TM2D1

Summary

TM2D1 (TM2 domain containing 1, HGNC:24142) is a protein-coding gene on chromosome 1p31.3, encoding TM2 domain-containing protein 1 (Q9BX74). May participate in amyloid-beta-induced apoptosis via its interaction with beta-APP42.

The protein encoded by this gene is a beta-amyloid peptide-binding protein. It contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily and known to be important in heterotrimeric G protein activation. Beta-amyloid peptide has been established to be a causative factor in neuron death and the consequent diminution of cognitive abilities observed in Alzheimer’s disease. This protein may be a target of neurotoxic beta-amyloid peptide, and may mediate cellular vulnerability to beta-amyloid peptide toxicity through a G protein-regulated program of cell death. Several transcript variants have been found for this gene.

Source: NCBI Gene 83941 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 24 total
• MANE Select transcript: NM_032027

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24142
Approved symbol	TM2D1
Name	TM2 domain containing 1
Location	1p31.3
Locus type	gene with protein product
Status	Approved
Aliases	BBP
Ensembl gene	ENSG00000162604
Ensembl biotype	protein_coding
OMIM	610080
Entrez	83941

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 13 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000371177, ENST00000371178, ENST00000371180, ENST00000468586, ENST00000472357, ENST00000472989, ENST00000488206, ENST00000488410, ENST00000494926, ENST00000496465, ENST00000606498, ENST00000855758, ENST00000855759, ENST00000855760, ENST00000855761, ENST00000922030, ENST00000922031, ENST00000922032, ENST00000964148, ENST00000964149, ENST00000964150

RefSeq mRNA: 1 — MANE Select: NM_032027 NM_032027

CCDS: CCDS65554

Canonical transcript exons

ENST00000606498 — 7 exons

Exon	Start	End
ENSE00003493747	61683417	61683546
ENSE00003627880	61694697	61694770
ENSE00003695212	61724957	61725141
ENSE00003697357	61709329	61709437
ENSE00003698924	61700934	61701025
ENSE00003700344	61723713	61723786
ENSE00003701843	61681046	61681350

Expression profiles

Bgee: expression breadth ubiquitous, 296 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 51.2073 / max 285.4464, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12607	51.2073	1828

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	99.08	gold quality
calcaneal tendon	UBERON:0003701	98.23	gold quality
choroid plexus epithelium	UBERON:0003911	97.67	gold quality
germinal epithelium of ovary	UBERON:0001304	97.39	gold quality
oocyte	CL:0000023	96.73	gold quality
descending thoracic aorta	UBERON:0002345	96.65	gold quality
parotid gland	UBERON:0001831	96.28	gold quality
thoracic aorta	UBERON:0001515	96.09	gold quality
adrenal tissue	UBERON:0018303	96.06	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.05	gold quality
ascending aorta	UBERON:0001496	96.02	gold quality
corpus epididymis	UBERON:0004359	95.86	gold quality
visceral pleura	UBERON:0002401	95.70	gold quality
aorta	UBERON:0000947	95.48	gold quality
left ovary	UBERON:0002119	95.46	gold quality
left coronary artery	UBERON:0001626	95.43	gold quality
parietal pleura	UBERON:0002400	95.39	gold quality
pleura	UBERON:0000977	95.35	gold quality
coronary artery	UBERON:0001621	95.21	gold quality
caput epididymis	UBERON:0004358	95.12	gold quality
rectum	UBERON:0001052	95.08	gold quality
right ovary	UBERON:0002118	95.08	gold quality
endometrium	UBERON:0001295	95.07	gold quality
trigeminal ganglion	UBERON:0001675	95.05	gold quality
right lung	UBERON:0002167	95.04	gold quality
popliteal artery	UBERON:0002250	95.04	gold quality
tibial artery	UBERON:0007610	95.04	gold quality
gall bladder	UBERON:0002110	95.00	gold quality
renal medulla	UBERON:0000362	94.99	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	94.98	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-112	no	2.64
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

22 targeting TM2D1, 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-5692A	100.00	74.40	6850
HSA-MIR-3662	99.99	73.82	5684
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-4762-5P	99.57	68.54	1424
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-12125	98.59	67.54	1044
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-1285-5P	98.01	68.71	779
HSA-MIR-342-3P	96.44	67.48	1344
HSA-MIR-4704-5P	96.13	68.67	608

Literature-anchored findings (GeneRIF, showing 3)

• sAPP increased the proportion of migrating keratinocytes and their directional persistence. sAPP appeared to operate synergistically with fibronectin with respect to its motogenic effect. (PMID:12553667)
• A two-electrode voltage-clamp technique is used to determine that BBP is not directly coupled to G alpha(i/o), G alpha(s), or G alpha(q) proteins and that BBP may need a component other than amyloid precursor protein to exert its toxic effect with A beta. (PMID:12836168)
• These findings reveal that low density lipoprotein receptor-related protein 1B is a novel binding partner of beta-amyloid precursor protein (APP) that functions to decrease APP processing to amyloid beta peptides. (PMID:15126508)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tm2d1	ENSDARG00000057042
mus_musculus	Tm2d1	ENSMUSG00000028563
rattus_norvegicus	Tm2d1	ENSRNOG00000007527
drosophila_melanogaster	bisc	FBGN0034626
caenorhabditis_elegans		WBGENE00013446

Paralogs (2): TM2D2 (ENSG00000169490), TM2D3 (ENSG00000184277)

Protein

Protein identifiers

TM2 domain-containing protein 1 — Q9BX74 (reviewed: Q9BX74)

Alternative names: Amyloid-beta-binding protein

All UniProt accessions (7): Q9BX74, J3KPA2, U3KPS6, U3KPW4, U3KQ44, U3KQF9, U3KQS3

UniProt curated annotations — full annotation on UniProt →

Function. May participate in amyloid-beta-induced apoptosis via its interaction with beta-APP42.

Subunit / interactions. Interacts with APP beta-APP42 (amyloid-beta protein 42).

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Post-translational modifications. N-glycosylated.

Similarity. Belongs to the TM2 family.

RefSeq proteins (1): NP_114416* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007829	TM2	Domain
IPR050932	TM2D1-3-like	Family

Pfam: PF05154

UniProt features (13 total): glycosylation site 5, topological domain 3, transmembrane region 2, signal peptide 1, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BX74-F1	82.85	0.57

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 (5): 87, 96, 197, 72, 75

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 117 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, ONKEN_UVEAL_MELANOMA_UP, GOBP_APOPTOTIC_SIGNALING_PATHWAY, DAZARD_RESPONSE_TO_UV_SCC_UP, DEBIASI_APOPTOSIS_BY_REOVIRUS_INFECTION_UP, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, ACEVEDO_LIVER_CANCER_UP, MODULE_491, CHANDRAN_METASTASIS_UP, CTCTATG_MIR368, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_DN, GARY_CD5_TARGETS_UP, BLALOCK_ALZHEIMERS_DISEASE_DN

GO Biological Process (3): apoptotic signaling pathway (GO:0097190), apoptotic process (GO:0006915), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (3): amyloid-beta binding (GO:0001540), G protein-coupled receptor activity (GO:0004930), protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
apoptotic process	1
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
G protein-coupled receptor activity	1
peptide binding	1
transmembrane signaling receptor activity	1
G protein-coupled receptor signaling pathway	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

614 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM2D1	TM2D2	Q9BX73	978
TM2D1	NHLRC2	Q8NBF2	566
TM2D1	C2CD2	Q9Y426	508
TM2D1	APP	P05067	496
TM2D1	FGGY	Q96C11	493
TM2D1	ENDOD1	O94919	475
TM2D1	UBTD2	Q8WUN7	460
TM2D1	CCDC86	Q9H6F5	458
TM2D1	HSD17B10	Q99714	446
TM2D1	LAMTOR4	Q0VGL1	432
TM2D1	IQGAP3	Q86VI3	429
TM2D1	LAMTOR3	Q9UHA4	423
TM2D1	FBXO4	Q9UKT5	421
TM2D1	LAMTOR2	Q9Y2Q5	420
TM2D1	UBE2L5	A0A1B0GUS4	416

IntAct

11 interactions, top by confidence:

A	B	Type	Score
TM2D1	APLP2	psi-mi:“MI:0915”(physical association)	0.560
CASP1	TM2D1	psi-mi:“MI:0915”(physical association)	0.560
APP	TM2D1	psi-mi:“MI:0915”(physical association)	0.560
TM2D1	DPY19L4	psi-mi:“MI:0914”(association)	0.350

BioGRID (9): TM2D3 (Affinity Capture-MS), PCNXL3 (Affinity Capture-MS), DPY19L4 (Affinity Capture-MS), ATG9A (Affinity Capture-MS), TM2D1 (Negative Genetic), TM2D1 (Affinity Capture-RNA), TM2D1 (Affinity Capture-RNA), TM2D1 (Two-hybrid), TM2D1 (Affinity Capture-Western)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GVT2, A2RRL7, A3KN25, A4IFL1, G1TZA0, O18968, O54851, O70610, P08033, P0DKX4, P28230, P28234, P28235, P29414, P33725, P35212, P36382, P41987, P56513, Q01231, Q03190, Q08755, Q08EA8, Q0VCR2, Q2TA35, Q3MHM8, Q58CU5, Q5HZE8, Q5M8E3, Q5RCC0, Q60HF7, Q64448, Q6WGK6, Q7TNI2, Q866T7, Q8BSD4, Q8CFA6, Q8N6S5, Q8R0I4

Diamond homologs: A5PLF5, A5PLH4, P61228, Q07FZ2, Q2TA35, Q566R2, Q5M8E3, Q5RCC0, Q5XGR4, Q6DE06, Q6DHN3, Q8BJ83, Q8R0I4, Q95PJ8, Q95QZ5, Q99MB3, Q9BRN9, Q9BX73, Q9BX74, Q9U4H5, Q9VY86, Q9W2H1, Q9GPR3

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	15
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1603 predictions. Top by Δscore:

Variant	Effect	Δscore
1:61709321:GTAC:G	donor_loss	1.0000
1:61709322:TACT:T	donor_loss	1.0000
1:61709323:AC:A	donor_loss	1.0000
1:61709324:CTT:C	donor_loss	1.0000
1:61709325:TTACA:T	donor_loss	1.0000
1:61709326:T:TC	donor_loss	1.0000
1:61709327:A:AC	donor_gain	1.0000
1:61709328:C:A	donor_loss	1.0000
1:61709328:C:CC	donor_gain	1.0000
1:61709328:CA:C	donor_gain	1.0000
1:61709328:CACA:C	donor_gain	1.0000
1:61709328:CACAT:C	donor_gain	1.0000
1:61709433:GGAAA:G	acceptor_gain	1.0000
1:61709434:GAAA:G	acceptor_gain	1.0000
1:61709435:AAA:A	acceptor_gain	1.0000
1:61709436:AA:A	acceptor_gain	1.0000
1:61709438:C:CC	acceptor_gain	1.0000
1:61723785:A:C	acceptor_gain	1.0000
1:61683482:AGT:A	donor_gain	0.9900
1:61683543:CAAT:C	acceptor_gain	0.9900
1:61701023:TTT:T	acceptor_gain	0.9900
1:61701026:C:CC	acceptor_gain	0.9900
1:61709320:TGTAC:T	donor_loss	0.9900
1:61709445:C:CT	acceptor_gain	0.9900
1:61709446:A:T	acceptor_gain	0.9900
1:61723775:T:C	acceptor_gain	0.9900
1:61723775:T:TC	acceptor_gain	0.9900
1:61723781:A:AC	acceptor_gain	0.9900
1:61723781:A:C	acceptor_gain	0.9900
1:61723783:A:C	acceptor_gain	0.9900

AlphaMissense

1329 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:61700963:T:A	D137V	1.000
1:61700969:C:T	G135E	1.000
1:61694718:A:C	D164E	0.999
1:61694718:A:T	D164E	0.999
1:61694719:T:A	D164V	0.999
1:61694719:T:C	D164G	0.999
1:61694719:T:G	D164A	0.999
1:61694720:C:G	D164H	0.999
1:61694727:G:C	S161R	0.999
1:61694727:G:T	S161R	0.999
1:61694729:T:G	S161R	0.999
1:61694737:C:T	G158E	0.999
1:61694746:C:T	G155E	0.999
1:61694747:C:G	G155R	0.999
1:61694747:C:T	G155R	0.999
1:61694756:A:G	C152R	0.999
1:61694770:C:T	G147D	0.999
1:61700934:C:G	G147R	0.999
1:61700948:C:A	G142V	0.999
1:61700948:C:T	G142E	0.999
1:61700951:A:G	L141P	0.999
1:61700955:A:C	Y140D	0.999
1:61700960:C:G	R138P	0.999
1:61700963:T:G	D137A	0.999
1:61700964:C:A	D137Y	0.999
1:61700969:C:A	G135V	0.999
1:61700970:C:G	G135R	0.999
1:61700970:C:T	G135R	0.999
1:61700976:A:G	W133R	0.999
1:61700976:A:T	W133R	0.999

dbSNP variants (sampled 300 via entrez): RS1000037178 (1:61695402 G>C), RS1000121072 (1:61685056 C>T), RS1000172170 (1:61703108 A>T), RS1000398432 (1:61691876 C>G), RS1000422467 (1:61698241 A>G), RS1000479548 (1:61722025 T>C), RS1000519272 (1:61689390 G>A,T), RS1000539120 (1:61726835 T>C), RS1000743627 (1:61709482 A>G), RS1000759058 (1:61689094 A>C), RS1000785618 (1:61699804 CTTAG>C), RS1000857393 (1:61698541 A>G), RS1000944063 (1:61714573 T>C,G), RS1000953980 (1:61714813 C>T), RS1001012729 (1:61722365 T>TA)

Disease associations

OMIM: gene MIM:610080 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004031_11	QT interval (sulfonylurea treatment interaction)	8.000000e-07
GCST004032_10	JT interval (sulfonylurea treatment interaction)	2.000000e-08
GCST007008_2	Cerebrospinal fluid p-tau levels	7.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0007922	response to sulfonylurea
EFO:0007885	JT interval
EFO:0004763	p-tau measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression	3
Smoke	decreases expression	2
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
bisphenol A	affects cotreatment, increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
ICG 001	increases expression	1
bisphenol S	decreases methylation	1
Decitabine	affects expression	1
Air Pollutants	decreases expression, increases abundance	1
Arsenic	affects methylation	1
Cisplatin	affects expression	1
Dexamethasone	affects cotreatment, increases expression	1
Diethylstilbestrol	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1
Mercury	increases expression	1
Sarin	increases expression	1
Selenium	decreases expression	1
Vincristine	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
Uranium Compounds	increases expression	1
Lactic Acid	decreases expression	1
Chlorodiphenyl (54% Chlorine)	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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