EMC6

Summary

EMC6 (ER membrane protein complex subunit 6, HGNC:28430) is a protein-coding gene on chromosome 17p13.2, encoding ER membrane protein complex subunit 6 (Q9BV81). 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: 16.7% of cell lines).

Contributes to membrane insertase activity. Involved in autophagosome assembly; 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 and omegasome membrane. Part of EMC complex.

Source: NCBI Gene 83460 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 14 total
• Cancer dependency (DepMap): dependent in 16.7% of screened cell lines
• MANE Select transcript: NM_031298

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28430
Approved symbol	EMC6
Name	ER membrane protein complex subunit 6
Location	17p13.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC2963, RAB5IFL
Ensembl gene	ENSG00000127774
Ensembl biotype	protein_coding
OMIM	620261
Entrez	83460

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 4 protein_coding

ENST00000248378, ENST00000397133, ENST00000890763, ENST00000890764

RefSeq mRNA: 2 — MANE Select: NM_031298 NM_001014764, NM_031298

CCDS: CCDS11033

Canonical transcript exons

ENST00000248378 — 2 exons

Exon	Start	End
ENSE00001308926	3668812	3668899
ENSE00002752197	3669098	3669665

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 97.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 78.9518 / max 375.5162, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
158879	78.9518	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	97.22	gold quality
gastrocnemius	UBERON:0001388	97.21	gold quality
muscle of leg	UBERON:0001383	96.61	gold quality
muscle organ	UBERON:0001630	96.22	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.84	gold quality
apex of heart	UBERON:0002098	95.60	gold quality
vastus lateralis	UBERON:0001379	95.43	silver quality
quadriceps femoris	UBERON:0001377	95.39	gold quality
heart left ventricle	UBERON:0002084	95.29	gold quality
cardiac ventricle	UBERON:0002082	95.20	gold quality
diaphragm	UBERON:0001103	95.17	silver quality
biceps brachii	UBERON:0001507	95.01	gold quality
skeletal muscle tissue	UBERON:0001134	94.79	gold quality
right testis	UBERON:0004534	94.73	gold quality
right atrium auricular region	UBERON:0006631	94.64	gold quality
deltoid	UBERON:0001476	94.57	silver quality
triceps brachii	UBERON:0001509	94.56	gold quality
gluteal muscle	UBERON:0002000	94.53	gold quality
left testis	UBERON:0004533	94.52	gold quality
heart right ventricle	UBERON:0002080	94.42	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	94.37	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.33	gold quality
mucosa of transverse colon	UBERON:0004991	94.24	gold quality
adult organism	UBERON:0007023	93.99	gold quality
right adrenal gland cortex	UBERON:0035827	93.92	gold quality
right adrenal gland	UBERON:0001233	93.90	gold quality
cardiac atrium	UBERON:0002081	93.81	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	93.78	gold quality
left adrenal gland	UBERON:0001234	93.61	gold quality
left adrenal gland cortex	UBERON:0035825	93.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.07

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

20 targeting EMC6, 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-3185	99.99	68.12	1959
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-579-3P	99.86	71.66	3628
HSA-MIR-664B-3P	99.84	71.65	3590
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-10522-5P	99.26	68.50	2087
HSA-MIR-5100	99.11	67.52	1098
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-4511	98.32	67.97	1500
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-4438	97.96	63.70	947
HSA-MIR-503-5P	97.87	66.83	575
HSA-MIR-1255B-2-3P	97.80	67.04	880
HSA-MIR-4521	97.73	67.64	684
HSA-MIR-4694-5P	94.62	65.39	532

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 6)

• Endoplasmic membrane protein complex subunit 6 (EMC6) interacted with both RAB5A and BECN1/Beclin 1 and colocalized with the omegasome marker ZFYVE1/DFCP1. (PMID:23182941)
• This is the first study to show that EMC6 induces cell death in gastric cancer cells. The molecular mechanism of how EMC6 functions as a tumor suppressor needs to be further explored. (PMID:28648145)
• The expression level of EMC-6 is significantly elevated in cervical cancer, without significant correlation with Beclin1 and Rab5a. (PMID:28742203)
• Adenovirus-mediated ectopic overexpression of EMC6 (Ad5-EMC6) decreases the activity of ERK1/2, down-regulates the levels of BCL-2 and increases the ratio of BAX/BCL-2. Ad5-EMC6 mediates anti-tumor activity through the mitochondrial apoptosis pathway. Ad5-EMC6 enhances the sensitivity of gastric cancer cells to the etoposide. (PMID:30982575)
• EMC6 regulates acinar apoptosis via APAF1 in acute and chronic pancreatitis. (PMID:33177505)
• Inhibition of UBA52 induces autophagy via EMC6 to suppress hepatocellular carcinoma tumorigenesis and progression. (PMID:38445807)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	emc6	ENSDARG00000035282
mus_musculus	Emc6	ENSMUSG00000047260
rattus_norvegicus	Emc6	ENSRNOG00000019352
drosophila_melanogaster	EMC6	FBGN0039259
caenorhabditis_elegans		WBGENE00017999

Protein

Protein identifiers

ER membrane protein complex subunit 6 — Q9BV81 (reviewed: Q9BV81)

Alternative names: Transmembrane protein 93

All UniProt accessions (1): Q9BV81

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.

Similarity. Belongs to the EMC6 family.

RefSeq proteins (2): NP_001014764, NP_112588* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008504	Emc6	Family
IPR029008	EMC6-like	Family

Pfam: PF07019

UniProt features (19 total): helix 6, topological domain 4, transmembrane region 3, mutagenesis site 2, initiator methionine 1, chain 1, strand 1, modified residue 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
8J0O	ELECTRON MICROSCOPY	3.32
7ADO	ELECTRON MICROSCOPY	3.39
6WW7	ELECTRON MICROSCOPY	3.4
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-Q9BV81-F1	82.32	0.46

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 (1): 2

Mutagenesis-validated functional residues (2):

Position	Phenotype
27	no effect on emc assembly but decreased membrane insertion of hydrophobic transmembrane helices-containing proteins by t
31	no effect on emc assembly but decreased membrane insertion of hydrophobic transmembrane helices-containing proteins by t

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 138 (showing top): TSENG_IRS1_TARGETS_UP, GOBP_VACUOLE_ORGANIZATION, PAL_PRMT5_TARGETS_UP, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GGGTGGRR_PAX4_03, YY1_Q6, GOBP_MACROAUTOPHAGY, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, GOBP_ORGANELLE_ASSEMBLY, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_MEMBRANE_ORGANIZATION, GOBP_ENDOPLASMIC_RETICULUM_ORGANIZATION, GOBP_LOCALIZATION_WITHIN_MEMBRANE

GO Biological Process (3): autophagosome assembly (GO:0000045), 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 (5): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020), EMC complex (GO:0072546), omegasome membrane (GO:1903349), endoplasmic reticulum (GO:0005783)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein insertion into ER membrane	2
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	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
bounding membrane of organelle	1
omegasome	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1174 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EMC6	EMC1	Q8N766	961
EMC6	EMC4	Q5J8M3	934
EMC6	EMC2	Q15006	932
EMC6	EMC3	Q9P0I2	904
EMC6	MMGT1	Q8N4V1	898
EMC6	BECN1	Q14457	807
EMC6	EMC7	Q9NPA0	806
EMC6	EMC9	Q9Y3B6	792
EMC6	RAB5A	P20339	771
EMC6	EMC8	O43402	735
EMC6	EMC10	Q5UCC4	716
EMC6	GET1	O00258	623
EMC6	OXA1L	Q15070	621
EMC6	GET3	O43681	606
EMC6	PIK3C3	Q8NEB9	535

IntAct

92 interactions, top by confidence:

A	B	Type	Score
EMC2	EMC8	psi-mi:“MI:0914”(association)	0.940
EMC8	EMC2	psi-mi:“MI:0914”(association)	0.940
MMGT1	EMC6	psi-mi:“MI:0915”(physical association)	0.810
EMC6	MMGT1	psi-mi:“MI:0915”(physical association)	0.810
EMC2	EMC10	psi-mi:“MI:0914”(association)	0.800
EMC7	EMC8	psi-mi:“MI:0914”(association)	0.790
MMGT1	EMC8	psi-mi:“MI:0914”(association)	0.730
EMC3	EMC8	psi-mi:“MI:0914”(association)	0.730
EMC10	EMC8	psi-mi:“MI:0915”(physical association)	0.620
TMEM237	EMC6	psi-mi:“MI:0915”(physical association)	0.560
EMC6	SLC39A2	psi-mi:“MI:0915”(physical association)	0.560
EMC6	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
EMC6	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
MUC1	EMC6	psi-mi:“MI:0915”(physical association)	0.560
PDZK1IP1	EMC6	psi-mi:“MI:0915”(physical association)	0.560
AQP6	EMC6	psi-mi:“MI:0915”(physical association)	0.560
MFSD14B	EMC6	psi-mi:“MI:0915”(physical association)	0.560
AQP9	EMC6	psi-mi:“MI:0915”(physical association)	0.560
SLC10A6	EMC6	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	EMC6	psi-mi:“MI:0915”(physical association)	0.560
MMD	EMC6	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (100): EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-RNA), EMC6 (Proximity Label-MS), EMC6 (Proximity Label-MS), EMC6 (Proximity Label-MS), EMC6 (Two-hybrid), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-MS), EMC6 (Affinity Capture-RNA), EMC6 (Affinity Capture-MS), EMC6 (Negative Genetic)

ESM2 similar proteins: A1CKG4, A1D708, A2XSY1, A4K2N5, A4K2W1, A4R2N5, A6RRF7, A7EMV1, B0XXU1, O43934, O80594, O81214, O95214, O95427, P56982, P56983, P56984, P57758, Q0CNZ5, Q0JDK9, Q1RMQ3, Q32PD8, Q3ZBX1, Q3ZCG8, Q4WXT2, Q56P28, Q5BJW3, Q5PQQ4, Q5RCQ5, Q5RDE9, Q5RFE0, Q5ZLL0, Q62302, Q68EU8, Q6GLC5, Q6P0F0, Q6PDU4, Q6UWH6, Q78S06, Q7ZUA6

Diamond homologs: Q1ZXH4, Q3ZCG8, Q68EU8, Q6GLC5, Q6P0F0, Q9BV81, Q9CQW0

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
EMC6	“form complex”	“Endoplasmic reticulum membrane complex- EMC9 variant”	binding
EMC6	“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 50 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	7	152.4×	2e-12

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

164 predictions. Top by Δscore:

Variant	Effect	Δscore
17:3668984:G:GT	donor_gain	1.0000
17:3669001:G:GT	donor_gain	1.0000
17:3669019:G:GT	donor_gain	1.0000
17:3668870:C:G	donor_gain	0.9900
17:3669096:A:AG	acceptor_gain	0.9900
17:3669097:G:GG	acceptor_gain	0.9900
17:3669097:GCTCC:G	acceptor_gain	0.9900
17:3669002:A:T	donor_gain	0.9700
17:3669093:CGCA:C	acceptor_loss	0.9700
17:3669094:GCA:G	acceptor_loss	0.9700
17:3669096:AGCT:A	acceptor_loss	0.9700
17:3669097:GCT:G	acceptor_gain	0.9600
17:3669097:GCTC:G	acceptor_gain	0.9600
17:3668869:GC:G	donor_gain	0.9500
17:3668870:C:CG	donor_gain	0.9500
17:3668895:TCCAG:T	donor_loss	0.9500
17:3668896:CCAG:C	donor_loss	0.9500
17:3668897:CAGG:C	donor_loss	0.9500
17:3668898:AG:A	donor_loss	0.9500
17:3668899:GG:G	donor_loss	0.9500
17:3668900:GTAA:G	donor_loss	0.9500
17:3668901:T:A	donor_loss	0.9500
17:3669097:GC:G	acceptor_gain	0.9500
17:3669007:TGCC:T	donor_gain	0.9300
17:3669008:GCCA:G	donor_gain	0.9300
17:3669008:GCCAG:G	donor_loss	0.9300
17:3669010:CAGGT:C	donor_loss	0.9300
17:3669014:T:A	donor_loss	0.9300
17:3669019:G:T	donor_gain	0.9300
17:3669009:CCAG:C	donor_gain	0.9200

AlphaMissense

681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:3669259:G:A	G38E	0.999
17:3669258:G:T	G38W	0.998
17:3669268:C:A	A41D	0.998
17:3669270:G:C	G42R	0.998
17:3669271:G:A	G42D	0.998
17:3669235:G:C	R30P	0.997
17:3669258:G:A	G38R	0.997
17:3669258:G:C	G38R	0.997
17:3669444:T:A	W100R	0.997
17:3669444:T:C	W100R	0.997
17:3669250:C:A	A35E	0.996
17:3669259:G:T	G38V	0.996
17:3669267:G:C	A41P	0.996
17:3669270:G:T	G42C	0.996
17:3669271:G:T	G42V	0.996
17:3669297:G:C	G51R	0.996
17:3669298:G:A	G51D	0.996
17:3669459:G:C	G105R	0.996
17:3669436:T:A	V97D	0.994
17:3669262:C:A	A39D	0.993
17:3669439:T:A	L98Q	0.993
17:3669265:C:A	T40K	0.992
17:3669283:T:C	L46P	0.992
17:3669298:G:T	G51V	0.992
17:3669246:T:C	S34P	0.991
17:3669261:G:C	A39P	0.991
17:3669439:T:C	L98P	0.991
17:3669231:T:C	C29R	0.990
17:3669280:G:T	G45V	0.990
17:3669297:G:T	G51C	0.990

dbSNP variants (sampled 300 via entrez): RS1000985695 (17:3669891 G>A), RS1002998018 (17:3667316 C>A), RS1004511970 (17:3669629 C>T), RS1005127053 (17:3669976 G>A), RS1005429563 (17:3668836 C>A,T), RS1005811241 (17:3669029 G>A,C,T), RS1006401292 (17:3667950 G>A), RS1006842701 (17:3667654 T>G), RS1009211895 (17:3668297 G>A), RS1009262881 (17:3668072 C>T), RS1010302024 (17:3668041 C>T), RS1011670925 (17:3667075 G>A), RS1012854546 (17:3669560 G>A,T), RS1013031124 (17:3670117 A>T), RS1013067275 (17:3669974 C>T)

Disease associations

OMIM: gene MIM:620261 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	2
aristolochic acid I	increases expression	1
triphenyl phosphate	affects expression	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
sodium arsenite	increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression	1
cylindrospermopsin	increases expression	1
abrine	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	increases abundance, increases expression	1
Atrazine	decreases expression	1
Benzo(a)pyrene	increases methylation	1
Diethylhexyl Phthalate	decreases methylation, increases abundance	1
Doxorubicin	decreases expression	1
Manganese	increases abundance, increases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Vitamin E	increases expression	1
Aflatoxin B1	increases expression	1
Copper Sulfate	decreases expression	1
Lactic Acid	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1R4	Abcam HeLa EMC6 KO	Cancer cell line	Female
CVCL_SL93	HAP1 EMC6 (-) 1	Cancer cell line	Male
CVCL_SL94	HAP1 EMC6 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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