TMIGD2

Summary

TMIGD2 (transmembrane and immunoglobulin domain containing 2, HGNC:28324) is a protein-coding gene on chromosome 19p13.3, encoding Transmembrane and immunoglobulin domain-containing protein 2 (Q96BF3). Plays a role in cell-cell interaction, cell migration, and angiogenesis.

Enables coreceptor activity. Involved in positive regulation of T cell activation; positive regulation of angiogenesis; and positive regulation of cytokine production. Predicted to be located in plasma membrane. Predicted to be active in neuron projection.

Source: NCBI Gene 126259 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 64 total
• MANE Select transcript: NM_001169126

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28324
Approved symbol	TMIGD2
Name	transmembrane and immunoglobulin domain containing 2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC23244, CD28H, IGPR-1
Ensembl gene	ENSG00000167664
Ensembl biotype	protein_coding
OMIM	614715
Entrez	126259

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000301272, ENST00000595645, ENST00000600114, ENST00000600349, ENST00000932938

RefSeq mRNA: 4 — MANE Select: NM_001169126 NM_001169126, NM_001308232, NM_001395549, NM_144615

CCDS: CCDS12126, CCDS59334, CCDS77217

Canonical transcript exons

ENST00000595645 — 5 exons

Exon	Start	End
ENSE00001115432	4297986	4298345
ENSE00001115435	4294775	4294816
ENSE00001208238	4292227	4292885
ENSE00002976140	4302340	4302389
ENSE00003225522	4294579	4294680

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 94.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5905 / max 55.7967, expressed in 118 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178421	0.5757	116
178420	0.0147	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	94.25	silver quality
vena cava	UBERON:0004087	94.23	gold quality
buccal mucosa cell	CL:0002336	93.91	gold quality
cardiac muscle of right atrium	UBERON:0003379	93.81	silver quality
cerebellar vermis	UBERON:0004720	93.50	silver quality
myocardium	UBERON:0002349	93.22	silver quality
thymus	UBERON:0002370	92.63	gold quality
nasal cavity epithelium	UBERON:0005384	92.30	silver quality
superficial temporal artery	UBERON:0001614	92.10	gold quality
upper arm skin	UBERON:0004263	91.89	silver quality
pancreatic ductal cell	CL:0002079	91.71	silver quality
cardia of stomach	UBERON:0001162	91.31	gold quality
kidney epithelium	UBERON:0004819	91.15	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	90.97	silver quality
body of tongue	UBERON:0011876	90.69	gold quality
gingival epithelium	UBERON:0001949	90.33	silver quality
pylorus	UBERON:0001166	90.22	gold quality
ventral tegmental area	UBERON:0002691	89.98	gold quality
tongue	UBERON:0001723	89.86	silver quality
inferior vagus X ganglion	UBERON:0005363	89.83	gold quality
tendon of biceps brachii	UBERON:0008188	89.70	silver quality
subthalamic nucleus	UBERON:0001906	89.64	gold quality
pharyngeal mucosa	UBERON:0000355	89.59	silver quality
lateral globus pallidus	UBERON:0002476	89.44	gold quality
vastus lateralis	UBERON:0001379	89.30	silver quality
superior surface of tongue	UBERON:0007371	89.26	gold quality
nipple	UBERON:0002030	89.08	silver quality
trachea	UBERON:0003126	88.90	silver quality
mucosa of paranasal sinus	UBERON:0005030	88.78	silver quality
dorsal plus ventral thalamus	UBERON:0001897	88.75	gold quality

Single-cell (SCXA)

Detected in 12 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-MTAB-6701	yes	102.67
E-MTAB-6678	yes	25.94
E-CURD-88	yes	24.75
E-CURD-122	yes	18.90
E-HCAD-9	yes	18.36
E-CURD-46	yes	18.11
E-MTAB-8410	yes	14.35
E-HCAD-10	yes	9.27
E-CURD-112	yes	9.20
E-ANND-3	yes	9.00
E-HCAD-1	yes	7.54
E-GEOD-70580	no	388.95

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting TMIGD2, 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-185-3P	99.95	67.01	1743
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6504-3P	99.17	69.31	2891
HSA-MIR-10399-5P	99.17	69.87	2610
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-615-5P	98.10	63.76	591
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-6090	91.01	62.65	222

Literature-anchored findings (GeneRIF, showing 13)

• Authors identified IGPR-1, also called TMIGD2, gene as a novel cell adhesion receptor that is expressed in various human organs and tissues, mainly in cells with epithelium and endothelium origins. (PMID:22419821)
• B7 homologue 5 (B7-H5), was identified as a specific ligand for CD28H. (PMID:23784006)
• The authors demonstrate that IGPR-1 is localized to endothelial adherens junctions and, through trans-homophilic dimerization, regulates endothelial cell-cell adhesion and barrier function. (PMID:27838321)
• B7-H5/CD28H is a co-stimulatory signal pathway, and expression of B7-H5 is associated with improved disease prognosis in patients with pancreatic cancer. (PMID:30548441)
• High TMIGD2 expression levels in oral squamous cell carcinoma cells indicate poor prognosis. TMIGD2 expression inversely correlated with the TIM3, LAG3, and B7H3 levels. (PMID:31089395)
• Findings indicate that IGPR-1 is an important player in endothelial cell mechanosensing, insights that have important implications for the pathogenesis of common maladies, including ischemic heart diseases and inflammation. (PMID:31341021)
• Overexpression of B7H5/CD28H is associated with worse survival in human gastric cancer. (PMID:31883303)
• VISTA protein (B7-H5) is a ligand for transmembrane and immunoglobulin domain containing 2 protein (CD28H) and is widely expressed in tumor cells. B7-H5 expression is closely related to the prognosis of the tumor [Review]. (PMID:31901178)
• Cell adhesion molecule IGPR-1 activates AMPK connecting cell adhesion to autophagy. (PMID:32978258)
• NEDD4 regulates ubiquitination and stability of the cell adhesion molecule IGPR-1 via lysosomal pathway. (PMID:33962630)
• HHLA2 Activates the JAK/STAT Signaling Pathway by Binding to TMIGD2 in Hepatocellular Carcinoma Cells. (PMID:35175496)
• KIR3DL3-HHLA2 and TMIGD2-HHLA2 pathways: The dual role of HHLA2 in immune responses and its potential therapeutic approach for cancer immunotherapy. (PMID:35933091)
• TMIGD2 as a potential therapeutic target in glioma patients. (PMID:37261362)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Transmembrane and immunoglobulin domain-containing protein 2 — Q96BF3 (reviewed: Q96BF3)

Alternative names: CD28 homolog, Immunoglobulin and proline-rich receptor 1

All UniProt accessions (3): A0A0B4J2A9, A0A0B4J2B0, Q96BF3

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in cell-cell interaction, cell migration, and angiogenesis. Through interaction with HHLA2, costimulates T-cells in the context of TCR-mediated activation. Enhances T-cell proliferation and cytokine production via an AKT-dependent signaling cascade.

Subunit / interactions. May form homophilic interactions that could regulate cell-cell interaction. Interacts with CACNB2, DST, MIA and NCKIPSD. Interacts with HHLA2.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed, mainly by epithelial and endothelial cells, including bronchial epithelial cells of lung, breast glandular and lobular epithelia cells, urothelium of the bladder, skin epidermis, epithelium of gastrointestinal, rectum, endometrial glands of the uterus, ureter, fallopian tube epithelium, colonic epithelium, small bowl epithelium, stomach epithelium, including both chief and parietal cells, trophoblastic epithelium of placenta, and pancreatic acinar cells (at protein level). Consistently expressed in veins and arteries (at protein level). Not detected in thyroid, cerebellum, cerebral cortex and thymus (at protein level). Expressed in lymphoid organs, with highest levels in thymus, spleen, peripheral blood lymphocytes and liver. In the thymus, expressed in CD4+ and CD8+ single- and double-positive cells, but not in immature CD4- and CD8- double-negative cells (at protein level). In peripheral blood mononuclear cells, highly expressed on CD56+ or CD16+ natural killer cells and CD3+ T-cells(at protein level). Not detected on B-cells(at protein level). Expressed in tonsils (at protein level).

Post-translational modifications. N-glycosylated.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96BF3-1	1	yes
Q96BF3-2	2

RefSeq proteins (4): NP_001162597, NP_001295161, NP_001382478, NP_653216 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily

Pfam: PF07686

UniProt features (23 total): modified residue 3, glycosylation site 3, mutagenesis site 3, compositionally biased region 3, sequence variant 2, topological domain 2, signal peptide 1, chain 1, disulfide bond 1, splice variant 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96BF3-F1	68.95	0.35

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 (3): 192, 220, 222

Disulfide bonds (1): 44–112

Glycosylation sites (3): 73, 105, 127

Mutagenesis-validated functional residues (3):

Position	Phenotype
192	partial loss of phosphorylation; when associated with f-197. complete loss of phosphorylation; when associated with f-22
197	partial loss of phosphorylation; when associated with f-192 or with f-222.
222	partial loss of phosphorylation; when tested individually or when associated with f-197. complete loss of phosphorylatio

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 83 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GOBP_LYMPHOCYTE_COSTIMULATION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_CELL_CELL_ADHESION, GOBP_LEUKOCYTE_PROLIFERATION, GOBP_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, GOBP_BLOOD_VESSEL_MORPHOGENESIS, GOBP_POSITIVE_REGULATION_OF_ACTIVATED_T_CELL_PROLIFERATION, GOBP_LEUKOCYTE_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_CELL_CELL_ADHESION

GO Biological Process (4): positive regulation of cytokine production (GO:0001819), T cell costimulation (GO:0031295), positive regulation of activated T cell proliferation (GO:0042104), positive regulation of angiogenesis (GO:0045766)

GO Molecular Function (2): coreceptor activity (GO:0015026), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), neuron projection (GO:0043005), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
lymphocyte costimulation	1
positive regulation of T cell activation	1
positive regulation of T cell proliferation	1
regulation of activated T cell proliferation	1
activated T cell proliferation	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
signaling receptor activity	1
binding	1
membrane	1
cell periphery	1
plasma membrane bounded cell projection	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1269 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMIGD2	HHLA2	Q9UM44	923
TMIGD2	CTLA4	P16410	778
TMIGD2	VTCN1	Q7Z7D3	755
TMIGD2	CD80	P33681	728
TMIGD2	VSIR	Q9H7M9	728
TMIGD2	CD28	P10747	610
TMIGD2	A0A087X1L8	A0A087X1L8	593
TMIGD2	ICOSLG	O75144	592
TMIGD2	CD276	Q5ZPR3	581
TMIGD2	PDCD1LG2	Q9BQ51	581
TMIGD2	ICOS	Q9Y6W8	580
TMIGD2	CD86	P42081	570
TMIGD2	TNFSF14	O43557	511
TMIGD2	BTLA	Q7Z6A9	510
TMIGD2	PDCD1	Q15116	507
TMIGD2	CD274	Q9NZQ7	507

IntAct

3 interactions, top by confidence:

A	B	Type	Score
HHLA2	TMIGD2	psi-mi:“MI:0915”(physical association)	0.400
TMIGD2	HHLA2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (4): TMIGD2 (Biochemical Activity), TMIGD2 (Reconstituted Complex), NEDD4 (Affinity Capture-Western), TMIGD2 (Affinity Capture-Luminescence)

ESM2 similar proteins: A2A7V7, A2TGX5, A5D7B2, A8K4G0, D3ZQX2, D7PDD4, O15389, O43699, O95866, O95944, P0C1X9, P12318, P20138, P43626, Q02242, Q13291, Q1ERP8, Q2YFS3, Q3LRV9, Q3U497, Q566E6, Q60513, Q6DN72, Q6MG59, Q6SJQ0, Q6SJQ5, Q6SJQ7, Q6UXG3, Q7TSN2, Q80ZE3, Q86YW5, Q8BG84, Q8K558, Q8N109, Q8NHJ6, Q8NHK3, Q8R4Y0, Q8TDQ1, Q8VCH2, Q91Y57

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
AKT1	“up-regulates activity”	TMIGD2	phosphorylation
IKBKB	“up-regulates activity”	TMIGD2	phosphorylation
TMIGD2	“up-regulates activity”	AMPK	phosphorylation
Mir-615-5p	“down-regulates quantity by destabilization”	TMIGD2	“post transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	44
Likely benign	9
Benign	5

Top pathogenic / likely-pathogenic (0)

SpliceAI

524 predictions. Top by Δscore:

Variant	Effect	Δscore
19:4294771:TCAC:T	donor_loss	1.0000
19:4294772:CACCT:C	donor_loss	1.0000
19:4294774:C:CG	donor_loss	1.0000
19:4294817:C:CC	acceptor_gain	1.0000
19:4294773:A:AC	donor_gain	0.9900
19:4294774:C:CC	donor_gain	0.9900
19:4294813:TCAT:T	acceptor_gain	0.9900
19:4294814:CAT:C	acceptor_gain	0.9900
19:4294814:CATC:C	acceptor_gain	0.9900
19:4294815:AT:A	acceptor_gain	0.9900
19:4294816:TC:T	acceptor_loss	0.9900
19:4294817:CTG:C	acceptor_loss	0.9900
19:4294818:T:A	acceptor_loss	0.9900
19:4297980:CCGTA:C	donor_loss	0.9900
19:4297981:CGTA:C	donor_loss	0.9900
19:4297982:GTAC:G	donor_loss	0.9900
19:4297983:TA:T	donor_loss	0.9900
19:4297984:ACCTG:A	donor_loss	0.9900
19:4297985:C:CA	donor_loss	0.9900
19:4292886:C:CG	acceptor_loss	0.9800
19:4292887:T:C	acceptor_loss	0.9800
19:4294685:G:C	acceptor_gain	0.9800
19:4292882:TTTC:T	acceptor_gain	0.9700
19:4292886:C:CC	acceptor_gain	0.9700
19:4294679:TCCT:T	acceptor_loss	0.9700
19:4294680:CCTG:C	acceptor_loss	0.9700
19:4294681:C:CA	acceptor_loss	0.9700
19:4294681:C:CC	acceptor_gain	0.9700
19:4294682:T:A	acceptor_loss	0.9700
19:4294812:GTCAT:G	acceptor_gain	0.9700

AlphaMissense

1801 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:4298215:C:A	W59C	0.995
19:4298215:C:G	W59C	0.995
19:4298217:A:G	W59R	0.992
19:4298217:A:T	W59R	0.992
19:4298125:C:A	W89C	0.991
19:4298125:C:G	W89C	0.991
19:4298057:C:G	C112S	0.988
19:4298058:A:G	C112R	0.988
19:4298058:A:T	C112S	0.988
19:4298261:C:G	C44S	0.988
19:4298262:A:G	C44R	0.988
19:4298262:A:T	C44S	0.988
19:4298057:C:T	C112Y	0.986
19:4298056:G:C	C112W	0.985
19:4298236:C:A	W52C	0.984
19:4298236:C:G	W52C	0.984
19:4298228:A:G	L55P	0.983
19:4298102:A:G	L97P	0.980
19:4298216:C:G	W59S	0.979
19:4298261:C:T	C44Y	0.978
19:4298070:C:A	G108W	0.976
19:4298192:C:G	C67S	0.976
19:4298193:A:G	C67R	0.976
19:4298193:A:T	C67S	0.976
19:4298064:A:C	Y110D	0.973
19:4298222:A:T	V57D	0.973
19:4298260:G:C	C44W	0.972
19:4298039:A:G	I118T	0.971
19:4298311:C:A	Q27H	0.971
19:4298311:C:G	Q27H	0.971

dbSNP variants (sampled 300 via entrez): RS1000216130 (19:4295134 G>A), RS1000393430 (19:4300284 T>G), RS1000463355 (19:4298651 G>A), RS1000700299 (19:4301728 G>A,T), RS1000764193 (19:4299685 G>A,T), RS1000769317 (19:4300501 G>A,C), RS1000796682 (19:4299945 T>C), RS1001048562 (19:4292234 T>C), RS1001062694 (19:4291965 A>G,T), RS1001070187 (19:4294289 A>G,T), RS1001383505 (19:4292275 A>G), RS1001452410 (19:4297465 G>A), RS1001481654 (19:4297671 A>G), RS1001680590 (19:4302492 C>A,T), RS1001749407 (19:4292014 G>A)

Disease associations

OMIM: gene MIM:614715 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011800_11	Post-bronchodilator lung function in asthma (FVC)	5.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004312	vital capacity

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

15 total (human), top 15 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
benzo(e)pyrene	increases methylation	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	decreases expression	1
Caffeine	increases phosphorylation	1
Cisplatin	increases expression	1
Dimethyl Sulfoxide	affects expression	1
Methapyrilene	increases methylation	1
Niclosamide	increases expression	1
Sodium Selenite	decreases expression	1
Antirheumatic Agents	increases expression	1
Cadmium Chloride	increases expression	1

Clinical trials (associated diseases)

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