TMED4

Summary

TMED4 (transmembrane p24 trafficking protein 4, HGNC:22301) is a protein-coding gene on chromosome 7p13, encoding Transmembrane emp24 domain-containing protein 4 (Q7Z7H5). Involved in vesicular protein trafficking, mainly in the early secretory pathway. targeting.

Involved in positive regulation of canonical NF-kappaB signal transduction. Predicted to be located in endoplasmic reticulum membrane. Predicted to be active in several cellular components, including COPII-coated ER to Golgi transport vesicle; Golgi apparatus; and endoplasmic reticulum-Golgi intermediate compartment.

Source: NCBI Gene 222068 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 32 total
• MANE Select transcript: NM_182547

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:22301
Approved symbol	TMED4
Name	transmembrane p24 trafficking protein 4
Location	7p13
Locus type	gene with protein product
Status	Approved
Aliases	HNLF, p24alpha3, p24a3
Ensembl gene	ENSG00000158604
Ensembl biotype	protein_coding
OMIM	612038
Entrez	222068

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000289577, ENST00000444131, ENST00000457408, ENST00000477639, ENST00000481238, ENST00000947445

RefSeq mRNA: 6 — MANE Select: NM_182547 NM_001303058, NM_001303059, NM_001303060, NM_001303061, NM_001303062, NM_182547

CCDS: CCDS5493, CCDS78226, CCDS78227

Canonical transcript exons

ENST00000457408 — 5 exons

Exon	Start	End
ENSE00001039816	44581723	44581823
ENSE00001795091	44582047	44582231
ENSE00003676999	44581093	44581239
ENSE00003683759	44581449	44581574
ENSE00004034842	44577894	44579628

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 56.4738 / max 371.8532, expressed in 1825 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
83889	55.1718	1825
83890	0.6144	361
83888	0.5163	281
83887	0.1713	99

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oviduct epithelium	UBERON:0004804	99.51	gold quality
kidney epithelium	UBERON:0004819	98.80	gold quality
corpus epididymis	UBERON:0004359	98.53	gold quality
caput epididymis	UBERON:0004358	98.41	gold quality
trachea	UBERON:0003126	98.03	gold quality
superior surface of tongue	UBERON:0007371	97.82	gold quality
cauda epididymis	UBERON:0004360	97.76	gold quality
saphenous vein	UBERON:0007318	97.67	gold quality
ileal mucosa	UBERON:0000331	97.41	gold quality
duodenum	UBERON:0002114	97.35	gold quality
left lobe of thyroid gland	UBERON:0001120	97.19	gold quality
thyroid gland	UBERON:0002046	97.15	gold quality
renal medulla	UBERON:0000362	97.02	gold quality
right lobe of thyroid gland	UBERON:0001119	96.90	gold quality
fallopian tube	UBERON:0003889	96.85	gold quality
tongue	UBERON:0001723	96.74	gold quality
cortex of kidney	UBERON:0001225	96.67	gold quality
trigeminal ganglion	UBERON:0001675	96.48	gold quality
jejunal mucosa	UBERON:0000399	96.41	gold quality
adenohypophysis	UBERON:0002196	96.38	gold quality
pituitary gland	UBERON:0000007	96.36	gold quality
vena cava	UBERON:0004087	96.30	gold quality
left ovary	UBERON:0002119	96.19	gold quality
body of pancreas	UBERON:0001150	96.15	gold quality
pharyngeal mucosa	UBERON:0000355	96.09	gold quality
metanephros cortex	UBERON:0010533	96.05	gold quality
ovary	UBERON:0000992	96.01	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.98	gold quality
adult mammalian kidney	UBERON:0000082	95.91	gold quality
pons	UBERON:0000988	95.86	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-7303	no	2118.10
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

113 targeting TMED4, 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-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-10401-5P	99.99	65.79	948
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-5696	99.98	72.36	4487
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562

Literature-anchored findings (GeneRIF, showing 1)

• ERS25 may play a critical role in regulation of heat-shock response and apoptosis (PMID:18326488)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	tmed4	ENSDARG00000024954
mus_musculus	Tmed4	ENSMUSG00000004394
rattus_norvegicus	Tmed4	ENSRNOG00000005016
drosophila_melanogaster	p24-2	FBGN0053105
drosophila_melanogaster	eca	FBGN0069242
caenorhabditis_elegans		WBGENE00011606

Paralogs (8): TMED2 (ENSG00000086598), TMED1 (ENSG00000099203), TMED5 (ENSG00000117500), TMED7 (ENSG00000134970), TMED6 (ENSG00000157315), TMED3 (ENSG00000166557), TMED10 (ENSG00000170348), TMED9 (ENSG00000184840)

Protein

Protein identifiers

Transmembrane emp24 domain-containing protein 4 — Q7Z7H5 (reviewed: Q7Z7H5)

Alternative names: Endoplasmic reticulum stress-response protein 25, GMP25iso, Putative NF-kappa-B-activating protein 156, p24 family protein alpha-3

All UniProt accessions (2): Q7Z7H5, F8W7F7

UniProt curated annotations — full annotation on UniProt →

Function. Involved in vesicular protein trafficking, mainly in the early secretory pathway. targeting. Involved in the maintenance of the Golgi apparatus. Appears to play a role in the biosynthesis of secreted cargo including processing. Involved in endoplasmic reticulum stress response. May play a role in the regulation of heat-shock response and apoptosis.

Subcellular location. Endoplasmic reticulum membrane.

Similarity. Belongs to the EMP24/GP25L family.

Isoforms (3)

UniProt ID	Names	Canonical?
Q7Z7H5-1	1	yes
Q7Z7H5-2	2
Q7Z7H5-3	3

RefSeq proteins (6): NP_001289987, NP_001289988, NP_001289989, NP_001289990, NP_001289991, NP_872353* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009038	GOLD_dom	Domain
IPR015720	Emp24-like	Family

Pfam: PF01105

UniProt features (13 total): splice variant 3, topological domain 2, short sequence motif 2, signal peptide 1, chain 1, transmembrane region 1, domain 1, coiled-coil region 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7Z7H5-F1	86.02	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Glycosylation sites (1): 117

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 155 (showing top): TGCGCANK_UNKNOWN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_ENDOPLASMIC_RETICULUM_TO_GOLGI_VESICLE_MEDIATED_TRANSPORT, GOCC_COATED_VESICLE, HNF4_01, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, DODD_NASOPHARYNGEAL_CARCINOMA_UP, GUO_HEX_TARGETS_DN, BASAKI_YBX1_TARGETS_DN, chr7p13, GOBP_POSITIVE_REGULATION_OF_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (5): intracellular protein transport (GO:0006886), endoplasmic reticulum to Golgi vesicle-mediated transport (GO:0006888), Golgi organization (GO:0007030), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), protein transport (GO:0015031)

GO Molecular Function (0):

GO Cellular Component (6): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), endoplasmic reticulum-Golgi intermediate compartment (GO:0005793), Golgi apparatus (GO:0005794), COPII-coated ER to Golgi transport vesicle (GO:0030134), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
intracellular membrane-bounded organelle	3
intracellular protein localization	2
intracellular transport	2
endomembrane system	2
protein transport	1
intercellular transport	1
Golgi vesicle transport	1
organelle organization	1
endomembrane system organization	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
transport	1
establishment of protein localization	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
coated vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

874 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMED4	TMED5	Q9Y3A6	689
TMED4	TMED10	P49755	657
TMED4	TMED1	Q13445	622
TMED4	TM9SF3	Q9HD45	481
TMED4	ACBD3	Q9H3P7	434
TMED4	SSMEM1	Q8WWF3	421
TMED4	TMED2	Q15363	420
TMED4	EMC7	Q9NPA0	411
TMED4	DYM	Q7RTS9	385
TMED4	RNF212B	A8MTL3	371
TMED4	UFC1	Q9Y3C8	358
TMED4	IFT74	Q96LB3	358
TMED4	TMED6	Q8WW62	356
TMED4	MCFD2	Q8NI22	356
TMED4	PITPNM1	O00562	353

IntAct

95 interactions, top by confidence:

A	B	Type	Score
GORASP2	GOLGA2	psi-mi:“MI:0914”(association)	0.880
RFX3	RFX1	psi-mi:“MI:0914”(association)	0.730
TMED10	TMED1	psi-mi:“MI:0914”(association)	0.730
TMED9	TMED10	psi-mi:“MI:0914”(association)	0.730
DDRGK1	UFL1	psi-mi:“MI:0914”(association)	0.710
TMED2	ATP9A	psi-mi:“MI:0914”(association)	0.640
CHST8	CANX	psi-mi:“MI:0914”(association)	0.640
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
FGF3	GTPBP10	psi-mi:“MI:0914”(association)	0.530
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
NUP62	RGPD8	psi-mi:“MI:0914”(association)	0.530
LIPG	NRP1	psi-mi:“MI:0914”(association)	0.530
CDK5RAP3	PLD2	psi-mi:“MI:0914”(association)	0.530
HEATR3	SLC27A2	psi-mi:“MI:0914”(association)	0.530
SCN3B	ABCC5	psi-mi:“MI:0914”(association)	0.530
TMED3	HS1BP3	psi-mi:“MI:0914”(association)	0.530
rev	TMED10	psi-mi:“MI:0914”(association)	0.460
Gorasp1	CLIP-170	psi-mi:“MI:0915”(physical association)	0.400
Dennd6a	IFT88	psi-mi:“MI:0914”(association)	0.350
Tmed10	TARS3	psi-mi:“MI:0914”(association)	0.350
Tmed10	NDUFS8	psi-mi:“MI:0914”(association)	0.350
Tmed2		psi-mi:“MI:0914”(association)	0.350
PDHA1		psi-mi:“MI:0914”(association)	0.350
ENG	IGKV2-28	psi-mi:“MI:0914”(association)	0.350
PEBP1	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (132): TMED4 (Affinity Capture-RNA), TMED4 (Affinity Capture-RNA), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Co-fractionation), TMED4 (Co-fractionation), TMED4 (Co-fractionation), TMED4 (Co-fractionation), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), TMED4 (Affinity Capture-MS)

ESM2 similar proteins: A0AQ71, B3LVB0, B3P6T8, B4GE47, B4HJV5, B4JYU5, B4K4G5, B4KB41, B4LYB8, B4MGF8, B4NIY1, B4NKL0, B4PUZ3, B4QWH9, F4J4Y0, O13770, O13946, O14324, O35587, O81045, P27869, P32803, P38819, P49755, P53198, Q05359, Q12403, Q12450, Q28735, Q3T133, Q4P958, Q54BN0, Q5E971, Q5I0E7, Q5RE32, Q63584, Q6C503, Q759T8, Q7Z7H5, Q8GYG1

Diamond homologs: A7SXK3, D3ZTX0, O17528, P32803, P49020, Q15363, Q3T133, Q54BN0, Q5I0E7, Q63524, Q6AY25, Q6BTC2, Q769F9, Q78IS1, Q7Z7H5, Q8R1V4, Q99KF1, Q9P7I9, Q9R0Q3, Q9Y3B3, Q9Y3Q3, B3MTS8, B3NZM5, B4GMC3, B4HJV5, B4JG34, B4KB41, B4LYB8, B4NKL0, B4PVC6, B4QWH9, O14324, O35587, P0CN72, P0CN73, P27869, P49755, P53198, Q28735, Q295B2

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 122 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
COPI-dependent Golgi-to-ER retrograde traffic	7	9.7×	2e-03
COPI-mediated anterograde transport	7	9.6×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
endoplasmic reticulum to Golgi vesicle-mediated transport	10	13.1×	4e-06
Golgi organization	9	11.6×	3e-05
intracellular protein transport	10	6.2×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	26
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

427 predictions. Top by Δscore:

Variant	Effect	Δscore
7:44579480:TA:T	donor_gain	1.0000
7:44579624:CGATA:C	acceptor_gain	1.0000
7:44579627:TA:T	acceptor_gain	1.0000
7:44579629:C:CC	acceptor_gain	1.0000
7:44581103:T:TA	donor_gain	1.0000
7:44581235:ACCCG:A	acceptor_gain	1.0000
7:44581236:CCCG:C	acceptor_gain	1.0000
7:44581236:CCCGC:C	acceptor_gain	1.0000
7:44581237:CCG:C	acceptor_gain	1.0000
7:44581237:CCGC:C	acceptor_gain	1.0000
7:44581238:CG:C	acceptor_gain	1.0000
7:44581238:CGC:C	acceptor_gain	1.0000
7:44581239:GC:G	acceptor_loss	1.0000
7:44581240:C:CC	acceptor_gain	1.0000
7:44581443:TCTTA:T	donor_loss	1.0000
7:44581444:CTTA:C	donor_loss	1.0000
7:44581445:TTAC:T	donor_loss	1.0000
7:44581446:TAC:T	donor_loss	1.0000
7:44581447:A:AC	donor_gain	1.0000
7:44581447:ACC:A	donor_loss	1.0000
7:44581448:C:CA	donor_loss	1.0000
7:44581448:C:CC	donor_gain	1.0000
7:44581448:CCAG:C	donor_gain	1.0000
7:44581717:CCTTA:C	donor_loss	1.0000
7:44581718:CTTAC:C	donor_loss	1.0000
7:44581719:TTACC:T	donor_loss	1.0000
7:44581720:TA:T	donor_loss	1.0000
7:44581721:A:T	donor_loss	1.0000
7:44581722:C:CA	donor_loss	1.0000
7:44581823:CCTG:C	acceptor_loss	1.0000

AlphaMissense

1488 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:44579624:C:G	R180P	1.000
7:44579496:C:G	A223P	0.999
7:44579501:A:C	F221C	0.999
7:44579503:G:C	F220L	0.999
7:44579503:G:T	F220L	0.999
7:44579505:A:G	F220L	0.999
7:44579513:A:G	L217P	0.999
7:44579534:C:T	G210D	0.999
7:44579535:C:G	G210R	0.999
7:44579546:A:T	L206H	0.999
7:44579571:A:G	W198R	0.999
7:44579571:A:T	W198R	0.999
7:44579599:G:C	S188R	0.999
7:44579599:G:T	S188R	0.999
7:44579601:T:G	S188R	0.999
7:44579609:C:G	R185P	0.999
7:44579611:G:C	F184L	0.999
7:44579611:G:T	F184L	0.999
7:44579613:A:G	F184L	0.999
7:44581106:T:G	Q174P	0.999
7:44581145:C:G	R161P	0.999
7:44581154:A:G	L158P	0.999
7:44581196:T:C	Y144C	0.999
7:44581229:A:G	L133P	0.999
7:44581498:C:G	C113S	0.999
7:44581498:C:T	C113Y	0.999
7:44581499:A:G	C113R	0.999
7:44581499:A:T	C113S	0.999
7:44581508:G:C	H110D	0.999
7:44581513:C:A	G108V	0.999

dbSNP variants (sampled 300 via entrez): RS1000017430 (7:44583714 A>G), RS1000063199 (7:44584130 C>T), RS1000161456 (7:44583226 T>C), RS1000359756 (7:44577813 A>G), RS1001407164 (7:44577424 C>A), RS1001671719 (7:44582704 G>C), RS1001703745 (7:44583087 C>T), RS1002023198 (7:44581571 C>A), RS1002977856 (7:44582166 C>G,T), RS1003684397 (7:44580083 G>T), RS1003736807 (7:44580396 T>G), RS1004138038 (7:44581894 G>T), RS1005808276 (7:44580242 G>A,C), RS1005866149 (7:44579979 A>G), RS1006497063 (7:44583395 C>G,T)

Disease associations

OMIM: gene MIM:612038 | 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

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression	2
entinostat	decreases expression, affects cotreatment	2
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	2
Hydrogen Peroxide	affects cotreatment, increases expression, affects expression	2
Dronabinol	decreases expression, increases expression	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
methylmercuric chloride	decreases expression	1
trichostatin A	decreases expression	1
tetrahydropalmatine	decreases expression	1
o,p’-DDT	decreases expression	1
cupric oxide	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
glycidamide	increases expression	1
bisphenol B	increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
NSC 689534	affects binding, decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	increases expression	1
Acetaminophen	increases expression	1
Copper	affects binding, decreases expression	1
Diethylstilbestrol	increases expression	1
Doxorubicin	decreases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Smoke	decreases expression	1
Theophylline	affects cotreatment, increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3JE	Abcam HEK293T TMED4 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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