TMEM219

Summary

TMEM219 (transmembrane protein 219, HGNC:25201) is a protein-coding gene on chromosome 16p11.2, encoding Insulin-like growth factor-binding protein 3 receptor (Q86XT9). Cell death receptor specific for IGFBP3, may mediate caspase-8-dependent apoptosis upon ligand binding.

Predicted to be involved in apoptotic process. Predicted to be located in plasma membrane.

Source: NCBI Gene 124446 — RefSeq curated summary.

At a glance

• GWAS associations: 13
• Clinical variants (ClinVar): 56 total — 3 pathogenic
• MANE Select transcript: NM_001083613

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25201
Approved symbol	TMEM219
Name	transmembrane protein 219
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Aliases	IGFBP-3R
Ensembl gene	ENSG00000149932
Ensembl biotype	protein_coding
OMIM	620290
Entrez	124446

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 25 protein_coding, 1 nonsense_mediated_decay

ENST00000279396, ENST00000414689, ENST00000561899, ENST00000566848, ENST00000569445, ENST00000569481, ENST00000570255, ENST00000575829, ENST00000892936, ENST00000892937, ENST00000892938, ENST00000892939, ENST00000892940, ENST00000892941, ENST00000892942, ENST00000892943, ENST00000892944, ENST00000892945, ENST00000892946, ENST00000892947, ENST00000933381, ENST00000933382, ENST00000933383, ENST00000933384, ENST00000958118, ENST00000958119

RefSeq mRNA: 5 — MANE Select: NM_001083613 NM_001083613, NM_001369688, NM_001369689, NM_001369690, NM_194280

CCDS: CCDS42145

Canonical transcript exons

ENST00000279396 — 6 exons

Exon	Start	End
ENSE00000993050	29963400	29963589
ENSE00001110798	29968025	29968254
ENSE00001339426	29963107	29963308
ENSE00001535283	29962079	29962132
ENSE00002589799	29972950	29973048
ENSE00003525982	29971408	29971578

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 98.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.8767 / max 216.9864, expressed in 1819 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
153562	23.3399	1808
153563	5.9610	1750
153567	2.9449	938
153568	0.3677	164
153566	0.1597	39
153564	0.0791	9
153565	0.0244	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right testis	UBERON:0004534	98.83	gold quality
left testis	UBERON:0004533	98.79	gold quality
right uterine tube	UBERON:0001302	98.72	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	98.60	gold quality
mucosa of transverse colon	UBERON:0004991	98.50	gold quality
apex of heart	UBERON:0002098	98.44	gold quality
body of stomach	UBERON:0001161	98.41	gold quality
ileal mucosa	UBERON:0000331	98.34	gold quality
right adrenal gland	UBERON:0001233	98.34	gold quality
right adrenal gland cortex	UBERON:0035827	98.34	gold quality
body of pancreas	UBERON:0001150	98.29	gold quality
left adrenal gland cortex	UBERON:0035825	98.28	gold quality
left adrenal gland	UBERON:0001234	98.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	98.10	gold quality
anterior cingulate cortex	UBERON:0009835	98.03	gold quality
adrenal cortex	UBERON:0001235	97.93	gold quality
metanephros cortex	UBERON:0010533	97.93	gold quality
minor salivary gland	UBERON:0001830	97.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.89	gold quality
transverse colon	UBERON:0001157	97.88	gold quality
amygdala	UBERON:0001876	97.87	gold quality
lower esophagus mucosa	UBERON:0035834	97.87	gold quality
right lung	UBERON:0002167	97.86	gold quality
putamen	UBERON:0001874	97.85	gold quality
nucleus accumbens	UBERON:0001882	97.84	gold quality
gall bladder	UBERON:0002110	97.82	gold quality
granulocyte	CL:0000094	97.81	gold quality
hypothalamus	UBERON:0001898	97.75	gold quality
right frontal lobe	UBERON:0002810	97.75	gold quality
spinal cord	UBERON:0002240	97.74	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	8.55
E-MTAB-6379	no	693.89
E-ENAD-17	no	325.71
E-CURD-112	no	2.47
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

15 targeting TMEM219, 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-4267	99.96	66.53	2368
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-3136-3P	99.57	66.59	781
HSA-MIR-7155-3P	99.57	66.48	794
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-6837-3P	98.42	66.71	1149
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-3622B-3P	96.82	66.36	988

Literature-anchored findings (GeneRIF, showing 3)

• critical role in Chi3l1-induced IL-13Ralpha2 mediated signalling and tissue responses (PMID:27629921)
• The IGFBP3/TMEM219 pathway regulates beta cell homeostasis. (PMID:35115561)
• TMEM219 regulates the transcription factor expression and proliferation of beta cells. (PMID:38318298)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	zgc:158398	ENSDARG00000074226
mus_musculus	Tmem219	ENSMUSG00000060538
rattus_norvegicus	Tmem219	ENSRNOG00000020000

Paralogs (1): TMEM248 (ENSG00000106609)

Protein

Protein identifiers

Insulin-like growth factor-binding protein 3 receptor — Q86XT9 (reviewed: Q86XT9)

Alternative names: Transmembrane protein 219

All UniProt accessions (5): Q86XT9, A0A024R618, H3BML8, I3L2J7, I3L4B3

UniProt curated annotations — full annotation on UniProt →

Function. Cell death receptor specific for IGFBP3, may mediate caspase-8-dependent apoptosis upon ligand binding.

Subunit / interactions. Interacts with IGFBP3. Interacts with CASP8.

Subcellular location. Cell membrane.

Tissue specificity. Widely expressed in normal tissues but suppressed in prostate and breast tumor.

RefSeq proteins (5): NP_001077082, NP_001356617, NP_001356618, NP_001356619, NP_919256 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR039493	TMEM248/TMEM219	Family
IPR039587	TMEM248/TMEM219_dom	Domain

Pfam: PF14940

UniProt features (8 total): glycosylation site 3, topological domain 2, signal peptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XT9-F1	67.34	0.10

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 (3): 73, 101, 167

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803211	TP53 Regulates Transcription of Death Receptors and Ligands

MSigDB gene sets: 105 (showing top): GOBP_INFLAMMATORY_RESPONSE, GOZGIT_ESR1_TARGETS_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, MOLENAAR_TARGETS_OF_CCND1_AND_CDK4_UP, FOSTER_TOLERANT_MACROPHAGE_UP, GOBP_CYTOKINE_PRODUCTION, chr16p11, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_NEGATIVE_REGULATION_OF_DEFENSE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, GOBP_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_POSITIVE_REGULATION_OF_ERK1_AND_ERK2_CASCADE, GOBP_REGULATION_OF_INFLAMMATORY_RESPONSE, GOBP_REGULATION_OF_DEFENSE_RESPONSE

GO Biological Process (1): apoptotic process (GO:0006915)

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

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
TP53 Regulates Transcription of Cell Death Genes	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

560 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM219	IL13RA2	Q14627	782
TMEM219	CHI3L1	P30923	705
TMEM219	IGFBP3	P17936	668
TMEM219	INO80E	Q8NBZ0	668
TMEM219	C16orf54	Q6UWD8	662
TMEM219	KCTD13	Q8WZ19	648
TMEM219	ASPHD1	Q5U4P2	632
TMEM219	HIRIP3	Q9BW71	605
TMEM219	FIMP1	Q96LL3	592
TMEM219	SEZ6L2	Q6UXD5	588
TMEM219	YPEL3	P61236	574
TMEM219	QPRT	Q15274	545
TMEM219	KIF22	Q14807	524
TMEM219	DOC2A	Q14183	522
TMEM219	PAGR1	Q9BTK6	520

IntAct

53 interactions, top by confidence:

A	B	Type	Score
CHI3L1	IL13RA2	psi-mi:“MI:0915”(physical association)	0.800
IL13	IL13RA2	psi-mi:“MI:0915”(physical association)	0.800
IL13RA2	IL13	psi-mi:“MI:0915”(physical association)	0.800
TMEM219	IL13RA2	psi-mi:“MI:0915”(physical association)	0.710
IL13RA2	TMEM219	psi-mi:“MI:0915”(physical association)	0.710
IGFBP3	TMEM219	psi-mi:“MI:0915”(physical association)	0.660
TMEM219	IGFBP3	psi-mi:“MI:0407”(direct interaction)	0.660
TMEM219	IGFBP3	psi-mi:“MI:0915”(physical association)	0.660
MCOLN3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
ZACN	GPAA1	psi-mi:“MI:0914”(association)	0.530
TCTN2	TPST2	psi-mi:“MI:0914”(association)	0.530
CLGN	NPC1	psi-mi:“MI:0914”(association)	0.530
NRN1	SLC1A1	psi-mi:“MI:0914”(association)	0.530
IL13RA2	LGALS3	psi-mi:“MI:0914”(association)	0.500
SHANK1	TMEM219	psi-mi:“MI:0407”(direct interaction)	0.440
	TMEM219	psi-mi:“MI:0915”(physical association)	0.400
CASP8	TMEM219	psi-mi:“MI:0915”(physical association)	0.400
UPK1A	TMEM223	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS), TMEM219 (Affinity Capture-MS)

ESM2 similar proteins: A0A140LIA7, A0A2Y9GDB5, A0JNN2, A6NJJ6, A6QNY1, E1BLZ4, E1C7U0, E9PXB6, O88324, P01586, P06740, P08700, P16772, P20109, P35225, P42203, P51748, Q08648, Q08E62, Q0MUT8, Q13790, Q1HVF6, Q1JQE1, Q28809, Q3KSS3, Q4KM46, Q5EAA5, Q5JTB6, Q5M889, Q5R7E2, Q5U2R2, Q5XIF1, Q63072, Q6P0A1, Q6PDA7, Q6UJB9, Q6UW10, Q7TSF4, Q86XT9, Q8N6T0

Diamond homologs: Q1JQE1, Q86XT9, Q9D123

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 51 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.

GO biological processes:

GO term	Partners	Fold	FDR
monoatomic ion transmembrane transport	5	23.1×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	32
Likely benign	1
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1176676	GRCh37/hg19 16p11.2(chr16:29675050-30200008)x1	Pathogenic
1808476	GRCh37/hg19 16p11.2(chr16:29567296-30240227)x1	Pathogenic
3024604	GRCh37/hg19 16p11.2(chr16:29495010-30200397)x1	Pathogenic

SpliceAI

762 predictions. Top by Δscore:

Variant	Effect	Δscore
16:29963569:G:GT	donor_gain	1.0000
16:29963569:G:T	donor_gain	1.0000
16:29941000:G:GT	donor_gain	0.9900
16:29941016:AG:A	donor_loss	0.9900
16:29941017:GG:G	donor_loss	0.9900
16:29941018:GTAT:G	donor_loss	0.9900
16:29941019:T:G	donor_loss	0.9900
16:29950607:T:G	donor_gain	0.9900
16:29963586:AAAGG:A	donor_loss	0.9900
16:29963587:AAG:A	donor_loss	0.9900
16:29963588:AG:A	donor_loss	0.9900
16:29963589:GGTGA:G	donor_loss	0.9900
16:29963590:GTGAG:G	donor_loss	0.9900
16:29963591:T:A	donor_loss	0.9900
16:29968085:G:GT	donor_gain	0.9900
16:29963305:CCAGG:C	donor_loss	0.9800
16:29963306:CAGG:C	donor_loss	0.9800
16:29963307:AGG:A	donor_loss	0.9800
16:29963308:GGTA:G	donor_loss	0.9800
16:29963309:GT:G	donor_loss	0.9800
16:29963310:T:A	donor_loss	0.9800
16:29963397:CAGGA:C	acceptor_loss	0.9800
16:29963398:A:AC	acceptor_loss	0.9800
16:29963398:A:AG	acceptor_gain	0.9800
16:29963399:G:GC	acceptor_loss	0.9800
16:29963399:G:GG	acceptor_gain	0.9800
16:29963399:GGACT:G	acceptor_gain	0.9800
16:29971396:A:AG	acceptor_gain	0.9800
16:29971397:C:G	acceptor_gain	0.9800
16:29971406:A:AG	acceptor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000050047 (16:29970514 T>C), RS1000106990 (16:29969316 G>GC), RS1000177830 (16:29963944 A>G), RS1000904307 (16:29964451 C>T), RS1000999790 (16:29969097 T>C), RS1001081050 (16:29970681 A>G,T), RS1001345628 (16:29964285 T>C), RS1001453834 (16:29963828 A>G), RS1001537936 (16:29969609 T>TTC), RS1001593646 (16:29969857 A>G), RS1001795296 (16:29963988 C>G,T), RS1001864093 (16:29964095 C>G,T), RS1002400235 (16:29969939 C>G), RS1002406108 (16:29962642 T>C,G), RS1002544151 (16:29971074 GTC>G)

Disease associations

OMIM: gene MIM:620290 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST002539_82	Schizophrenia	5.000000e-11
GCST004521_236	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST004946_142	Schizophrenia	8.000000e-13
GCST006803_23	Schizophrenia	6.000000e-13
GCST007293_15	Body fat distribution (arm fat ratio)	6.000000e-06
GCST007293_81	Body fat distribution (arm fat ratio)	4.000000e-08
GCST007611_22	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7.000000e-09
GCST007710_18	Anxiety/tension (special factor of neuroticism)	5.000000e-09
GCST008295_9	Number of decayed, missing and filled tooth surfaces or use of dentures	2.000000e-09
GCST008306_8	Dentures	4.000000e-08
GCST009600_79	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	4.000000e-11
GCST010703_269	Brain morphology (MOSTest)	4.000000e-13
GCST90020029_566	Waist circumference adjusted for body mass index	3.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0009863	anxiety measurement
EFO:0010078	dentures
EFO:0004346	neuroimaging measurement
EFO:0007789	BMI-adjusted waist circumference

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
Valproic Acid	decreases expression, increases methylation, affects expression	3
arsenite	affects binding, increases reaction	1
2-palmitoylglycerol	increases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Air Pollutants, Occupational	affects expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	increases methylation	1
Doxorubicin	decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Cyclosporine	decreases expression	1
Asbestos, Crocidolite	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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