258935:TCAC:T	donor_loss	1.0000
21:46258936:CA:C	donor_loss	1.0000

AlphaMissense

12981 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:46273414:A:G	W724R	0.999
21:46273414:A:T	W724R	0.999
21:46266008:A:G	F983S	0.998
21:46272671:G:C	S785R	0.998
21:46272671:G:T	S785R	0.998
21:46272673:T:G	S785R	0.998
21:46272701:A:C	N775K	0.998
21:46272701:A:T	N775K	0.998
21:46272716:A:C	F770L	0.998
21:46272716:A:T	F770L	0.998
21:46272718:A:G	F770L	0.998
21:46273392:C:G	R731P	0.998
21:46273402:G:T	R728S	0.998
21:46275238:C:G	R649P	0.998
21:46266007:G:C	F983L	0.997
21:46266007:G:T	F983L	0.997
21:46266009:A:G	F983L	0.997
21:46266155:A:G	L934P	0.997
21:46267138:C:G	R878P	0.997
21:46272669:A:G	L786P	0.997
21:46272692:G:C	N778K	0.997
21:46272692:G:T	N778K	0.997
21:46273395:A:T	I730K	0.997
21:46273401:C:G	R728P	0.997
21:46273407:C:G	R726P	0.997
21:46273412:C:A	W724C	0.997
21:46273412:C:G	W724C	0.997
21:46273558:A:G	Y676H	0.997
21:46273562:T:A	K674N	0.997
21:46273562:T:G	K674N	0.997

dbSNP variants (sampled 300 via entrez): RS1000077044 (21:46251249 A>G), RS1000104642 (21:46287421 C>G,T), RS1000112917 (21:46267462 G>C), RS1000127780 (21:46255767 G>A,C), RS1000169714 (21:46264620 G>A), RS1000186222 (21:46251378 T>C), RS1000226371 (21:46267264 C>T), RS1000262928 (21:46250853 G>A), RS1000400560 (21:46250314 C>G), RS1000452696 (21:46282577 G>C), RS1000465422 (21:46261607 C>T), RS1000524236 (21:46278588 G>A), RS1000546458 (21:46239849 A>C), RS1000553390 (21:46278766 C>A,T), RS1000575088 (21:46254304 A>G)

Disease associations

OMIM: gene MIM:603294 | disease phenotypes: MIM:618124, MIM:135700

GenCC curated gene-disease

Disease	Classification	Inheritance
peripheral neuropathy, autosomal recessive, with or without impaired intellectual development	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
peripheral neuropathy, autosomal recessive, with or without impaired intellectual development	Definitive	AR

Mondo (4): peripheral neuropathy, autosomal recessive, with or without impaired intellectual development (MONDO:0029131), peripheral neuropathy (MONDO:0005244), congenital fibrosis of extraocular muscles (MONDO:0007614), autism spectrum disorder (MONDO:0005258)

Orphanet (2): Congenital fibrosis of extraocular muscles (Orphanet:45358), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000486	Strabismus
HP:0000496	Abnormality of eye movement
HP:0000602	Ophthalmoplegia
HP:0000750	Delayed speech and language development
HP:0001171	Split hand
HP:0001249	Intellectual disability
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001513	Obesity
HP:0001761	Pes cavus
HP:0002317	Unsteady gait
HP:0002460	Distal muscle weakness
HP:0002505	Loss of ambulation
HP:0002522	Areflexia of lower limbs
HP:0002650	Scoliosis
HP:0002705	High, narrow palate
HP:0002808	Kyphosis
HP:0002870	Obstructive sleep apnea
HP:0002936	Distal sensory impairment
HP:0003477	Peripheral axonal neuropathy
HP:0003577	Congenital onset
HP:0003621	Juvenile onset
HP:0003677	Slowly progressive
HP:0004322	Short stature
HP:0007141	Sensorimotor neuropathy
HP:0007328	Impaired pain sensation

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST002022_14	Testicular germ cell tumor	1.000000e-09
GCST002855_7	Testicular germ cell tumor	3.000000e-06
GCST004635_42	Testicular germ cell tumor	7.000000e-12
GCST006486_3	Periodontitis	9.000000e-07
GCST90002394_201	Monocyte percentage of white cells	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007989	monocyte percentage of leukocytes

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C580012	congenital fibrosis of the extraocular muscles (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1815857	MCM3AP		0.00	0

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	decreases expression, increases expression	2
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
Acetaminophen	decreases expression	1
Amphotericin B	increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Hydrogen Peroxide	affects expression	1
Methotrexate	increases expression	1
Quercetin	increases phosphorylation	1
Valproic Acid	affects cotreatment, decreases expression	1
Vitamin E	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Aflatoxin B1	increases methylation	1
Fenretinide	affects expression	1
Asbestos, Amosite	increases methylation	1
Cadmium Chloride	increases abundance, increases expression	1
Lactic Acid	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.