EMC4

Summary

EMC4 (ER membrane protein complex subunit 4, HGNC:28032) is a protein-coding gene on chromosome 15q14, encoding ER membrane protein complex subunit 4 (Q5J8M3). Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. It is a selective cancer dependency (DepMap: 47.5% of cell lines).

Contributes to membrane insertase activity. Involved in protein insertion into ER membrane by stop-transfer membrane-anchor sequence and tail-anchored membrane protein insertion into ER membrane. Located in endoplasmic reticulum membrane. Part of EMC complex.

Source: NCBI Gene 51234 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 25 total
• Cancer dependency (DepMap): dependent in 47.5% of screened cell lines
• MANE Select transcript: NM_016454

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28032
Approved symbol	EMC4
Name	ER membrane protein complex subunit 4
Location	15q14
Locus type	gene with protein product
Status	Approved
Aliases	FLJ90746, MGC24415, PIG17
Ensembl gene	ENSG00000128463
Ensembl biotype	protein_coding
OMIM	616245
Entrez	51234

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 12 protein_coding, 3 retained_intron, 3 nonsense_mediated_decay

ENST00000249209, ENST00000267750, ENST00000557879, ENST00000557941, ENST00000558102, ENST00000558205, ENST00000558810, ENST00000559078, ENST00000559421, ENST00000560911, ENST00000560947, ENST00000561246, ENST00000561372, ENST00000854599, ENST00000854600, ENST00000854601, ENST00000918920, ENST00000918922

RefSeq mRNA: 3 — MANE Select: NM_016454 NM_001286420, NM_001351373, NM_016454

CCDS: CCDS10035, CCDS66732

Canonical transcript exons

ENST00000267750 — 5 exons

Exon	Start	End
ENSE00001825858	34225016	34225200
ENSE00003496505	34225536	34225650
ENSE00003689263	34229753	34230156
ENSE00003691355	34228429	34228589
ENSE00003786109	34227693	34227846

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 99.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 100.0569 / max 443.1959, expressed in 1827 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
145789	78.4022	1826
145790	21.6547	1801

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	99.09	gold quality
calcaneal tendon	UBERON:0003701	99.02	gold quality
upper arm skin	UBERON:0004263	98.97	gold quality
tibialis anterior	UBERON:0001385	98.90	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.80	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.38	gold quality
ileal mucosa	UBERON:0000331	98.24	gold quality
kidney epithelium	UBERON:0004819	98.23	gold quality
quadriceps femoris	UBERON:0001377	98.07	gold quality
pons	UBERON:0000988	98.00	gold quality
deltoid	UBERON:0001476	97.98	gold quality
vastus lateralis	UBERON:0001379	97.91	gold quality
corpus epididymis	UBERON:0004359	97.91	gold quality
muscle of leg	UBERON:0001383	97.82	gold quality
myocardium	UBERON:0002349	97.82	gold quality
skeletal muscle organ	UBERON:0014892	97.81	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.76	gold quality
gastrocnemius	UBERON:0001388	97.71	gold quality
anterior cingulate cortex	UBERON:0009835	97.71	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.70	gold quality
hypothalamus	UBERON:0001898	97.65	gold quality
cerebellar vermis	UBERON:0004720	97.60	gold quality
right frontal lobe	UBERON:0002810	97.57	gold quality
muscle tissue	UBERON:0002385	97.55	gold quality
biceps brachii	UBERON:0001507	97.54	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.51	gold quality
skeletal muscle tissue	UBERON:0001134	97.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.44	gold quality
prefrontal cortex	UBERON:0000451	97.43	gold quality
caudate nucleus	UBERON:0001873	97.42	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6379	no	890.10
E-CURD-10	no	497.49
E-CURD-89	no	465.44
E-MTAB-6524	no	286.60
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting EMC4, 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-4531	99.99	69.70	3181
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-8062	99.88	68.43	995
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-659-3P	99.85	70.69	1620
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-586	99.65	70.40	2051
HSA-MIR-7156-5P	99.64	68.81	1369
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-142-5P	99.48	70.92	2416
HSA-MIR-5590-3P	99.48	70.91	2429

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 47.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 2)

• TMEM85 is a complex gene that encodes a novel conserved anti-apoptotic protein. (PMID:18586032)
• ER membrane protein complex subunit 4 (EMC4) and EMC7 support SV40 infection by promoting from the late endosome (LE) to the endoplasmic reticulum (ER) targeting of the virus. They do this by engaging LE-associated Rab7, to stabilize contact between the LE and ER. These EMC subunits also bind to the ER-resident fusion machinery component syntaxin18, which is required for SV40-arrival to the ER. (PMID:32111841)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	emc4	ENSDARG00000039268
		ENSDARG00000102733
mus_musculus	Emc4	ENSMUSG00000027131
rattus_norvegicus	Emc4	ENSRNOG00000005719
drosophila_melanogaster	EMC4	FBGN0037199
caenorhabditis_elegans		WBGENE00022776

Protein

Protein identifiers

ER membrane protein complex subunit 4 — Q5J8M3 (reviewed: Q5J8M3)

Alternative names: Cell proliferation-inducing gene 17 protein, Transmembrane protein 85

All UniProt accessions (11): Q5J8M3, A0A024R9N3, A0A0S2Z598, H0YK61, H0YKL2, H0YLP8, H0YMH5, H0YN63, H0YNK0, H0YNK8, S4R329

UniProt curated annotations — full annotation on UniProt →

Function. Part of the endoplasmic reticulum membrane protein complex (EMC) that enables the energy-independent insertion into endoplasmic reticulum membranes of newly synthesized membrane proteins. Preferentially accommodates proteins with transmembrane domains that are weakly hydrophobic or contain destabilizing features such as charged and aromatic residues. Involved in the cotranslational insertion of multi-pass membrane proteins in which stop-transfer membrane-anchor sequences become ER membrane spanning helices. It is also required for the post-translational insertion of tail-anchored/TA proteins in endoplasmic reticulum membranes. By mediating the proper cotranslational insertion of N-terminal transmembrane domains in an N-exo topology, with translocated N-terminus in the lumen of the ER, controls the topology of multi-pass membrane proteins like the G protein-coupled receptors. By regulating the insertion of various proteins in membranes, it is indirectly involved in many cellular processes.

Subunit / interactions. Component of the ER membrane protein complex (EMC).

Subcellular location. Endoplasmic reticulum membrane.

Tissue specificity. Isoform 1 is expressed in brain and heart. Isoform 2 is expressed in heart.

Similarity. Belongs to the EMC4 family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5J8M3-1	1, TMEM85v1	yes
Q5J8M3-2	2, TMEM85v2
Q5J8M3-3	3

RefSeq proteins (3): NP_001273349, NP_001338302, NP_057538* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009445	TMEM85/Emc4	Family

Pfam: PF06417

UniProt features (28 total): helix 6, splice variant 4, topological domain 4, transmembrane region 3, modified residue 2, sequence conflict 2, strand 2, initiator methionine 1, chain 1, sequence variant 1, turn 1, region of interest 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
8J0O	ELECTRON MICROSCOPY	3.32
7ADO	ELECTRON MICROSCOPY	3.39
8EOI	ELECTRON MICROSCOPY	3.4
8J0N	ELECTRON MICROSCOPY	3.47
7ADP	ELECTRON MICROSCOPY	3.6
8S9S	ELECTRON MICROSCOPY	3.6
9ZZ6	ELECTRON MICROSCOPY	4.16
6Z3W	ELECTRON MICROSCOPY	6.4
9C7V	ELECTRON MICROSCOPY	6.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5J8M3-F1	67.65	0.00

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 (2): 2, 36

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9918485	Dengue Virus Attachment and Entry

MSigDB gene sets: 143 (showing top): GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, chr15q14, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, ACTTTAT_MIR1425P, GOBP_MEMBRANE_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, GOBP_LOCALIZATION_WITHIN_MEMBRANE, GOBP_PROTEIN_INSERTION_INTO_MEMBRANE, MOREAUX_MULTIPLE_MYELOMA_BY_TACI_DN

GO Biological Process (3): apoptotic process (GO:0006915), protein insertion into ER membrane by stop-transfer membrane-anchor sequence (GO:0045050), tail-anchored membrane protein insertion into ER membrane (GO:0071816)

GO Molecular Function (2): protein binding (GO:0005515), membrane insertase activity (GO:0032977)

GO Cellular Component (4): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), EMC complex (GO:0072546), endoplasmic reticulum (GO:0005783)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Dengue Virus Infection	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein insertion into ER membrane	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
binding	1
establishment of protein localization to membrane	1
protein carrier activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1
endoplasmic reticulum membrane	1
membrane protein complex	1
endoplasmic reticulum protein-containing complex	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1640 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EMC4	EMC1	Q8N766	946
EMC4	EMC6	Q9BV81	934
EMC4	EMC2	Q15006	920
EMC4	MMGT1	Q8N4V1	907
EMC4	EMC3	Q9P0I2	891
EMC4	EMC7	Q9NPA0	869
EMC4	EMC8	O43402	823
EMC4	EMC9	Q9Y3B6	792
EMC4	EMC10	Q5UCC4	731
EMC4	DDOST	P39656	548
EMC4	MRPL42	Q9Y6G3	486
EMC4	ERLIN1	O75477	447
EMC4	SEC61A1	P38378	446
EMC4	SPCS1	Q9Y6A9	445
EMC4	GARIN2	Q8N9W8	433

IntAct

105 interactions, top by confidence:

A	B	Type	Score
EMC2	EMC8	psi-mi:“MI:0914”(association)	0.940
EMC7	EMC8	psi-mi:“MI:0914”(association)	0.790
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
MMGT1	EMC8	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
EMC4	rep	psi-mi:“MI:0915”(physical association)	0.660
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
MUCL1	PDIA5	psi-mi:“MI:0914”(association)	0.640
EMC1	EMC8	psi-mi:“MI:0914”(association)	0.640
EMC4	EMC8	psi-mi:“MI:0914”(association)	0.640
EMC9	EMC4	psi-mi:“MI:0914”(association)	0.640
KLHL22	TMEM223	psi-mi:“MI:0914”(association)	0.640
SLC12A2	CLGN	psi-mi:“MI:0914”(association)	0.640
EMC10	EMC8	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (375): EMC4 (Affinity Capture-RNA), EMC4 (Affinity Capture-RNA), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Proximity Label-MS), EMC4 (Proximity Label-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS), EMC4 (Affinity Capture-MS)

ESM2 similar proteins: A4RME3, A5DRE8, A6L5L6, A6L9D2, A7A082, B2ALT5, B2RKS0, B3LQQ2, B5VLV9, B5XB24, D3GS80, O42816, O42940, O74432, O94520, P20424, P34669, P35180, P36039, P38379, P53073, P60036, P79088, Q0WT48, Q11S04, Q12116, Q3T0K8, Q47153, Q54TU8, Q54YN3, Q5J8M3, Q5LC41, Q5NNP2, Q5RC35, Q64T26, Q6BN08, Q6CPY9, Q6GR43, Q6P011, Q6PBF7

Diamond homologs: B5XB24, O94520, P53073, Q3T0K8, Q5J8M3, Q5RC35, Q6GR43, Q6P011, Q6PBF7, Q9CZX9

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EMC4	“form complex”	“Endoplasmic reticulum membrane complex- EMC9 variant”	binding
EMC4	“form complex”	“Endoplasmic reticulum membrane complex, EMC8 variant”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 106 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.

GO biological processes:

GO term	Partners	Fold	FDR
tail-anchored membrane protein insertion into ER membrane	9	92.6×	4e-14
ERAD pathway	7	13.9×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	13
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

711 predictions. Top by Δscore:

Variant	Effect	Δscore
15:34227691:A:AG	acceptor_gain	1.0000
15:34227692:G:GT	acceptor_gain	1.0000
15:34227692:GC:G	acceptor_gain	1.0000
15:34227692:GCGCT:G	acceptor_gain	1.0000
15:34227842:AGCCA:A	donor_gain	1.0000
15:34227843:GCCA:G	donor_gain	1.0000
15:34227843:GCCAG:G	donor_gain	1.0000
15:34227845:CA:C	donor_gain	1.0000
15:34227847:G:GG	donor_gain	1.0000
15:34229752:GA:G	acceptor_gain	1.0000
15:34229752:GAGA:G	acceptor_gain	1.0000
15:34225175:C:G	donor_gain	0.9900
15:34225530:TTTTA:T	acceptor_loss	0.9900
15:34225531:TTTA:T	acceptor_loss	0.9900
15:34225532:TTAG:T	acceptor_loss	0.9900
15:34225533:TA:T	acceptor_loss	0.9900
15:34225534:AG:A	acceptor_gain	0.9900
15:34225534:AGG:A	acceptor_gain	0.9900
15:34225535:GG:G	acceptor_gain	0.9900
15:34225535:GGG:G	acceptor_gain	0.9900
15:34225643:TGGAG:T	donor_gain	0.9900
15:34225646:AGAAG:A	donor_loss	0.9900
15:34225647:GAAGG:G	donor_loss	0.9900
15:34225648:AAG:A	donor_loss	0.9900
15:34225649:AGG:A	donor_loss	0.9900
15:34225650:GGT:G	donor_loss	0.9900
15:34225651:GT:G	donor_loss	0.9900
15:34225652:T:A	donor_loss	0.9900
15:34227686:GTTTT:G	acceptor_loss	0.9900
15:34227688:TTTA:T	acceptor_loss	0.9900

AlphaMissense

1194 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:34227709:C:A	A73D	1.000
15:34227748:T:A	I86N	0.999
15:34227781:T:G	F97C	0.999
15:34227798:T:C	C103R	0.999
15:34228489:G:A	G139E	0.999
15:34228523:G:C	K150N	0.999
15:34228523:G:T	K150N	0.999
15:34228524:T:C	C151R	0.999
15:34228540:T:C	L156P	0.999
15:34228543:T:C	L157S	0.999
15:34228561:A:T	D163V	0.999
15:34227699:T:A	W70R	0.998
15:34227699:T:C	W70R	0.998
15:34227701:G:C	W70C	0.998
15:34227701:G:T	W70C	0.998
15:34227725:A:C	K78N	0.998
15:34227725:A:T	K78N	0.998
15:34227740:T:A	N83K	0.998
15:34227740:T:G	N83K	0.998
15:34227742:T:C	L84P	0.998
15:34227763:G:T	G91V	0.998
15:34227778:T:A	I96N	0.998
15:34227778:T:C	I96T	0.998
15:34227780:T:C	F97L	0.998
15:34227782:C:A	F97L	0.998
15:34227782:C:G	F97L	0.998
15:34228488:G:A	G139R	0.998
15:34228488:G:C	G139R	0.998
15:34228513:C:A	A147D	0.998
15:34228521:A:G	K150E	0.998

dbSNP variants (sampled 300 via entrez): RS1000122605 (15:34228245 G>C), RS1000751613 (15:34225398 T>A,C), RS1001325164 (15:34227205 A>C), RS1001997978 (15:34224571 G>C), RS1002026914 (15:34224330 T>C), RS1002048647 (15:34224050 C>CAAAAG), RS1002491220 (15:34228695 T>C), RS1002513144 (15:34227327 T>C), RS1003461100 (15:34227616 G>A,T), RS1003518246 (15:34228692 T>A,C), RS1004251131 (15:34225126 G>A,C), RS1004390590 (15:34226093 T>C), RS1004851215 (15:34223984 C>A), RS1005369641 (15:34223585 C>A), RS1005677270 (15:34228333 C>T)

Disease associations

OMIM: gene MIM:616245 | disease phenotypes: MIM:218000

GenCC curated gene-disease

Mondo (1): agenesis of the corpus callosum with peripheral neuropathy (MONDO:0000902)

Orphanet (1): Corpus callosum agenesis-neuronopathy syndrome (Orphanet:1496)

HPO phenotypes

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

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536446	Corpus callosum agenesis neuronopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

21 total (human), top 21 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
bleomycetin	decreases expression	1
ICG 001	increases expression	1
bisphenol S	increases expression	1
Resveratrol	increases expression, affects cotreatment	1
Air Pollutants	increases abundance, decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	decreases phosphorylation	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	increases expression	1
Valproic Acid	increases expression	1
Aflatoxin B1	increases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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