TM2D3

Summary

TM2D3 (TM2 domain containing 3, HGNC:24128) is a protein-coding gene on chromosome 15q26.3, encoding TM2 domain-containing protein 3 (Q9BRN9). Probable positive regulator of Notch signaling.

The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. Several alternatively spliced transcript variants of this gene are described but the full length nature of some variants has not been determined. Multiple polyadenylation sites have been found in this gene.

Source: NCBI Gene 80213 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 45 total — 1 likely-pathogenic
• Phenotypes (HPO): 91
• MANE Select transcript: NM_078474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24128
Approved symbol	TM2D3
Name	TM2 domain containing 3
Location	15q26.3
Locus type	gene with protein product
Status	Approved
Aliases	BLP2, FLJ22604
Ensembl gene	ENSG00000184277
Ensembl biotype	protein_coding
OMIM	610014
Entrez	80213

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000333202, ENST00000347970, ENST00000428002, ENST00000558129, ENST00000558677, ENST00000559024, ENST00000559107, ENST00000559891, ENST00000560013, ENST00000560212, ENST00000560390, ENST00000560883, ENST00000560910, ENST00000561356, ENST00000561373, ENST00000619579, ENST00000896613, ENST00000922193

RefSeq mRNA: 4 — MANE Select: NM_078474 NM_001307960, NM_001308026, NM_025141, NM_078474

CCDS: CCDS10392, CCDS10393, CCDS76795, CCDS76796

Canonical transcript exons

ENST00000333202 — 6 exons

Exon	Start	End
ENSE00001838012	101652271	101652381
ENSE00003459003	101646725	101646899
ENSE00003504940	101645087	101645162
ENSE00003506251	101651696	101651773
ENSE00003669357	101641848	101642644
ENSE00003692652	101650004	101650161

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.64.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2235 / max 214.5342, expressed in 1817 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
151842	22.9736	1813
151840	3.1336	1192
151841	0.5136	245
151838	0.2321	79
151839	0.1647	62
151835	0.1498	34
151837	0.0561	35

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.64	gold quality
oocyte	CL:0000023	98.86	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.76	gold quality
orbitofrontal cortex	UBERON:0004167	98.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	98.55	gold quality
middle temporal gyrus	UBERON:0002771	98.50	gold quality
tibia	UBERON:0000979	98.49	gold quality
postcentral gyrus	UBERON:0002581	97.54	gold quality
germinal epithelium of ovary	UBERON:0001304	97.52	gold quality
parietal lobe	UBERON:0001872	97.46	gold quality
CA1 field of hippocampus	UBERON:0003881	97.41	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.39	gold quality
superior vestibular nucleus	UBERON:0007227	97.38	gold quality
medial globus pallidus	UBERON:0002477	97.32	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.22	gold quality
hypothalamus	UBERON:0001898	97.18	gold quality
entorhinal cortex	UBERON:0002728	97.18	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.18	gold quality
superior frontal gyrus	UBERON:0002661	97.17	gold quality
pons	UBERON:0000988	97.16	gold quality
substantia nigra pars compacta	UBERON:0001965	97.06	gold quality
globus pallidus	UBERON:0001875	97.00	gold quality
adult organism	UBERON:0007023	96.97	gold quality
buccal mucosa cell	CL:0002336	96.91	gold quality
tendon of biceps brachii	UBERON:0008188	96.90	gold quality
parietal pleura	UBERON:0002400	96.86	gold quality
cerebral cortex	UBERON:0000956	96.80	gold quality
prefrontal cortex	UBERON:0000451	96.75	gold quality
cortical plate	UBERON:0005343	96.68	gold quality
pleura	UBERON:0000977	96.66	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.71
E-CURD-112	no	2.67

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting TM2D3, 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-1277-5P	100.00	73.95	5056
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-548D-3P	99.87	70.67	4362
HSA-MIR-548BB-3P	99.86	70.58	4354
HSA-MIR-548AC	99.84	70.77	4351
HSA-MIR-548H-3P	99.84	70.80	4349
HSA-MIR-548Z	99.84	70.80	4349
HSA-MIR-323A-3P	99.79	70.30	1739
HSA-MIR-200A-5P	99.76	69.10	949
HSA-MIR-200B-5P	99.76	69.05	948
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-4470	99.66	69.35	1767
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-12122	99.56	69.33	1672
HSA-MIR-17-3P	99.55	66.77	1311
HSA-MIR-4643	99.49	67.63	1791
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-5683	99.36	68.59	2083

Literature-anchored findings (GeneRIF, showing 3)

• Our approach yielded 26 candidate genes differentially expressed between patients (Osteoarthritis) and controls. BLP2 and CIAS1 seem to be trans-regulated, as the absence of allelic expression imbalances suggests. (PMID:16642435)
• Our results establish a rare TM2D3 variant in association with late-onset Alzheimer’s disease susceptibility, and together with prior work suggests possible links to the beta-amyloid cascade (PMID:27764101)
• These findings indicated that the TT genotype and T allele frequencies of TM2D3 rs675436 were associated with an increased risk of Epstein-Barr virus-associated gastric carcinoma, while allele A or G of FGFR2 rs755793 had no effect on the occurrence of Epstein-Barr virus-associated tumors in Chinese Han population. (PMID:29446487)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tm2d3	ENSDARG00000076618
mus_musculus	Tm2d3	ENSMUSG00000078681
rattus_norvegicus	Tm2d3	ENSRNOG00000011290
drosophila_melanogaster	amx	FBGN0000077
caenorhabditis_elegans	C41D11.9	WBGENE00016567

Paralogs (2): TM2D1 (ENSG00000162604), TM2D2 (ENSG00000169490)

Protein

Protein identifiers

TM2 domain-containing protein 3 — Q9BRN9 (reviewed: Q9BRN9)

Alternative names: Beta-amyloid-binding protein-like protein 2

All UniProt accessions (7): B3KT51, E7EPS7, Q9BRN9, H0YM84, H0YNF6, H0YNS4, H3BSX6

UniProt curated annotations — full annotation on UniProt →

Function. Probable positive regulator of Notch signaling.

Subcellular location. Membrane.

Tissue specificity. Widely expressed.

Disease relevance. Alzheimer disease (AD) [MIM:104300] Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid deposits. The major constituents of these plaques are neurotoxic amyloid-beta protein 40 and amyloid-beta protein 42, that are produced by the proteolysis of the transmembrane APP protein. The cytotoxic C-terminal fragments (CTFs) and the caspase-cleaved products, such as C31, are also implicated in neuronal death. Disease susceptibility may be associated with variants affecting the gene represented in this entry.

Similarity. Belongs to the TM2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BRN9-1	1	yes
Q9BRN9-2	2

RefSeq proteins (4): NP_001294889, NP_001294955, NP_079417, NP_510883* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF05154

UniProt features (17 total): glycosylation site 6, topological domain 3, transmembrane region 2, signal peptide 1, chain 1, splice variant 1, sequence variant 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRN9-F1	80.45	0.63

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 (6): 140, 157, 169, 179, 87, 122

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 131 (showing top): MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_POSITIVE_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, AAAYRNCTG_UNKNOWN, GOBP_CELL_CELL_SIGNALING, NIKOLSKY_BREAST_CANCER_15Q26_AMPLICON, GOBP_REGULATION_OF_NOTCH_SIGNALING_PATHWAY, BASAKI_YBX1_TARGETS_DN, NRF2_01, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, GOBP_CELL_FATE_COMMITMENT, MILI_PSEUDOPODIA_CHEMOTAXIS_DN, OSMAN_BLADDER_CANCER_DN, ATGTACA_MIR493, BLALOCK_ALZHEIMERS_DISEASE_DN, KIM_WT1_TARGETS_DN

GO Biological Process (2): positive regulation of Notch signaling pathway (GO:0045747), lateral inhibition (GO:0046331)

GO Molecular Function (0):

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

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Notch signaling pathway	1
regulation of Notch signaling pathway	1
positive regulation of signal transduction	1
cell-cell signaling involved in cell fate commitment	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

548 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TM2D3	NME8	Q8N427	695
TM2D3	TARS3	A2RTX5	680
TM2D3	LRCH1	Q9Y2L9	648
TM2D3	NHLRC2	Q8NBF2	625
TM2D3	OR4F15	Q8NGB8	599
TM2D3	TNFAIP6	P98066	588
TM2D3	A0A590UK56	A0A590UK56	587
TM2D3	SNRPA1	P09661	572
TM2D3	RHOB	P01121	554
TM2D3	LPAR1	P78351	549
TM2D3	LARP6	Q9BRS8	514
TM2D3	FRZB	Q92765	496
TM2D3	ANKLE2	Q86XL3	474
TM2D3	PCSK6	P29122	461
TM2D3	MCEE	Q96PE7	448

IntAct

42 interactions, top by confidence:

A	B	Type	Score
TM2D3	TXNDC12	psi-mi:“MI:0914”(association)	0.640
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
SLC2A12	METTL15	psi-mi:“MI:0914”(association)	0.530
TSPAN17	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
SPACA1	GOLIM4	psi-mi:“MI:0914”(association)	0.530
LRRC8B	SLC25A17	psi-mi:“MI:0914”(association)	0.530
TXNDC12	TUBG1	psi-mi:“MI:0914”(association)	0.530
TM2D2	TMEM97	psi-mi:“MI:0914”(association)	0.530
IL9R	RETSAT	psi-mi:“MI:0914”(association)	0.530
	PLOD2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
CAV3	SHTN1	psi-mi:“MI:0914”(association)	0.350
BTNL8	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NRG1	HS6ST1	psi-mi:“MI:0914”(association)	0.350
TM2D3	DDX39A	psi-mi:“MI:0914”(association)	0.350
TNF	NRP1	psi-mi:“MI:0914”(association)	0.350
COMMD6	VPS26C	psi-mi:“MI:0914”(association)	0.350
	PLSCR1	psi-mi:“MI:0914”(association)	0.350
CD3E	HLA-A	psi-mi:“MI:0914”(association)	0.350
CANX	HLA-A	psi-mi:“MI:0914”(association)	0.350
PTH2R	METTL15	psi-mi:“MI:0914”(association)	0.350
IGFL3	CBX4	psi-mi:“MI:0914”(association)	0.350
TMEM128	PLSCR1	psi-mi:“MI:0914”(association)	0.350
LDAF1	SLC19A2	psi-mi:“MI:0914”(association)	0.350
TM2D3	SEMG1	psi-mi:“MI:0914”(association)	0.350

BioGRID (118): TM2D3 (Affinity Capture-MS), C17orf80 (Affinity Capture-MS), OAF (Affinity Capture-MS), CLSTN1 (Affinity Capture-MS), SPCS2 (Affinity Capture-MS), DDX39A (Affinity Capture-MS), MTFP1 (Affinity Capture-MS), NR2F2 (Affinity Capture-MS), SPCS1 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS), TM2D3 (Affinity Capture-MS)

ESM2 similar proteins: A0A023FBW4, A0A023FBW7, A0A023FDY8, A0A023FF81, A0A023FFB5, A0A023FFD0, A0A023FT45, A0A023G6B6, A0A023G9N9, A0A0C9S461, A0A0K8R374, A0A0K8R5I2, A0A0K8R726, A0A0K8RCU3, A0A0K8RDJ1, A0A141SFN4, A0A141SFN5, A0A146B485, A0A146B5A4, A0A158RFT4, C0HKG1, E2J6T4, F5HC14, F6KSY1, G3MIX6, G3MJ83, L7M8Z8, L7MB58, L7MC74, P03218, P0C8E7, P0C8E9, P0DQG5, P0DQV0, P16739, P17146, P18535, P22650, P22651, P33500

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

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	35
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3370441	NM_078474.3(TM2D3):c.677C>T (p.Thr226Met)	Likely pathogenic

SpliceAI

979 predictions. Top by Δscore:

Variant	Effect	Δscore
15:101642643:TG:T	acceptor_gain	1.0000
15:101642645:C:CC	acceptor_gain	1.0000
15:101645081:GCTTA:G	donor_loss	1.0000
15:101645082:CTTAC:C	donor_loss	1.0000
15:101645084:TACCT:T	donor_loss	1.0000
15:101645085:ACC:A	donor_loss	1.0000
15:101645086:C:G	donor_loss	1.0000
15:101645160:TACC:T	acceptor_loss	1.0000
15:101645161:ACCT:A	acceptor_loss	1.0000
15:101645163:C:CG	acceptor_loss	1.0000
15:101645164:T:C	acceptor_gain	1.0000
15:101645164:T:TC	acceptor_gain	1.0000
15:101646899:CCTA:C	acceptor_gain	1.0000
15:101650002:A:AC	donor_gain	1.0000
15:101650003:C:CC	donor_gain	1.0000
15:101650158:CTTT:C	acceptor_gain	1.0000
15:101642640:TGATG:T	acceptor_gain	0.9900
15:101642642:ATGCT:A	acceptor_loss	0.9900
15:101642644:GC:G	acceptor_loss	0.9900
15:101642645:C:G	acceptor_loss	0.9900
15:101642646:T:G	acceptor_loss	0.9900
15:101645085:A:AC	donor_gain	0.9900
15:101645086:C:CC	donor_gain	0.9900
15:101645162:CCT:C	acceptor_gain	0.9900
15:101645163:C:CC	acceptor_gain	0.9900
15:101645897:TTAAG:T	donor_gain	0.9900
15:101645919:C:CT	donor_gain	0.9900
15:101646723:A:AC	donor_gain	0.9900
15:101646724:C:CC	donor_gain	0.9900
15:101646899:CCTAT:C	acceptor_loss	0.9900

AlphaMissense

1603 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:101642537:T:A	D229V	1.000
15:101642537:T:C	D229G	1.000
15:101642537:T:G	D229A	1.000
15:101642550:A:G	W225R	1.000
15:101642550:A:T	W225R	1.000
15:101642569:G:C	S218R	1.000
15:101642569:G:T	S218R	1.000
15:101642571:T:G	S218R	1.000
15:101642578:C:A	K215N	1.000
15:101642578:C:G	K215N	1.000
15:101642624:C:T	G200E	1.000
15:101642528:A:G	L232P	0.999
15:101642536:G:C	D229E	0.999
15:101642536:G:T	D229E	0.999
15:101642538:C:A	D229Y	0.999
15:101642538:C:G	D229H	0.999
15:101642538:C:T	D229N	0.999
15:101642548:C:A	W225C	0.999
15:101642548:C:G	W225C	0.999
15:101642555:C:T	G223E	0.999
15:101642564:C:T	G220D	0.999
15:101642570:C:T	S218N	0.999
15:101642576:A:G	L216P	0.999
15:101642576:A:T	L216H	0.999
15:101642580:T:C	K215E	0.999
15:101642582:C:T	G214D	0.999
15:101642589:C:G	G212R	0.999
15:101642596:C:A	W209C	0.999
15:101642596:C:G	W209C	0.999
15:101642606:A:G	L206P	0.999

dbSNP variants (sampled 300 via entrez): RS1000169868 (15:101652474 C>T), RS1000228998 (15:101636975 A>G), RS1000245959 (15:101633978 T>C), RS1000315610 (15:101650706 T>C), RS1000530524 (15:101635304 A>G,T), RS1000555975 (15:101652008 C>T), RS1000561511 (15:101635598 C>T), RS1000827214 (15:101646476 A>G), RS1001027092 (15:101640943 G>A), RS1001499074 (15:101641133 C>G,T), RS1001601281 (15:101642061 C>A,T), RS1001654254 (15:101636232 T>C), RS1001752908 (15:101646759 G>C,T), RS1001914428 (15:101634584 A>G), RS1001924636 (15:101641670 A>G,T)

Disease associations

OMIM: gene MIM:610014 | disease phenotypes: MIM:621379

GenCC curated gene-disease

Mondo (1): neurocardiorenal malformation syndrome (MONDO:0980704)

Orphanet (0):

HPO phenotypes

91 total (30 of 91 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000046	Small scrotum
HP:0000085	Horseshoe kidney
HP:0000160	Narrow mouth
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000307	Pointed chin
HP:0000324	Facial asymmetry
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000444	Convex nasal ridge
HP:0000460	Narrow nose
HP:0000486	Strabismus
HP:0000494	Downslanted palpebral fissures
HP:0000540	Hypermetropia
HP:0000618	Blindness
HP:0000680	Delayed eruption of primary teeth
HP:0000691	Microdontia
HP:0000713	Agitation
HP:0000718	Aggressive behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000954	Single transverse palmar crease
HP:0000958	Dry skin

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010173_109	Triglyceride levels	1.000000e-12
GCST011679_3	Depression in multiple sclerosis (pre-diagnosis)	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression	2
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
potassium chromate(VI)	decreases expression	1
beta-methylcholine	affects expression	1
Bortezomib	increases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benzo(a)pyrene	decreases methylation	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Formaldehyde	decreases expression	1
Lead	affects expression	1
Phenylmercuric Acetate	increases expression	1
Quercetin	decreases expression	1
Silver	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Cyclosporine	increases expression	1
Copper Sulfate	decreases expression	1
Vitamin K 3	affects expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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