TRAM2

Summary

TRAM2 (translocation associated membrane protein 2, HGNC:16855) is a protein-coding gene on chromosome 6p12.2, encoding Translocating chain-associated membrane protein 2 (Q15035). Necessary for collagen type I synthesis.

TRAM2 is a component of the translocon, a gated macromolecular channel that controls the posttranslational processing of nascent secretory and membrane proteins at the endoplasmic reticulum (ER) membrane.

Source: NCBI Gene 9697 — RefSeq curated summary.

At a glance

• GWAS associations: 8
• Clinical variants (ClinVar): 49 total
• MANE Select transcript: NM_012288

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16855
Approved symbol	TRAM2
Name	translocation associated membrane protein 2
Location	6p12.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0057
Ensembl gene	ENSG00000065308
Ensembl biotype	protein_coding
OMIM	608485
Entrez	9697

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 12 protein_coding

ENST00000182527, ENST00000863425, ENST00000863426, ENST00000863427, ENST00000912004, ENST00000912005, ENST00000956690, ENST00000956691, ENST00000956692, ENST00000956693, ENST00000956694, ENST00000956695

RefSeq mRNA: 1 — MANE Select: NM_012288 NM_012288

CCDS: CCDS34477

Canonical transcript exons

ENST00000182527 — 11 exons

Exon	Start	End
ENSE00000756186	52504591	52504754
ENSE00000756188	52505599	52505742
ENSE00000756189	52506032	52506136
ENSE00000756190	52507553	52507623
ENSE00000756191	52508234	52508318
ENSE00000756192	52509528	52509586
ENSE00000756194	52516006	52516122
ENSE00000756196	52516628	52516737
ENSE00000756197	52535783	52535846
ENSE00001183055	52497408	52503270
ENSE00001830214	52576796	52577060

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 97.58.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 23.4631 / max 181.8741, expressed in 1722 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
73968	20.1786	1713
73966	1.7689	686
73967	1.1986	608
73964	0.3170	179

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
oocyte	CL:0000023	97.58	gold quality
secondary oocyte	CL:0000655	96.87	gold quality
stromal cell of endometrium	CL:0002255	96.73	gold quality
placenta	UBERON:0001987	93.74	gold quality
cartilage tissue	UBERON:0002418	93.02	gold quality
tibia	UBERON:0000979	92.33	gold quality
blood vessel layer	UBERON:0004797	91.34	gold quality
layer of synovial tissue	UBERON:0007616	90.99	gold quality
synovial joint	UBERON:0002217	90.86	gold quality
ileal mucosa	UBERON:0000331	89.93	gold quality
visceral pleura	UBERON:0002401	89.87	gold quality
pleura	UBERON:0000977	89.25	gold quality
tendon of biceps brachii	UBERON:0008188	89.25	gold quality
parietal pleura	UBERON:0002400	89.10	gold quality
right coronary artery	UBERON:0001625	88.84	gold quality
renal glomerulus	UBERON:0000074	88.74	gold quality
skin of hip	UBERON:0001554	88.46	gold quality
metanephric glomerulus	UBERON:0004736	88.28	gold quality
decidua	UBERON:0002450	88.09	gold quality
upper leg skin	UBERON:0004262	87.26	gold quality
superficial temporal artery	UBERON:0001614	87.14	gold quality
gall bladder	UBERON:0002110	86.57	gold quality
descending thoracic aorta	UBERON:0002345	86.57	gold quality
mucosa of sigmoid colon	UBERON:0004993	86.57	gold quality
thoracic aorta	UBERON:0001515	85.92	gold quality
subcutaneous adipose tissue	UBERON:0002190	85.86	gold quality
ascending aorta	UBERON:0001496	85.79	gold quality
left coronary artery	UBERON:0001626	85.67	gold quality
mucosa of stomach	UBERON:0001199	85.64	gold quality
duodenum	UBERON:0002114	85.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-83139	yes	6.99
E-MTAB-6678	yes	6.75
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RUNX2

miRNA regulators (miRDB)

194 targeting TRAM2, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4668-3P	100.00	68.74	2635
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-6856-5P	100.00	65.47	1298
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-4723-5P	99.97	68.70	2034

Literature-anchored findings (GeneRIF, showing 5)

• TRAM2, as a part of the translocon, is required for the biosynthesis of type I collagen by coupling the activity of SERCA2b with the activity of the translocon (PMID:14749390)
• results support a role of DAP12 in stabilizing TREM2-CTF, thereby protecting against excessive pro-inflammatory responses. (PMID:25957402)
• A comprehensive enhancer screen identifies TRAM2 as a key and novel mediator of YAP oncogenesis. (PMID:33514403)
• Identification of TRAMs as sphingolipid-binding proteins using a photoactivatable and clickable short-chain ceramide analog. (PMID:34793833)
• TRAM2 promotes the malignant progression of glioma through PI3K/AKT/mTOR pathway. (PMID:34826698)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tram2	ENSDARG00000030092
mus_musculus	Tram2	ENSMUSG00000041779
rattus_norvegicus	Tram2	ENSRNOG00000064843
drosophila_melanogaster	TRAM	FBGN0040340
caenorhabditis_elegans		WBGENE00007696

Paralogs (2): TRAM1 (ENSG00000067167), TRAM1L1 (ENSG00000174599)

Protein

Protein identifiers

Translocating chain-associated membrane protein 2 — Q15035 (reviewed: Q15035)

All UniProt accessions (2): Q15035, A0A024RD84

UniProt curated annotations — full annotation on UniProt →

Function. Necessary for collagen type I synthesis. May couple the activity of the ER Ca(2+) pump SERCA2B with the activity of the translocon. This coupling may increase the local Ca(2+) concentration at the site of collagen synthesis, and a high Ca(2+) concentration may be necessary for the function of molecular chaperones involved in collagen folding. Required for proper insertion of the first transmembrane helix N-terminus of TM4SF20 into the ER lumen, may act as a ceramide sensor for regulated alternative translocation (RAT).

Subunit / interactions. Interacts with SERCA2B and COL1A1.

Subcellular location. Membrane.

Similarity. Belongs to the TRAM family.

RefSeq proteins (1): NP_036420* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006634	TLC-dom	Domain
IPR016447	Translocation_assoc_membrane	Family

Pfam: PF03798

UniProt features (21 total): topological domain 9, transmembrane region 8, chain 1, domain 1, region of interest 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15035-F1	85.96	0.66

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): 55

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 269 (showing top): MODULE_52, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_PROTEIN_TARGETING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ENDOPLASMIC_RETICULUM, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, TERAMOTO_OPN_TARGETS_CLUSTER_3, GTGCCTT_MIR506, GOBP_PROTEIN_TARGETING_TO_MEMBRANE, chr6p12, LI_WILMS_TUMOR_VS_FETAL_KIDNEY_1_UP, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_MEMBRANE, DACOSTA_UV_RESPONSE_VIA_ERCC3_COMMON_DN

GO Biological Process (4): SRP-dependent cotranslational protein targeting to membrane, translocation (GO:0006616), collagen biosynthetic process (GO:0032964), protein insertion into ER membrane (GO:0045048), protein transport (GO:0015031)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): endoplasmic reticulum membrane (GO:0005789), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
SRP-dependent cotranslational protein targeting to membrane	1
intracellular protein transmembrane transport	1
biosynthetic process	1
collagen metabolic process	1
endoplasmic reticulum organization	1
protein localization to organelle	1
protein insertion into membrane	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
cellular anatomical structure	1

Protein interactions and networks

STRING

654 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TRAM2	DTL	Q9NZJ0	826
TRAM2	ATP2A3	Q93084	766
TRAM2	SLN	O00631	764
TRAM2	PLN	P26678	763
TRAM2	PKHD1	P08F94	741
TRAM2	ATP2A1	O14983	603
TRAM2	ATP2A2	P16614	548
TRAM2	PRELID3B	Q9Y3B1	531
TRAM2	TMEM170B	Q5T4T1	472
TRAM2	TLX2	O43763	469
TRAM2	TMEM14A	Q9Y6G1	463
TRAM2	CCDC80	Q76M96	457
TRAM2	KLHL18	O94889	435
TRAM2	ATP2B1	P20020	427
TRAM2	SLC8A1	P32418	426

IntAct

18 interactions, top by confidence:

A	B	Type	Score
MANSC1	KLRG2	psi-mi:“MI:0914”(association)	0.530
MANSC1	SMPD2	psi-mi:“MI:0914”(association)	0.530
CXCR3	RIMOC1	psi-mi:“MI:0914”(association)	0.350
HTR1E	ESYT2	psi-mi:“MI:0914”(association)	0.350
RETREG3	NPC1	psi-mi:“MI:0914”(association)	0.350
ZDHHC11	NRP1	psi-mi:“MI:0914”(association)	0.350
SLC15A3	GXYLT2	psi-mi:“MI:0914”(association)	0.350
SLC18A3	ORC4	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC30A7	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC35F1	C15orf61	psi-mi:“MI:0914”(association)	0.350
SLC39A14	ESYT2	psi-mi:“MI:0914”(association)	0.350
SLC39A8	CEBPZOS	psi-mi:“MI:0914”(association)	0.350
ATF3	TMEM223	psi-mi:“MI:0914”(association)	0.350
CASP3	TMEM223	psi-mi:“MI:0914”(association)	0.350
FOS	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (17): TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-RNA), TRAM2 (Proximity Label-MS), TRAM2 (Proximity Label-MS), TRAM2 (Proximity Label-MS), TRAM2 (Proximity Label-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-RNA), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS), TRAM2 (Affinity Capture-MS)

ESM2 similar proteins: A0PK00, A1L2R7, A2BIE7, A2VE61, A3KNK1, A6QPF8, A7XZ53, A8DZH4, B1AZA5, D3ZEH5, D3ZXD8, E1BD52, O35052, P58749, P98191, Q05B45, Q0VFK3, Q15035, Q17QL9, Q1LY80, Q3TA38, Q3UMR5, Q5EAX9, Q5EAY8, Q5FWV6, Q5HZE2, Q5R7B1, Q5U239, Q5ZMP3, Q63ZG0, Q68EY2, Q6DE21, Q6ZMG9, Q8BXA5, Q8C172, Q8C1E7, Q8CIF6, Q8N5B7, Q8NBJ9, Q8WVP7

Diamond homologs: Q01685, Q15035, Q15629, Q5E9R6, Q5R7Z3, Q5XI41, Q6DED0, Q8N609, Q8QZR0, Q91V04, Q924Z5, Q9GKZ4, A6ZSP9, O59735, P27544, P38703, P78970, Q1A3B0, Q3ZBF8, Q6EUN0, Q6NQI8, Q6YWS8, Q6ZMG9, Q84QC0, Q8C172, Q8IU89, Q8N5B7, Q8W4Y5, Q924Z4, Q96G23, Q9D6J1, Q9D6K9, Q9HA82, Q9LDF2, Q9LJK3, Q9M6A3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	32
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2013 predictions. Top by Δscore:

Variant	Effect	Δscore
6:52503186:G:C	donor_gain	1.0000
6:52503218:AGT:A	donor_gain	1.0000
6:52505595:TCA:T	donor_loss	1.0000
6:52505596:CA:C	donor_loss	1.0000
6:52505750:C:CT	acceptor_gain	1.0000
6:52507548:CTCA:C	donor_gain	1.0000
6:52507551:A:AC	donor_gain	1.0000
6:52507552:C:CC	donor_gain	1.0000
6:52508229:CTCA:C	donor_loss	1.0000
6:52508230:TCA:T	donor_loss	1.0000
6:52508231:CA:C	donor_loss	1.0000
6:52508232:A:AT	donor_loss	1.0000
6:52508233:C:A	donor_loss	1.0000
6:52516626:A:AC	donor_gain	1.0000
6:52516627:C:CC	donor_gain	1.0000
6:52516627:CAT:C	donor_gain	1.0000
6:52516734:CTGT:C	acceptor_gain	1.0000
6:52576790:TCTCA:T	donor_loss	1.0000
6:52576792:TCAC:T	donor_loss	1.0000
6:52576793:CA:C	donor_loss	1.0000
6:52503175:T:TA	donor_gain	0.9900
6:52503184:TAGC:T	donor_gain	0.9900
6:52503185:AG:A	donor_gain	0.9900
6:52503185:AGCA:A	donor_gain	0.9900
6:52503191:TTG:T	donor_gain	0.9900
6:52504584:CACT:C	donor_loss	0.9900
6:52504585:ACTC:A	donor_loss	0.9900
6:52504586:CTCA:C	donor_loss	0.9900
6:52504587:TCA:T	donor_loss	0.9900
6:52504588:CA:C	donor_loss	0.9900

AlphaMissense

2425 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:52508306:C:A	K161N	0.998
6:52508306:C:G	K161N	0.998
6:52516702:C:G	D74H	0.998
6:52576865:G:C	F17L	0.998
6:52576865:G:T	F17L	0.998
6:52576867:A:G	F17L	0.998
6:52516064:C:T	G118E	0.997
6:52516654:C:G	A90P	0.997
6:52516682:G:C	F80L	0.997
6:52516682:G:T	F80L	0.997
6:52516684:A:G	F80L	0.997
6:52516701:T:G	D74A	0.997
6:52576806:A:G	L37P	0.997
6:52508308:T:C	K161E	0.996
6:52516093:T:A	K108N	0.996
6:52516093:T:G	K108N	0.996
6:52516094:T:A	K108I	0.996
6:52516720:A:C	Y68D	0.996
6:52535812:G:C	P52R	0.996
6:52535818:A:T	I50N	0.996
6:52576810:C:G	G36R	0.996
6:52576810:C:T	G36R	0.996
6:52576815:A:T	L34H	0.996
6:52506123:C:G	G214R	0.995
6:52508262:G:C	P176R	0.995
6:52509554:C:A	W148C	0.995
6:52509554:C:G	W148C	0.995
6:52509556:A:G	W148R	0.995
6:52509556:A:T	W148R	0.995
6:52516029:A:G	W130R	0.995

dbSNP variants (sampled 300 via entrez): RS1000020715 (6:52535104 CA>C), RS1000021770 (6:52529415 C>T), RS1000082424 (6:52523465 A>G), RS1000139462 (6:52567149 A>G), RS1000264472 (6:52529151 G>A,C), RS1000302892 (6:52535416 C>T), RS1000327772 (6:52501164 G>A), RS1000370694 (6:52565137 C>T), RS1000386345 (6:52505711 T>C,G), RS1000387428 (6:52561280 T>C), RS1000394479 (6:52535699 T>A), RS1000418600 (6:52576514 A>G), RS1000438674 (6:52503866 A>C), RS1000596217 (6:52559034 A>G), RS1000612234 (6:52500846 A>C,G,T)

Disease associations

OMIM: gene MIM:608485 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST003180_2	Atopic march	2.000000e-08
GCST004233_32	LDL cholesterol levels	2.000000e-08
GCST004235_48	Total cholesterol levels	3.000000e-08
GCST005580_292	Intraocular pressure	2.000000e-09
GCST006667_10	Lipid traits (pleiotropy) (HIPO component 2)	2.000000e-08
GCST009150_11	Low density lipoprotein cholesterol levels	4.000000e-15
GCST010243_85	Apolipoprotein B levels	1.000000e-10
GCST90000025_53	Appendicular lean mass	2.000000e-27

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0007755	atopic march
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004695	intraocular pressure measurement
EFO:0004530	triglyceride measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004980	appendicular lean mass

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases methylation, decreases expression, affects expression, affects cotreatment	4
Valproic Acid	affects expression, increases expression	4
sodium arsenite	affects methylation, decreases expression, increases abundance	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	affects cotreatment, increases expression, decreases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
kojic acid	decreases expression	1
2-butenal	decreases expression	1
2,4,5,2’,4’,5’-hexachlorobiphenyl	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	decreases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
perfluorooctanoic acid	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
perfluorooctane sulfonic acid	decreases expression	1
deguelin	increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Arbutin	decreases expression	1
Arsenic	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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