REEP4

Summary

REEP4 (receptor accessory protein 4, HGNC:26176) is a protein-coding gene on chromosome 8p21.3, encoding Receptor expression-enhancing protein 4 (Q9H6H4). Microtubule-binding protein required to ensure proper cell division and nuclear envelope reassembly by sequestering the endoplasmic reticulum away from chromosomes during mitosis.

Predicted to enable microtubule binding activity. Involved in mitotic nuclear membrane reassembly. Located in endoplasmic reticulum.

Source: NCBI Gene 80346 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 70 total
• MANE Select transcript: NM_025232

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26176
Approved symbol	REEP4
Name	receptor accessory protein 4
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22246, FLJ22277, PP432, Yip2c
Ensembl gene	ENSG00000168476
Ensembl biotype	protein_coding
OMIM	609349
Entrez	80346

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 7 protein_coding, 3 retained_intron

ENST00000306306, ENST00000334530, ENST00000518664, ENST00000519074, ENST00000519875, ENST00000521744, ENST00000523293, ENST00000898472, ENST00000898473, ENST00000933331

RefSeq mRNA: 3 — MANE Select: NM_025232 NM_001316964, NM_001316965, NM_025232

CCDS: CCDS6024, CCDS83257, CCDS83258

Canonical transcript exons

ENST00000306306 — 8 exons

Exon	Start	End
ENSE00001159039	22138926	22139061
ENSE00003516497	22140625	22140697
ENSE00003565311	22140172	22140248
ENSE00003604090	22139963	22140083
ENSE00003626266	22138639	22138793
ENSE00003669906	22138020	22138552
ENSE00003733746	22139416	22139529
ENSE00003850602	22141451	22141907

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 97.65.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.4362 / max 273.1242, expressed in 1822 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
92202	40.4407	1821
92203	4.9955	1658

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	97.65	gold quality
skin of abdomen	UBERON:0001416	97.39	gold quality
skin of leg	UBERON:0001511	96.84	gold quality
esophagus mucosa	UBERON:0002469	96.17	gold quality
mucosa of transverse colon	UBERON:0004991	96.02	gold quality
zone of skin	UBERON:0000014	94.70	gold quality
granulocyte	CL:0000094	94.06	gold quality
left testis	UBERON:0004533	93.30	gold quality
monocyte	CL:0000576	92.89	gold quality
mononuclear cell	CL:0000842	92.81	gold quality
leukocyte	CL:0000738	92.76	gold quality
right testis	UBERON:0004534	92.76	gold quality
vagina	UBERON:0000996	91.88	gold quality
spleen	UBERON:0002106	91.36	gold quality
tibial nerve	UBERON:0001323	91.27	gold quality
testis	UBERON:0000473	90.80	gold quality
transverse colon	UBERON:0001157	90.30	gold quality
upper arm skin	UBERON:0004263	90.30	silver quality
right lung	UBERON:0002167	89.55	gold quality
esophagus	UBERON:0001043	89.43	gold quality
sperm	CL:0000019	89.14	silver quality
ileal mucosa	UBERON:0000331	89.04	silver quality
ectocervix	UBERON:0012249	88.94	gold quality
body of stomach	UBERON:0001161	88.44	gold quality
male germ cell	CL:0000015	88.17	silver quality
ventricular zone	UBERON:0003053	88.12	gold quality
cervix squamous epithelium	UBERON:0006922	88.04	silver quality
blood	UBERON:0000178	87.77	gold quality
small intestine Peyer’s patch	UBERON:0003454	87.63	gold quality
penis	UBERON:0000989	87.49	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.90

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

33 targeting REEP4, 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-8485	100.00	77.57	4731
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-6132	99.60	65.83	1554
HSA-MIR-6836-5P	99.60	65.62	1538
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-150-3P	99.43	70.51	920
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-1909-3P	99.03	66.56	1662
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-4755-3P	98.77	65.59	1915
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-4433A-3P	97.75	62.82	1435

Literature-anchored findings (GeneRIF, showing 3)

• Our results show that REEP3/4 function redundantly to clear the endoplasmic reticulum from metaphase chromatin, thereby ensuring correct progression through mitosis and proper nuclear envelope architecture. (PMID:23911198)
• the endoplasmic reticulum (ER) membrane proteins REEP3 and REEP4 as major determinants of ER morphology in metaphase cells. (PMID:30995177)
• Reticulon-like REEP4 at the inner nuclear membrane promotes nuclear pore complex formation. (PMID:34874453)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Reep4	ENSMUSG00000033589
rattus_norvegicus	Reep4	ENSRNOG00000011373
drosophila_melanogaster	Reepl1	FBGN0030313
drosophila_melanogaster	CG5539	FBGN0034907
caenorhabditis_elegans		WBGENE00011401
caenorhabditis_elegans		WBGENE00012180
caenorhabditis_elegans		WBGENE00018930
caenorhabditis_elegans		WBGENE00020562
caenorhabditis_elegans	yop-1	WBGENE00022127

Paralogs (5): REEP1 (ENSG00000068615), REEP6 (ENSG00000115255), REEP5 (ENSG00000129625), REEP2 (ENSG00000132563), REEP3 (ENSG00000165476)

Protein

Protein identifiers

Receptor expression-enhancing protein 4 — Q9H6H4 (reviewed: Q9H6H4)

All UniProt accessions (3): Q9H6H4, E5RGS2, E5RIB5

UniProt curated annotations — full annotation on UniProt →

Function. Microtubule-binding protein required to ensure proper cell division and nuclear envelope reassembly by sequestering the endoplasmic reticulum away from chromosomes during mitosis. Probably acts by clearing the endoplasmic reticulum membrane from metaphase chromosomes.

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in circumvallate papillae and testis.

Similarity. Belongs to the DP1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H6H4-1	1	yes
Q9H6H4-2	2

RefSeq proteins (3): NP_001303893, NP_001303894, NP_079508* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004345	TB2_DP1_HVA22	Family

Pfam: PF03134

UniProt features (14 total): modified residue 6, transmembrane region 2, splice variant 2, sequence conflict 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6H4-F1	64.64	0.06

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 (6): 152, 194, 196, 202, 250, 253

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 168 (showing top): GOBP_NUCLEAR_MEMBRANE_REASSEMBLY, GOBP_MEMBRANE_BIOGENESIS, NKX25_02, GGGTGGRR_PAX4_03, GOBP_ORGANELLE_FISSION, chr8p21, GOBP_NUCLEUS_ORGANIZATION, HFH8_01, GOBP_MITOTIC_NUCLEAR_DIVISION, HFH4_01, HFH3_01, TGANTCA_AP1_C, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_MITOTIC_CELL_CYCLE, CYTAGCAAY_UNKNOWN

GO Biological Process (4): nuclear envelope organization (GO:0006998), mitotic nuclear membrane reassembly (GO:0007084), cell division (GO:0051301), endoplasmic reticulum tubular network organization (GO:0071786)

GO Molecular Function (2): microtubule binding (GO:0008017), protein binding (GO:0005515)

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cytoplasmic microtubule (GO:0005881), endoplasmic reticulum tubular network (GO:0071782), microtubule (GO:0005874), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
endoplasmic reticulum subcompartment	2
nucleus organization	1
endomembrane system organization	1
membrane organization	1
mitotic cell cycle	1
nuclear membrane reassembly	1
mitotic nuclear membrane organization	1
cellular process	1
endoplasmic reticulum organization	1
tubulin binding	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
microtubule	1
microtubule cytoskeleton	1
polymeric cytoskeletal fiber	1
cellular anatomical structure	1

Protein interactions and networks

STRING

692 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REEP4	ATL1	Q8WXF7	605
REEP4	TOR2A	Q5JU69	579
REEP4	ATL3	Q6DD88	554
REEP4	CCDC150	Q8NCX0	528
REEP4	ATL2	Q8NHH9	518
REEP4	HS1BP3	Q53T59	501
REEP4	NEMP1	O14524	487
REEP4	CCDC77	Q9BR77	482
REEP4	CEP85	Q6P2H3	480
REEP4	CCDC34	Q96HJ3	458
REEP4	GSTCD	Q8NEC7	454
REEP4	RIBC2	Q9H4K1	439
REEP4	DEPDC1B	Q8WUY9	436
REEP4	SPAST	Q9UBP0	409
REEP4	LNPK	Q9C0E8	399

IntAct

421 interactions, top by confidence:

A	B	Type	Score
EZH2	EPOP	psi-mi:“MI:0914”(association)	0.730
YWHAH	FAM83G	psi-mi:“MI:0914”(association)	0.710
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
ATP6V0C	REEP4	psi-mi:“MI:0915”(physical association)	0.560
CACNG1	REEP4	psi-mi:“MI:0915”(physical association)	0.560
VAMP5	REEP4	psi-mi:“MI:0915”(physical association)	0.560
TMPPE	REEP4	psi-mi:“MI:0915”(physical association)	0.560
TMEM120A	REEP4	psi-mi:“MI:0915”(physical association)	0.560
SFXN1	REEP4	psi-mi:“MI:0915”(physical association)	0.560
MS4A1	REEP4	psi-mi:“MI:0915”(physical association)	0.560
DCBLD2	REEP4	psi-mi:“MI:0915”(physical association)	0.560
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
POMK	TMEM120B	psi-mi:“MI:0914”(association)	0.530
B4GALT3	SLC19A2	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
KCNA10	GAPDHS	psi-mi:“MI:0914”(association)	0.530
REEP1	PLSCR1	psi-mi:“MI:0914”(association)	0.530
SLC44A5	NME2P1	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
REEP4	TAX1BP1	psi-mi:“MI:0915”(physical association)	0.400
PHAX	RPL10	psi-mi:“MI:0914”(association)	0.350
GOLT1B		psi-mi:“MI:0914”(association)	0.350

BioGRID (260): TAX1BP1 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Proximity Label-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), REEP4 (Affinity Capture-MS), TAX1BP1 (Affinity Capture-MS), REEP4 (Affinity Capture-MS)

ESM2 similar proteins: A0JNJ3, A4IG66, A4IJ20, A8NJ91, A8WTH5, B1WC88, B4R3W7, C1BY38, C3KHG1, O01323, O76024, P0C8Y2, P0DKX4, P56695, Q02225, Q15053, Q16EE5, Q28HF6, Q28I13, Q2KI30, Q2TBG9, Q3ZC78, Q3ZCI8, Q4KMI4, Q4QQW1, Q56JY4, Q5BL63, Q5R598, Q5R7A0, Q5R891, Q6AZM3, Q6DFJ8, Q6NUK4, Q6PFM4, Q7TQ95, Q8BG50, Q8K072, Q8K2J7, Q8N0X7, Q8R1X6

Diamond homologs: A0A509ADH4, B2RZ37, P0CN16, P0CN17, Q00765, Q07764, Q10010, Q12402, Q29RM3, Q2KI30, Q32LG5, Q3ZCI8, Q4KMI4, Q4P0H0, Q4QQW1, Q4WTW3, Q51VY4, Q5BB01, Q5BL63, Q5HZP8, Q5R598, Q5RE33, Q5XI60, Q60870, Q66IF1, Q682H0, Q6AZM3, Q6BWH8, Q6CE07, Q6CP93, Q6FMU3, Q6NLY8, Q6NUK4, Q6PBX9, Q75A56, Q7ZVX5, Q871R7, Q8BGH4, Q8K072, Q8LE10

SIGNOR signaling

0 interactions.

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
Activation of BAD and translocation to mitochondria	5	53.6×	4e-06
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	47.3×	4e-06
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	5	47.3×	4e-06
Activation of BH3-only proteins	5	35.0×	1e-05
Intrinsic Pathway for Apoptosis	6	24.8×	9e-06
RHO GTPases activate PKNs	5	22.3×	1e-04
SARS-CoV-1-host interactions	6	14.8×	1e-04
Apoptosis	6	14.2×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	15.4×	4e-03
endoplasmic reticulum to Golgi vesicle-mediated transport	7	8.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	54
Likely benign	7
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1116 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22138634:CTGA:C	donor_loss	1.0000
8:22138636:GACC:G	donor_loss	1.0000
8:22138640:T:TA	donor_gain	1.0000
8:22138641:C:A	donor_gain	1.0000
8:22138656:T:TA	donor_gain	1.0000
8:22138790:TACC:T	acceptor_gain	1.0000
8:22138791:ACC:A	acceptor_gain	1.0000
8:22138792:CC:C	acceptor_gain	1.0000
8:22138792:CCC:C	acceptor_gain	1.0000
8:22138793:CC:C	acceptor_gain	1.0000
8:22138794:C:CC	acceptor_gain	1.0000
8:22138796:G:GC	acceptor_gain	1.0000
8:22139060:CT:C	acceptor_gain	1.0000
8:22139411:AGCAC:A	donor_loss	1.0000
8:22139412:GCAC:G	donor_loss	1.0000
8:22139413:CACCT:C	donor_loss	1.0000
8:22139415:CC:C	donor_loss	1.0000
8:22139466:T:TA	donor_gain	1.0000
8:22139467:C:A	donor_gain	1.0000
8:22139525:ATCTC:A	acceptor_gain	1.0000
8:22139527:CTC:C	acceptor_gain	1.0000
8:22139528:TC:T	acceptor_gain	1.0000
8:22139529:CC:C	acceptor_gain	1.0000
8:22139530:C:CC	acceptor_gain	1.0000
8:22139537:CCCAA:C	acceptor_gain	1.0000
8:22139538:CCAA:C	acceptor_gain	1.0000
8:22139539:C:CT	acceptor_gain	1.0000
8:22139539:C:T	acceptor_gain	1.0000
8:22139540:A:T	acceptor_gain	1.0000
8:22139958:GGTA:G	donor_loss	1.0000

AlphaMissense

1660 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22139447:G:T	A129D	0.996
8:22139991:A:T	V92D	0.996
8:22139435:G:T	A133D	0.993
8:22140043:A:G	W75R	0.993
8:22140043:A:T	W75R	0.993
8:22140059:C:A	K69N	0.992
8:22140059:C:G	K69N	0.992
8:22140655:C:A	K25N	0.990
8:22140655:C:G	K25N	0.990
8:22140039:A:G	L76P	0.989
8:22140662:G:A	S23F	0.989
8:22140230:A:G	W42R	0.988
8:22140230:A:T	W42R	0.988
8:22139423:G:T	A137D	0.986
8:22139444:G:T	A130D	0.984
8:22140654:C:G	A26P	0.984
8:22140019:C:G	G83R	0.983
8:22140217:G:T	A46E	0.983
8:22140660:A:C	Y24D	0.982
8:22140671:G:T	A20D	0.982
8:22140242:A:G	W38R	0.981
8:22140242:A:T	W38R	0.981
8:22140669:A:C	Y21D	0.981
8:22139427:C:G	A136P	0.980
8:22140662:G:T	S23Y	0.980
8:22140663:A:G	S23P	0.980
8:22139436:C:G	A133P	0.979
8:22140219:A:C	F45L	0.979
8:22140219:A:T	F45L	0.979
8:22140221:A:G	F45L	0.979

dbSNP variants (sampled 300 via entrez): RS1000350833 (8:22141428 G>A,C), RS1000533013 (8:22142318 G>A,C,T), RS1001417544 (8:22143205 A>C), RS1001526237 (8:22141812 C>G), RS1001998171 (8:22141582 G>T), RS1002595928 (8:22142546 C>T), RS1002749486 (8:22137539 G>A), RS1002910010 (8:22139106 T>C), RS1003130871 (8:22138998 C>A), RS1003932462 (8:22142015 G>A), RS1004695479 (8:22143788 T>G), RS1004706446 (8:22138253 C>G), RS1004898474 (8:22139099 A>G), RS1005605667 (8:22143488 G>A), RS1006283864 (8:22140486 G>A,C,T)

Disease associations

OMIM: gene MIM:609349 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001905_1	Hypertriglyceridemia	7.000000e-06
GCST90020053_9	Frailty index	4.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement
EFO:0009885	frailty measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
Tretinoin	decreases expression	2
Aflatoxin B1	affects expression, decreases methylation	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
sulforaphane	increases expression	1
perfluorooctanoic acid	decreases expression	1
benzo(e)pyrene	affects methylation	1
perfluorooctane sulfonic acid	increases expression	1
abrine	decreases expression	1
jinfukang	affects cotreatment, increases expression	1
MT19c compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acetaminophen	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	increases expression, increases abundance	1
Caffeine	decreases phosphorylation	1
Cisplatin	affects cotreatment, increases expression	1
Coumestrol	affects cotreatment, increases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Hydrogen Peroxide	affects expression	1
Methapyrilene	affects methylation	1
Smoke	decreases expression	1
Testosterone	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_F1QP	HyCyte Hs 683 KO-hREEP4	Cancer cell line	Male

Clinical trials (associated diseases)

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