MAPRE2

Summary

MAPRE2 (microtubule associated protein RP/EB family member 2, HGNC:6891) is a protein-coding gene on chromosome 18q12.1-q12.2, encoding Microtubule-associated protein RP/EB family member 2 (Q15555). Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes.

The protein encoded by this gene shares significant homology to the adenomatous polyposis coli (APC) protein-binding EB1 gene family. This protein is a microtubule-associated protein that is necessary for spindle symmetry during mitosis. It is thought to play a role in the tumorigenesis of colorectal cancers and the proliferative control of normal cells. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 10982 — RefSeq curated summary.

At a glance

• Gene–disease (curated): RP1-related dominant retinopathy (Definitive, ClinGen) — +5 more curated relationships
• GWAS associations: 27
• Clinical variants (ClinVar): 1,656 total — 206 pathogenic, 63 likely-pathogenic
• Phenotypes (HPO): 72
• Druggable target: yes
• MANE Select transcript: NM_014268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6891
Approved symbol	MAPRE2
Name	microtubule associated protein RP/EB family member 2
Location	18q12.1-q12.2
Locus type	gene with protein product
Status	Approved
Aliases	RP1, EB1, EB2
Ensembl gene	ENSG00000166974
Ensembl biotype	protein_coding
OMIM	605789
Entrez	10982

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 14 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000300249, ENST00000413393, ENST00000436190, ENST00000538170, ENST00000585592, ENST00000587359, ENST00000588085, ENST00000588349, ENST00000588910, ENST00000589180, ENST00000589699, ENST00000590793, ENST00000591734, ENST00000922166, ENST00000922167, ENST00000942657, ENST00000942658

RefSeq mRNA: 4 — MANE Select: NM_014268 NM_001143826, NM_001143827, NM_001256420, NM_014268

CCDS: CCDS11910, CCDS45850, CCDS45851, CCDS58619

Canonical transcript exons

ENST00000300249 — 7 exons

Exon	Start	End
ENSE00001266814	35041413	35041661
ENSE00002286299	35140295	35143470
ENSE00002983177	35126948	35127087
ENSE00003061470	35097446	35097591
ENSE00003086494	35132032	35132190
ENSE00003186267	35101946	35102159
ENSE00003651457	35070195	35070322

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 98.32.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.9897 / max 732.9232, expressed in 1804 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169923	49.8648	1792
169916	5.7824	951
169918	0.3589	164
169920	0.3210	155
169919	0.2865	135
169921	0.2649	115
169917	0.1113	60

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	98.32	gold quality
dorsal root ganglion	UBERON:0000044	98.02	gold quality
corpus callosum	UBERON:0002336	97.86	gold quality
inferior vagus X ganglion	UBERON:0005363	97.82	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.82	gold quality
spinal cord	UBERON:0002240	97.73	gold quality
parietal lobe	UBERON:0001872	97.55	gold quality
prefrontal cortex	UBERON:0000451	97.54	gold quality
subthalamic nucleus	UBERON:0001906	97.51	gold quality
postcentral gyrus	UBERON:0002581	97.45	gold quality
entorhinal cortex	UBERON:0002728	97.40	gold quality
pons	UBERON:0000988	97.30	gold quality
superior frontal gyrus	UBERON:0002661	97.29	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.27	gold quality
frontal pole	UBERON:0002795	97.00	gold quality
ventral tegmental area	UBERON:0002691	96.99	gold quality
frontal cortex	UBERON:0001870	96.90	gold quality
frontal lobe	UBERON:0016525	96.90	gold quality
middle temporal gyrus	UBERON:0002771	96.84	gold quality
superior vestibular nucleus	UBERON:0007227	96.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.75	gold quality
neocortex	UBERON:0001950	96.74	gold quality
medulla oblongata	UBERON:0001896	96.72	gold quality
adrenal tissue	UBERON:0018303	96.61	gold quality
cerebral cortex	UBERON:0000956	96.56	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.54	gold quality
temporal lobe	UBERON:0001871	96.47	gold quality
cingulate cortex	UBERON:0003027	96.43	gold quality
anterior cingulate cortex	UBERON:0009835	96.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	96.35	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	yes	32.17
E-HCAD-10	yes	15.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, FOS, JUN, MITF, USF2

miRNA regulators (miRDB)

107 targeting MAPRE2, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-204-5P	99.79	71.62	2439
HSA-MIR-211-5P	99.79	71.65	2440
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093
HSA-MIR-548G-5P	99.78	71.12	3085
HSA-MIR-548X-5P	99.78	71.12	3085
HSA-MIR-1299	99.77	71.24	2389

Literature-anchored findings (GeneRIF, showing 18)

• Data suggest that a functional interaction between EB1 and p150(Glued) is required for microtubule minus end anchoring at centrosomes during the assembly and maintenance of a radial microtubule array. (PMID:12388762)
• EB1 may modulate kinetochore microtubule polymerization and/or attachment (PMID:12475954)
• results support the novel hypothesis that EB1 overexpression may play a role in the development of esophageal squamous cell carcinoma by affecting APC function and activating the beta-catenin/TCF pathway (PMID:16007168)
• Impaired EB1 or APC function generates lesions invisible to the spindle checkpoint and thereby promotes low levels of chromosomal loss (CIN) expected to fuel aneuploidy and possibly tumorigenesis. (PMID:16763565)
• These data demonstrate that the COP9 signalosome-dependent protection of EB1 is important for microtubule function. (PMID:17350042)
• Crystal structures of the tubulin binding domains of XMAP215 (yeast Stu2p and Drosophila Msps), EB1 (yeast Bim1p and human EB1), and CLIP-170 (human), which reveal diverse tubulin binding interfaces, are reported. (PMID:17889670)
• p150Glued may activate and thereby facilitate the recruitment of EB1 to the tips of microtubules to regulate their dynamics. (PMID:18081319)
• EB1-tubulin interactions are mediated in part by the same tubulin acidic tails utilized by other MAPs (PMID:19778897)
• MAPRE2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion (PMID:19787265)
• heterodimer formation between EB1 and EB3, but not between EB2 and the other two EBs, occurs both in vitro and in cells as revealed by live cell imaging (PMID:20008324)
• results suggest that EB1 and ClipCG12 act cooperatively to regulate microtubule dynamics (EB1) (PMID:22424550)
• EB2 is evidently important for initial microtubule reorganisation during epithelial polarisation, whereas its downregulation facilitates EB1 and ACF7 microtubule lattice association, microtubule-actin filament co-alignment and bundle formation. (PMID:23813963)
• Mutations in either TUBB or MAPRE2 cause circumferential skin creases Kunze type. (PMID:26637975)
• Aurora B and CDK1 temporally regulate the binding affinity of EB2 for microtubules, thereby ensuring kinetochore microtubule dynamics, proper mitotic progression and genome stability. (PMID:27030108)
• MAPRE2 mutations result in altered human cranial neural crest migration, underlying craniofacial malformations in CSC-KT syndrome. (PMID:33654163)
• CircAGFG1 acts as a sponge of miR-4306 to stimulate esophageal cancer progression by modulating MAPRE2 expression. (PMID:34461454)
• JUND facilitates proliferation and angiogenesis of esophageal squamous cell carcinoma cell via MAPRE2 up-regulation. (PMID:36608637)
• The Role of MAPRE2 and Microtubules in Maintaining Normal Ventricular Conduction. (PMID:38095085)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	mapre2	ENSDARG00000099943
mus_musculus	Mapre2	ENSMUSG00000024277
rattus_norvegicus	AABR07031491.2	ENSRNOG00000049681
caenorhabditis_elegans		WBGENE00007062
caenorhabditis_elegans		WBGENE00012156
caenorhabditis_elegans		WBGENE00013344

Paralogs (2): MAPRE3 (ENSG00000084764), MAPRE1 (ENSG00000101367)

Protein

Protein identifiers

Microtubule-associated protein RP/EB family member 2 — Q15555 (reviewed: Q15555)

Alternative names: APC-binding protein EB2, End-binding protein 2

All UniProt accessions (5): Q15555, K7EL66, K7ENB3, K7ERD8, M0QX52

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein that is involved in microtubule polymerization, and spindle function by stabilizing microtubules and anchoring them at centrosomes. Therefore, ensures mitotic progression and genome stability. Acts as a central regulator of microtubule reorganization in apico-basal epithelial differentiation. Plays a role during oocyte meiosis by regulating microtubule dynamics. Participates in neurite growth by interacting with plexin B3/PLXNB3 and microtubule reorganization during apico-basal epithelial differentiation. Also plays an essential role for cell migration and focal adhesion dynamics. Mechanistically, recruits HAX1 to microtubules in order to regulate focal adhesion dynamics.

Subunit / interactions. Interacts with DCTN1. Interacts with APC (via C-terminal). Interacts with monomeric and polymerized tubulin. Interacts with SLAIN1. Interacts (via the N-terminal region) with BAG1. Interacts with ASB14. Interacts with HAX1; this interaction is essential for epidermal cell migration.

Subcellular location. Cytoplasm. Cytoskeleton.

Tissue specificity. Expressed in different tumor cell lines. Up-regulated in activated B- and T-lymphocytes.

Post-translational modifications. Phosphorylated at Ser-236 by CK2 leading to enhanced cell adhesion. Phosphorylated by CDK1 and AURKB during mitosis reduces the binding affinity of MAPRE2 for microtubules. Ubiquitinated in an ASB14-dependent manner; leading to proteasomal degradation.

Disease relevance. Skin creases, congenital symmetric circumferential, 2 (CSCSC2) [MIM:616734] An autosomal dominant disease characterized by multiple, symmetric, circumferential rings of folded skin, affecting primarily the limbs. Affected individuals also exhibit intellectual disability, cleft palate, and dysmorphic features. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Composed of two functionally independent domains. The N-terminal domain forms a hydrophobic cleft involved in microtubule binding and the C-terminal is involved in the formation of mutually exclusive complexes with APC and DCTN1.

Similarity. Belongs to the MAPRE family.

Isoforms (5)

UniProt ID	Names	Canonical?
Q15555-1	1	yes
Q15555-2	2
Q15555-3	3
Q15555-5	5
Q15555-4	4

RefSeq proteins (4): NP_001137298, NP_001137299, NP_001243349, NP_055083* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001715	CH_dom	Domain
IPR004953	EB1_C	Domain
IPR027328	MAPRE	Family
IPR036133	EB1_C_sf	Homologous_superfamily
IPR036872	CH_dom_sf	Homologous_superfamily

Pfam: PF00307, PF03271

UniProt features (32 total): modified residue 5, splice variant 5, sequence conflict 5, region of interest 5, sequence variant 4, compositionally biased region 3, domain 2, chain 1, mutagenesis site 1, initiator methionine 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15555-F1	75.12	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.

Post-translational modifications (5): 9, 167, 219, 236, 2

Mutagenesis-validated functional residues (1):

Position	Phenotype
236	significant loss of phosphorylation and cell adhesion activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 699 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_UP, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, HARRIS_HYPOXIA, GOBP_CELLULAR_RESPONSE_TO_LIGHT_STIMULUS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_EPITHELIAL_CELL_MIGRATION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_PHOTOTRANSDUCTION, GOBP_NEUROGENESIS, FOXO4_01, GOBP_NEURAL_RETINA_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION

GO Biological Process (7): regulation of microtubule polymerization or depolymerization (GO:0031110), positive regulation of ARF protein signal transduction (GO:0032014), protein localization to microtubule (GO:0035372), spindle assembly (GO:0051225), cell division (GO:0051301), positive regulation of keratinocyte migration (GO:0051549), positive regulation of focal adhesion disassembly (GO:0120183)

GO Molecular Function (5): microtubule binding (GO:0008017), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), microtubule plus-end binding (GO:0051010), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), microtubule organizing center (GO:0005815), cytoplasmic microtubule (GO:0005881), focal adhesion (GO:0005925), microtubule cytoskeleton (GO:0015630), microtubule plus-end (GO:0035371), spindle midzone (GO:0051233), cytoskeleton (GO:0005856), microtubule (GO:0005874)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
microtubule cytoskeleton	2
microtubule polymerization or depolymerization	1
regulation of microtubule cytoskeleton organization	1
ARF protein signal transduction	1
regulation of ARF protein signal transduction	1
positive regulation of small GTPase mediated signal transduction	1
protein localization to microtubule cytoskeleton	1
spindle organization	1
chromosome segregation	1
membraneless organelle assembly	1
cellular process	1
positive regulation of epithelial cell migration	1
keratinocyte migration	1
regulation of keratinocyte migration	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
positive regulation of cell-substrate junction organization	1
tubulin binding	1
kinase binding	1
protein binding	1
microtubule binding	1
binding	1
intracellular anatomical structure	1
cytoplasm	1
microtubule	1
cell-substrate junction	1
cytoskeleton	1
microtubule end	1
spindle	1
intracellular membraneless organelle	1
polymeric cytoskeletal fiber	1

Protein interactions and networks

STRING

1820 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAPRE2	RBM15B	Q8NDT2	903
MAPRE2	RAE1	P78406	799
MAPRE2	ZNF24	P17028	775
MAPRE2	KHK	P50053	771
MAPRE2	RBM15	Q96T37	765
MAPRE2	MAP4K4	O95819	700
MAPRE2	APC2	O95996	673
MAPRE2	NXF1	Q9UBU9	624
MAPRE2	SRSF3	P23152	621
MAPRE2	EFNB2	P52799	574
MAPRE2	EID1	Q9Y6B2	547
MAPRE2	XPO1	O14980	543
MAPRE2	CLIP1	P30622	530
MAPRE2	SRSF7	Q16629	507
MAPRE2	PABPC1	P11940	492

IntAct

198 interactions, top by confidence:

A	B	Type	Score
MAPRE2	MAPRE1	psi-mi:“MI:0915”(physical association)	0.930
MAPRE3	MAPRE2	psi-mi:“MI:0915”(physical association)	0.870
MAPRE2	MAPRE3	psi-mi:“MI:0915”(physical association)	0.870
MAPRE1	CLASP2	psi-mi:“MI:0914”(association)	0.850
MAPRE2	TRAF1	psi-mi:“MI:0915”(physical association)	0.840
TRAF1	MAPRE2	psi-mi:“MI:0915”(physical association)	0.840
MAPRE1	DST	psi-mi:“MI:0914”(association)	0.840
MAPRE2	CRTAC1	psi-mi:“MI:0915”(physical association)	0.830
CRTAC1	MAPRE2	psi-mi:“MI:0915”(physical association)	0.830
LMO2	MAPRE2	psi-mi:“MI:0915”(physical association)	0.800
MAPRE2	LMO2	psi-mi:“MI:0915”(physical association)	0.800

BioGRID (177): MAPRE2 (Affinity Capture-MS), MAPRE2 (Two-hybrid), MAPRE2 (Two-hybrid), MAPRE2 (Two-hybrid), MAPRE2 (Two-hybrid), MAPRE1 (Two-hybrid), PAXIP1 (Two-hybrid), TXN2 (Two-hybrid), CRTAC1 (Two-hybrid), MAPRE2 (Affinity Capture-MS), MAPRE2 (Affinity Capture-MS), MAPRE2 (Affinity Capture-MS), MAPRE2 (Two-hybrid), NIF3L1 (Two-hybrid), MAPRE2 (Two-hybrid)

ESM2 similar proteins: A0A0E0RU58, A1CW67, A7E8B6, C8V212, C8VTS4, G0RL42, G2XJ47, G4MRQ6, G4N525, G9NAW2, I1S5P3, J9N5P9, J9VGT6, M2SQ20, N1PZ58, O17583, O42632, P0CM59, P0CR60, P38093, P87253, Q0CT27, Q0U4Z8, Q0V0I4, Q15555, Q1E0A3, Q1EA11, Q2UUI3, Q3B8Q0, Q3SZP2, Q4IBS9, Q4P1V3, Q4X0Z5, Q5B778, Q5R4I6, Q6CHN0, Q6CY25, Q6FT03, Q7RZJ2, Q7SAN9

Diamond homologs: E2RU10, P40013, Q15555, Q15691, Q3B8Q0, Q3SZP2, Q3ZBD9, Q5R4I6, Q5R7Z5, Q5XIT1, Q5ZKK1, Q5ZLC7, Q61166, Q66HR2, Q66T82, Q6P848, Q6PER3, Q6V291, Q7XJ60, Q7ZXP1, Q8R001, Q8WQ86, Q9FGQ6, Q9FJJ5, Q9UPY8, Q10113

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AURKB	“up-regulates activity”	MAPRE2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	8	17.6×	9e-06
COPI-independent Golgi-to-ER retrograde traffic	6	14.2×	8e-04
Aggrephagy	5	14.1×	3e-03
Defective CFTR causes cystic fibrosis	5	12.5×	4e-03
SCF(Skp2)-mediated degradation of p27/p21	5	11.8×	4e-03
Regulation of HSF1-mediated heat shock response	7	11.1×	8e-04
PKR-mediated signaling	6	9.6×	4e-03
The role of GTSE1 in G2/M progression after G2 checkpoint	5	9.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of microtubule polymerization or depolymerization	6	48.6×	1e-06
establishment of mitotic spindle orientation	5	18.5×	3e-03
microtubule cytoskeleton organization	8	7.5×	4e-03
cell division	12	4.3×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

1656 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	206
Likely pathogenic	63
Uncertain significance	945
Likely benign	280
Benign	24

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069795	NM_006269.2(RP1):c.312_315del (p.Leu105fs)	Pathogenic
1070812	NM_006269.2(RP1):c.2352_2356del (p.Ile785fs)	Pathogenic
1071082	NM_006269.2(RP1):c.284dup (p.Glu96fs)	Pathogenic
1071351	NM_006269.2(RP1):c.2334del (p.Lys778fs)	Pathogenic
1073337	NM_006269.2(RP1):c.696T>G (p.Tyr232Ter)	Pathogenic
1074882	NM_006269.2(RP1):c.2105_2106insG (p.Ile702fs)	Pathogenic
1075497	NM_006269.2(RP1):c.3639_3652del (p.Thr1214fs)	Pathogenic
1075672	NM_006269.2(RP1):c.6154C>T (p.Gln2052Ter)	Pathogenic
1076686	NM_006269.2(RP1):c.513del (p.Leu171_Leu172insTer)	Pathogenic
1076794	NM_006269.2(RP1):c.2018del (p.Lys673fs)	Pathogenic
1213898	NM_006269.2(RP1):c.532C>T (p.Gln178Ter)	Pathogenic
1213902	NM_006269.2(RP1):c.2079del (p.Gly694fs)	Pathogenic
1284630	NM_006269.2(RP1):c.2732C>G (p.Ser911Ter)	Pathogenic
1323531	NM_006269.2(RP1):c.257dup (p.Arg87fs)	Pathogenic
1325011	NM_006269.2(RP1):c.1986del (p.Lys663fs)	Pathogenic
1358118	NM_006269.2(RP1):c.3728_3729del (p.Glu1243fs)	Pathogenic
1358934	NM_006269.2(RP1):c.1444C>T (p.Gln482Ter)	Pathogenic
1375325	NM_006269.2(RP1):c.2607del (p.Lys871fs)	Pathogenic
1385798	NM_006269.2(RP1):c.2072del (p.Ala691fs)	Pathogenic
1401598	NM_006269.2(RP1):c.150_168delinsAGACCCCCAATT (p.Val51fs)	Pathogenic
1406268	NM_006269.2(RP1):c.2321T>G (p.Leu774Ter)	Pathogenic
1410895	NM_006269.2(RP1):c.4587_4590del (p.Ser1529fs)	Pathogenic
1424798	NM_006269.2(RP1):c.72del (p.Arg25fs)	Pathogenic
1426124	NM_006269.2(RP1):c.2323del (p.Thr775fs)	Pathogenic
1428425	NM_006269.2(RP1):c.2747_2763del (p.Ile916fs)	Pathogenic
1430123	NM_006269.2(RP1):c.491del (p.Pro164fs)	Pathogenic
143137	NM_006269.2(RP1):c.650del (p.Gly217fs)	Pathogenic
1436096	NM_006269.2(RP1):c.1720_1721del (p.Ser574fs)	Pathogenic
1437029	NM_006269.2(RP1):c.2017A>T (p.Lys673Ter)	Pathogenic
1437481	NM_006269.2(RP1):c.2215G>T (p.Glu739Ter)	Pathogenic

SpliceAI

1133 predictions. Top by Δscore:

Variant	Effect	Δscore
18:35041629:G:GT	donor_gain	1.0000
18:35067742:T:G	donor_gain	1.0000
18:35070189:TTCTA:T	acceptor_loss	1.0000
18:35070190:TCTA:T	acceptor_loss	1.0000
18:35070191:CTAGT:C	acceptor_loss	1.0000
18:35070192:TA:T	acceptor_loss	1.0000
18:35070193:A:AG	acceptor_gain	1.0000
18:35070193:AGTT:A	acceptor_gain	1.0000
18:35070193:AGTTG:A	acceptor_gain	1.0000
18:35070194:G:GG	acceptor_gain	1.0000
18:35070194:GTT:G	acceptor_gain	1.0000
18:35070194:GTTG:G	acceptor_gain	1.0000
18:35070194:GTTGG:G	acceptor_gain	1.0000
18:35070319:TCAGG:T	donor_loss	1.0000
18:35070320:CAG:C	donor_loss	1.0000
18:35070321:AGGTA:A	donor_loss	1.0000
18:35070322:GGTAA:G	donor_loss	1.0000
18:35070324:T:G	donor_loss	1.0000
18:35097440:TTCCA:T	acceptor_loss	1.0000
18:35097443:CAGGA:C	acceptor_loss	1.0000
18:35097444:A:AG	acceptor_gain	1.0000
18:35097444:A:T	acceptor_loss	1.0000
18:35097444:AG:A	acceptor_gain	1.0000
18:35097445:G:GT	acceptor_gain	1.0000
18:35097445:GG:G	acceptor_gain	1.0000
18:35097445:GGA:G	acceptor_gain	1.0000
18:35097445:GGAGC:G	acceptor_gain	1.0000
18:35097587:ATAAG:A	donor_loss	1.0000
18:35097588:TAAG:T	donor_loss	1.0000
18:35097589:AAG:A	donor_loss	1.0000

AlphaMissense

2167 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:35070247:A:C	S59R	1.000
18:35070249:C:A	S59R	1.000
18:35070249:C:G	S59R	1.000
18:35070250:A:G	R60G	1.000
18:35070251:G:C	R60T	1.000
18:35070251:G:T	R60I	1.000
18:35070252:A:C	R60S	1.000
18:35070252:A:T	R60S	1.000
18:35070268:T:A	W66R	1.000
18:35070268:T:C	W66R	1.000
18:35070270:G:C	W66C	1.000
18:35070270:G:T	W66C	1.000
18:35070272:T:A	V67D	1.000
18:35070301:A:G	K77E	1.000
18:35070302:A:T	K77I	1.000
18:35070303:A:C	K77N	1.000
18:35070303:A:T	K77N	1.000
18:35070307:G:A	E79K	1.000
18:35070314:T:C	L81P	1.000
18:35070322:G:A	G84R	1.000
18:35070322:G:C	G84R	1.000
18:35097446:G:A	G84E	1.000
18:35097446:G:T	G84V	1.000
18:35097452:C:A	A86D	1.000
18:35097457:T:C	C88R	1.000
18:35097458:G:A	C88Y	1.000
18:35097459:C:G	C88W	1.000
18:35097478:T:C	F95L	1.000
18:35097480:C:A	F95L	1.000
18:35097480:C:G	F95L	1.000

dbSNP variants (sampled 300 via entrez): RS1000004091 (18:34988607 A>G), RS1000027410 (18:35060866 G>A), RS1000040239 (18:35038067 C>G), RS1000062651 (18:35096562 G>A,C), RS1000069147 (18:35076174 C>G), RS1000080916 (18:35122601 A>C,G), RS1000093304 (18:35096287 G>A), RS1000098471 (18:35075857 A>C), RS1000117889 (18:35103710 G>A), RS1000118291 (18:34988849 G>A,C), RS1000138643 (18:34991376 G>A), RS1000151397 (18:35052385 G>A,T), RS1000155807 (18:35009727 A>T), RS1000196877 (18:35051175 C>G), RS1000207914 (18:35058653 A>G)

Disease associations

OMIM: gene MIM:605789 | disease phenotypes: MIM:180100, MIM:268000, MIM:616734, MIM:204000, MIM:145750, MIM:120970, MIM:535000

GenCC curated gene-disease

Disease	Classification	Inheritance
RP1-related recessive retinopathy	Definitive	Autosomal recessive
RP1-related dominant retinopathy	Definitive	Semidominant
retinitis pigmentosa 1	Definitive	Autosomal dominant
skin creases, congenital symmetric circumferential, 2	Definitive	Autosomal recessive
retinitis pigmentosa	Supportive	Autosomal dominant
multiple benign circumferential skin creases on limbs	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (2)

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

Disease	Classification	Inheritance
RP1-related dominant retinopathy	Definitive	SD
RP1-related recessive retinopathy	Definitive	AR

Mondo (12): retinitis pigmentosa 1 (MONDO:0008377), retinitis pigmentosa (MONDO:0019200), inherited retinal dystrophy (MONDO:0019118), RP1-related recessive retinopathy (MONDO:0800399), skin creases, congenital symmetric circumferential, 2 (MONDO:0014755), retinal disorder (MONDO:0005283), Leber congenital amaurosis 1 (MONDO:0008764), hypertriglyceridemia 1 (MONDO:0007788), cone-rod dystrophy (MONDO:0015993), Leber hereditary optic neuropathy (MONDO:0010788), RP1-related dominant retinopathy (MONDO:0800400), multiple benign circumferential skin creases on limbs (MONDO:0007990)

Orphanet (5): Retinitis pigmentosa (Orphanet:791), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Leber congenital amaurosis (Orphanet:65), Cone rod dystrophy (Orphanet:1872), Leber hereditary optic neuropathy (Orphanet:104)

HPO phenotypes

72 total (30 of 72 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000045	Abnormal scrotum morphology
HP:0000046	Small scrotum
HP:0000047	Hypospadias
HP:0000070	Ureterocele
HP:0000160	Narrow mouth
HP:0000175	Cleft palate
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000271	Abnormality of the face
HP:0000276	Long face
HP:0000286	Epicanthus
HP:0000294	Low anterior hairline
HP:0000316	Hypertelorism
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000396	Overfolded helix
HP:0000431	Wide nasal bridge
HP:0000470	Short neck
HP:0000475	Broad neck
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000488	Retinopathy
HP:0000494	Downslanted palpebral fissures
HP:0000508	Ptosis

GWAS associations

27 associations (top):

Study	Trait	p-value
GCST003072_8	Cerebrospinal fluid AB1-42 levels	3.000000e-07
GCST004748_134	Lung cancer	2.000000e-06
GCST004749_24	Lung cancer in ever smokers	9.000000e-07
GCST004749_25	Lung cancer in ever smokers	2.000000e-06
GCST006108_2	Facial morphology	1.000000e-06
GCST007445_3	Factor VIII levels	2.000000e-07
GCST007445_32	Factor VIII levels	2.000000e-09
GCST008077_14	LDL cholesterol levels	6.000000e-11
GCST008077_72	LDL cholesterol levels	1.000000e-08
GCST008078_6	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-18
GCST008078_73	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-17
GCST008079_12	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-20
GCST008079_143	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	8.000000e-20
GCST008086_53	LDL cholesterol levels in current drinkers	4.000000e-13
GCST008086_86	LDL cholesterol levels in current drinkers	2.000000e-13
GCST008600_6	Longevity (age >90th survival percentile)	6.000000e-07
GCST009391_820	Metabolite levels	3.000000e-06
GCST010204_117	Low density lipoprotein cholesterol levels	3.000000e-23
GCST010796_1650	Electrocardiogram morphology (amplitude at temporal datapoints)	5.000000e-10
GCST010796_1901	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_1902	Electrocardiogram morphology (amplitude at temporal datapoints)	2.000000e-09
GCST010796_1903	Electrocardiogram morphology (amplitude at temporal datapoints)	1.000000e-09
GCST012354_17	Anxiety	5.000000e-30
GCST012355_22	Depression	6.000000e-42
GCST90006901_1	Epstein-Barr virus ZEBRA antibody levels	3.000000e-09
GCST90006924_3	Merkel cell polyomavirus VP1 antibody levels	3.000000e-08
GCST90086158_20	Brugada syndrome	3.000000e-09

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004670	beta-amyloid 1-42 measurement
EFO:0004743	facial morphology
EFO:0004630	factor VIII measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0010398	sphingomyelin 24:1 measurement
EFO:0004327	electrocardiography
EFO:0009863	anxiety measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000071700	Cone-Rod Dystrophies	C11.270.152; C11.768.585.658.250; C16.320.290.152
D029242	Optic Atrophy, Hereditary, Leber	C10.292.700.225.500.400; C10.574.500.662.400; C11.270.564.400; C11.640.451.451.400; C16.320.290.564.400; C16.320.400.630.400; C18.452.660.670
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684
C537575	Michelin tire baby syndrome (supp.)
C538365	Retinitis pigmentosa 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066505 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	Kd	30.2	nM	CHEMBL3752910
7.52	ED50	30.2	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148716: Binding affinity to human MAPRE2 incubated for 45 mins by Kinobead based pull down assay	kd	0.0302	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	4
Cyclosporine	decreases expression, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation	2
Okadaic Acid	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
lead acetate	decreases expression, affects cotreatment	1
methylselenic acid	increases expression	1
decabromobiphenyl ether	decreases expression	1
sodium arsenite	affects cotreatment, decreases expression	1
tetrabromobisphenol A	decreases expression	1
beta-methylcholine	affects expression	1
2,3-dimethoxy-1,4-naphthoquinone	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
rofecoxib	decreases expression	1
entinostat	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	increases expression, affects cotreatment	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
Cidofovir	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Bilirubin	decreases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651758	Binding	Binding affinity to human MAPRE2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00717080	PHASE4	COMPLETED	The Role of Capsular Tension Ring (CTR) in Anterior Capsular Contraction
NCT00000114	PHASE3	COMPLETED	Randomized Trial of Vitamin A and Vitamin E Supplementation for Retinitis Pigmentosa
NCT00000116	PHASE3	COMPLETED	Randomized Trial of DHA for Retinitis Pigmentosa Patients Receiving Vitamin A
NCT00346333	PHASE3	COMPLETED	Clinical Trial of Lutein for Patients With Retinitis Pigmentosa Receiving Vitamin A
NCT01786395	PHASE3	TERMINATED	Phase III Efficacy and Safety Clinical Study of UF-021 for Treatment of Retinitis Pigmentosa
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT04636853	PHASE3	COMPLETED	CB-PRP in Retinitis Pigmentosa and Dry Age-related Macular Degeneration
NCT05537220	PHASE3	ACTIVE_NOT_RECRUITING	Oral N-acetylcysteine for Retinitis Pigmentosa
NCT05800301	PHASE3	COMPLETED	Management of Retinitis Pigmentosa Via Combination of Wharton’s Jelly-derived Mesenchymal Stem Cells and Magnovision
NCT05926583	PHASE3	ACTIVE_NOT_RECRUITING	A Study of AAV5-hRKp.RPGR for the Treatment of Japanese Participants With X-linked Retinitis Pigmentosa
NCT06388200	PHASE3	ACTIVE_NOT_RECRUITING	A Phase 3 Study Of OCU400 Gene Therapy for the Treatment Of Retinitis Pigmentosa
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT07290530	PHASE3	NOT_YET_RECRUITING	24-Month Trial of NPI-001 for the Preservation of Photoreceptors in Retinitis Pigmentosa Associated With Usher Syndrome
NCT00100230	PHASE2	COMPLETED	DHA and X-Linked Retinitis Pigmentosa
NCT00447980	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Participants With Early Stage Retinitis Pigmentosa
NCT00447993	PHASE2	COMPLETED	A Study of Encapsulated Cell Technology (ECT) Implant for Patients With Late Stage Retinitis Pigmentosa
NCT01233609	PHASE2	COMPLETED	Trial of Oral Valproic Acid for Retinitis Pigmentosa
NCT01399515	PHASE2	COMPLETED	Efficacy and Safety of Oral Valproic Acid for Retinitis Pigmentosa
NCT01530659	PHASE2	COMPLETED	Retinal Imaging in CNTF -Releasing Encapsulated Cell Implant Treated Patients for Early-stage Retinitis Pigmentosa
NCT01560715	PHASE2	COMPLETED	Autologous Bone Marrow-Derived Stem Cells Transplantation For Retinitis Pigmentosa
NCT02609165	PHASE2	COMPLETED	Nerve Growth Factor Eye Drops Treatment in Patients With Retinitis Pigmentosa and Cystoid Macular Edema
NCT02661711	PHASE2	COMPLETED	Aflibercept for Macular Oedema With Underlying Retinitis Pigmentosa (AMOUR) Study
NCT02804360	PHASE2	UNKNOWN	Intravitreal Dexamethasone Implant in Retinitis Pigmentosa-related Macular Edema- a Retrospective Study
NCT02837640	PHASE2	UNKNOWN	Studying a Potential Protective Effect of L-Dopa on Retinitis Pigmentosa
NCT03073733	PHASE2	COMPLETED	Safety and Efficacy of Intravitreal Injection of Human Retinal Progenitor Cells in Adults With Retinitis Pigmentosa
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04356716	PHASE2	COMPLETED	Sildenafil for Treatment of Choroidal Ischemia
NCT04604899	PHASE2	COMPLETED	Safety of Repeat Intravitreal Injection of Human Retinal Progenitor Cells (jCell) in Adult Subjects With Retinitis Pigmentosa
NCT04763369	PHASE2	UNKNOWN	Investigation of Therapeutic Efficacy and Safety of UMSCs for the Management of Retinitis Pigmentosa (RP)
NCT04864496	PHASE2	UNKNOWN	Effects of Treatment With N- Acetylcysteine on Visual Outcomes in Patients With Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT05085964	PHASE2	TERMINATED	An Open-Label Extension Study to Evaluate Safety & Tolerability of QR-421a in Subjects With Retinitis Pigmentosa
NCT05392179	PHASE2	COMPLETED	A Study in Subjects With Retinitis Pigmentosa
NCT06627179	PHASE2	RECRUITING	Study to Evaluate Ultevursen in Subjects With Retinitis Pigmentosa (RP) Due to Mutations in Exon 13 of the USH2A Gene
NCT06628947	PHASE2	RECRUITING	A Phase II Study of Intravitreal KIO-301 in Patients With Late-stage Retinitis Pigmentosa
NCT06912633	PHASE2	RECRUITING	Safety of a Single, Intravitreal Injection of 6.0M jCell (Famzeretcel) in Retinitis Pigmentosa (RP)
NCT00063765	PHASE1	COMPLETED	Evaluation of Safety of Ciliary Neurotrophic Factor Implants in the Eye
NCT00065455	PHASE1	COMPLETED	Investigating the Effect of Vitamin A Supplementation on Retinitis Pigmentosa
NCT00458575	PHASE1	TERMINATED	A Study to Evaluate the Safety of CNTO 2476 in Patients With Advanced Retinitis Pigmentosa
NCT01014052	PHASE1	COMPLETED	Safety/Proof of Concept Study of Oral QLT091001 in Subjects With Leber Congenital Amaurosis (LCA) or Retinitis Pigmentosa (RP) Due to Retinal Pigment Epithelial 65 Protein (RPE65) or Lecithin:Retinol Acyltransferase (LRAT) Mutations