ITM2A

Summary

ITM2A (integral membrane protein 2A, HGNC:6173) is a protein-coding gene on chromosome Xq21.1, encoding Integral membrane protein 2A (O43736).

This gene encodes a type II membrane protein that belongs to the ITM2 family. Studies in mouse suggest that it may be involved in osteo- and chondrogenic differentiation. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 9452 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 79 total
• MANE Select transcript: NM_004867

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6173
Approved symbol	ITM2A
Name	integral membrane protein 2A
Location	Xq21.1
Locus type	gene with protein product
Status	Approved
Aliases	BRICD2A, E25A
Ensembl gene	ENSG00000078596
Ensembl biotype	protein_coding
OMIM	300222
Entrez	9452

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 4 protein_coding_CDS_not_defined

ENST00000373298, ENST00000434584, ENST00000461357, ENST00000462038, ENST00000469541, ENST00000482194, ENST00000865381, ENST00000865382, ENST00000865383, ENST00000933702, ENST00000933703, ENST00000933704, ENST00000933705, ENST00000933706, ENST00000944508, ENST00000944509

RefSeq mRNA: 2 — MANE Select: NM_004867 NM_001171581, NM_004867

CCDS: CCDS14444, CCDS55455

Canonical transcript exons

ENST00000373298 — 6 exons

Exon	Start	End
ENSE00001862058	79367105	79367334
ENSE00001906918	79360384	79361177
ENSE00003523927	79362942	79363139
ENSE00003530725	79363423	79363554
ENSE00003549191	79361329	79361479
ENSE00003578273	79362581	79362691

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.14.

FANTOM5 (CAGE): breadth broad, TPM avg 26.2639 / max 4706.1203, expressed in 790 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199831	25.1111	782
199830	0.5535	222
199829	0.2157	109
199828	0.1796	60
199823	0.0631	20
199825	0.0593	26
199817	0.0283	13
199824	0.0234	6
199827	0.0217	8
199826	0.0083	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	99.14	gold quality
cartilage tissue	UBERON:0002418	98.72	gold quality
vena cava	UBERON:0004087	98.67	gold quality
subthalamic nucleus	UBERON:0001906	98.29	gold quality
medial globus pallidus	UBERON:0002477	97.94	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.94	gold quality
inferior vagus X ganglion	UBERON:0005363	97.94	gold quality
mammary duct	UBERON:0001765	97.88	gold quality
ventral tegmental area	UBERON:0002691	97.82	gold quality
choroid plexus epithelium	UBERON:0003911	97.78	gold quality
tibia	UBERON:0000979	97.77	gold quality
globus pallidus	UBERON:0001875	97.72	gold quality
dorsal plus ventral thalamus	UBERON:0001897	97.61	gold quality
left ovary	UBERON:0002119	97.57	gold quality
cardiac atrium	UBERON:0002081	97.49	gold quality
right atrium auricular region	UBERON:0006631	97.45	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.43	gold quality
saphenous vein	UBERON:0007318	97.43	gold quality
epithelium of mammary gland	UBERON:0003244	97.42	gold quality
right ovary	UBERON:0002118	97.37	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.25	gold quality
synovial joint	UBERON:0002217	97.19	gold quality
lymph node	UBERON:0000029	97.12	gold quality
putamen	UBERON:0001874	97.11	gold quality
spinal cord	UBERON:0002240	97.06	gold quality
pons	UBERON:0000988	97.03	gold quality
pericardium	UBERON:0002407	97.01	gold quality
midbrain	UBERON:0001891	96.98	gold quality
endothelial cell	CL:0000115	96.94	gold quality
superior vestibular nucleus	UBERON:0007227	96.94	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 26.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	3403.67
E-CURD-79	yes	3168.56
E-HCAD-10	yes	2629.31
E-GEOD-134144	yes	2402.35
E-GEOD-135922	yes	1719.41
E-HCAD-56	yes	1570.11
E-MTAB-6505	yes	1093.57
E-GEOD-139324	yes	1052.07
E-GEOD-124472	yes	976.78
E-GEOD-75688	yes	974.37
E-HCAD-11	yes	640.84
E-MTAB-9801	yes	265.12
E-HCAD-4	yes	150.70
E-MTAB-10287	yes	86.35
E-MTAB-8142	yes	49.93

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting ITM2A, 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-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-5688	99.96	73.23	4504
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3065-3P	99.87	70.25	1407
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-556-3P	99.74	68.75	1203
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-2113	99.58	71.22	1521
HSA-MIR-217-5P	99.49	69.93	1419
HSA-MIR-20A-3P	99.44	69.10	1575
HSA-MIR-1276	99.36	68.18	1642
HSA-MIR-6505-3P	99.34	67.39	1071
HSA-MIR-1244	99.33	68.38	832
HSA-MIR-296-3P	99.21	66.56	474
HSA-MIR-4426	99.17	66.74	1949
HSA-MIR-5701	98.97	69.54	1502

Literature-anchored findings (GeneRIF, showing 12)

• Enhanced ITM2A expression inhibits chondrogenic differentiation of mesenchymal stem cells. (PMID:19541402)
• our results show one of the first links between phenotypic variation in a population sample and an XCI-escaping locus and pinpoint ITM2A as a potential contributor to the sexual dimorphism in height (PMID:24516404)
• ITM2A expression is positively regulated by PKA-CREB signaling and ITM2A expression interferes with autophagic flux by interacting with vacuolar ATPase. (PMID:25951193)
• The upregulated gene with the largest effect size in ankylosing spondylitis was ITM2A, which plays a role in activation of T cells. (Meta-analysis) (PMID:26125709)
• ITM2A is a new biomarker of poor prognosis in ovarian cancer and a novel tumor suppressor that induces cell cycle arrest, acts as a chemosensitizer, and has therapeutic potential for ovarian cancer. (PMID:26691219)
• ITM2A might be a susceptibility gene for Graves disease in the Xq21.1 locus, and environmental factors, such as viral and bacterial infections, probably contribute to GD pathogenesis by interacting with the risk SNP rs3827440 mediating the regulation of ITM2A expression. (PMID:27809695)
• The ITM2A is a novel positive regulator of autophagy through an mTOR-dependent manner. (PMID:31438969)
• GPR174 and ITM2A Gene Polymorphisms rs3827440 and rs5912838 on the X chromosome in Korean Children with Autoimmune Thyroid Disease. (PMID:32727090)
• Downregulation of ITM2A Gene Expression in Macrophages of Patients with Ankylosing Spondylitis. (PMID:34161951)
• Integral Membrane Protein 2A Is a Negative Regulator of Canonical and Non-Canonical Hedgehog Signalling. (PMID:34440772)
• [Study on the Relationship between Integrin 2A and Drug Resistance in Chronic Myeloid Leukemia]. (PMID:36765470)
• Association of ITM2A rs1751094 polymorphism on X chromosome in Korean pediatric patients with autoimmune thyroid disease. (PMID:36988246)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Itm2a	ENSMUSG00000031239
rattus_norvegicus	Itm2a	ENSRNOG00000002365
drosophila_melanogaster	CG3662	FBGN0031285
caenorhabditis_elegans		WBGENE00016106

Paralogs (2): ITM2C (ENSG00000135916), ITM2B (ENSG00000136156)

Protein

Protein identifiers

Integral membrane protein 2A — O43736 (reviewed: O43736)

Alternative names: Protein E25

All UniProt accessions (1): O43736

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Membrane.

Similarity. Belongs to the ITM2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43736-1	1	yes
O43736-2	2

RefSeq proteins (2): NP_001165052, NP_004858* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007084	BRICHOS_dom	Domain
IPR040145	ITM2	Family

Pfam: PF04089

UniProt features (9 total): sequence variant 2, chain 1, transmembrane region 1, domain 1, glycosylation site 1, disulfide bond 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43736-F1	80.66	0.51

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (1): 160–219

Glycosylation sites (1): 166

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 381 (showing top): VERHAAK_AML_WITH_NPM1_MUTATED_DN, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, YAGI_AML_WITH_INV_16_TRANSLOCATION, STAEGE_EWING_FAMILY_TUMOR, BASSO_B_LYMPHOCYTE_NETWORK, GOBP_B_CELL_ACTIVATION, JAEGER_METASTASIS_DN, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_1_UP, LINDGREN_BLADDER_CANCER_CLUSTER_2A_DN, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_DN, HERNANDEZ_MITOTIC_ARREST_BY_DOCETAXEL_2_UP, MODULE_66, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, TONKS_TARGETS_OF_RUNX1_RUNX1T1_FUSION_ERYTHROCYTE_DN

GO Biological Process (2): plasma cell differentiation (GO:0002317), negative regulation of amyloid precursor protein biosynthetic process (GO:0042985)

GO Molecular Function (2): amyloid-beta binding (GO:0001540), protein binding (GO:0005515)

GO Cellular Component (3): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
mature B cell differentiation involved in immune response	1
negative regulation of glycoprotein biosynthetic process	1
amyloid precursor protein biosynthetic process	1
regulation of amyloid precursor protein biosynthetic process	1
peptide binding	1
binding	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1365 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ITM2A	CD34	P28906	587
ITM2A	GPR174	Q9BXC1	418
ITM2A	SLC35A3	Q9Y2D2	367
ITM2A	LCN15	Q6UWW0	314
ITM2A	MZB1	Q8WU39	312
ITM2A	CPXCR1	Q8N123	310
ITM2A	MTFR1	Q15390	304
ITM2A	HUNK	P57058	300
ITM2A	GHITM	Q9H3K2	300
ITM2A	VAMP7	P51809	294
ITM2A	BLOC1S4	Q9NUP1	292
ITM2A	STMN2	Q93045	286
ITM2A	CD302	Q8IX05	283
ITM2A	TSEN15	Q8WW01	281
ITM2A	SLC38A11	Q08AI6	278

IntAct

28 interactions, top by confidence:

A	B	Type	Score
ITM2A	MEOX2	psi-mi:“MI:0915”(physical association)	0.560
MEOX2	ITM2A	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	TMEM179B	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	FNDC9	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	TMED9	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	CLDN7	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	FCGR1A	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	SIT1	psi-mi:“MI:0915”(physical association)	0.560
ITM2A	NDUFB5	psi-mi:“MI:0914”(association)	0.530
ITM2A	APP	psi-mi:“MI:0915”(physical association)	0.520
APP	ITM2A	psi-mi:“MI:0915”(physical association)	0.520
ITM2A	FNDC9	psi-mi:“MI:0915”(physical association)	0.000
ITM2A	TMED9	psi-mi:“MI:0915”(physical association)	0.000
ITM2A	CLDN7	psi-mi:“MI:0915”(physical association)	0.000
ITM2A	FCGR1A	psi-mi:“MI:0915”(physical association)	0.000
ITM2A	SIT1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (30): ITM2A (Two-hybrid), ITM2A (Affinity Capture-MS), ITM2A (Synthetic Lethality), KLHL36 (Affinity Capture-MS), NDUFB5 (Affinity Capture-MS), HLA-DOA (Affinity Capture-MS), RSPRY1 (Affinity Capture-MS), ATP12A (Affinity Capture-MS), DNAJC16 (Affinity Capture-MS), SLC22A18 (Affinity Capture-MS), ATP7B (Affinity Capture-MS), LGR4 (Affinity Capture-MS), ATP7A (Affinity Capture-MS), SPG7 (Affinity Capture-MS), ITM2A (Two-hybrid)

ESM2 similar proteins: A2VDN0, A5A6H8, B5DFM7, E9Q9F6, O18638, O42204, O43736, O88393, O89051, P0DP43, P21841, P26342, P58239, Q03167, Q06890, Q06AV4, Q14CH0, Q29TV8, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5SC59, Q5SC60, Q5SY80, Q5XIE8, Q60HC1, Q61500, Q6AYE5, Q6GPK2, Q6P7C7, Q6P995, Q6W3E5, Q71SY6, Q802A9, Q86XM0, Q86XP6, Q8BGN6

Diamond homologs: A2VDN0, A5A6H8, O42204, O43736, O89051, Q06AV4, Q3T0P7, Q4R540, Q52N47, Q5NVC3, Q5PQL7, Q5R876, Q5XIE8, Q60HC1, Q61500, Q91VK4, Q9NQX7, Q9Y287

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HUNK	“up-regulates activity”	ITM2A	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	2
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

398 predictions. Top by Δscore:

Variant	Effect	Δscore
X:79361323:ACTT:A	donor_loss	1.0000
X:79361324:CTT:C	donor_loss	1.0000
X:79361325:TTAC:T	donor_loss	1.0000
X:79361326:TA:T	donor_loss	1.0000
X:79361327:A:AC	donor_gain	1.0000
X:79361327:A:T	donor_loss	1.0000
X:79361327:AC:A	donor_gain	1.0000
X:79361327:ACC:A	donor_gain	1.0000
X:79361328:C:CT	donor_gain	1.0000
X:79361328:CC:C	donor_gain	1.0000
X:79361328:CCC:C	donor_gain	1.0000
X:79361328:CCCA:C	donor_gain	1.0000
X:79361328:CCCAG:C	donor_gain	1.0000
X:79361475:CCACT:C	acceptor_gain	1.0000
X:79361476:CACT:C	acceptor_gain	1.0000
X:79361476:CACTC:C	acceptor_gain	1.0000
X:79361477:ACTC:A	acceptor_loss	1.0000
X:79361477:ACTCT:A	acceptor_gain	1.0000
X:79361478:CT:C	acceptor_gain	1.0000
X:79361478:CTCTA:C	acceptor_gain	1.0000
X:79361480:C:CC	acceptor_gain	1.0000
X:79361480:CTAAA:C	acceptor_loss	1.0000
X:79361481:T:A	acceptor_loss	1.0000
X:79361488:C:CT	acceptor_gain	1.0000
X:79361489:A:T	acceptor_gain	1.0000
X:79362567:T:TA	donor_gain	1.0000
X:79362577:ATA:A	donor_loss	1.0000
X:79362578:TACCG:T	donor_loss	1.0000
X:79362579:A:AC	donor_gain	1.0000
X:79362579:A:C	donor_loss	1.0000

AlphaMissense

1732 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:79362948:A:C	F145L	0.994
X:79362948:A:T	F145L	0.994
X:79362950:A:G	F145L	0.994
X:79362949:A:C	F145C	0.993
X:79361376:C:G	C219S	0.992
X:79361377:A:T	C219S	0.992
X:79362654:C:G	C160S	0.989
X:79362655:A:T	C160S	0.989
X:79362681:G:T	A151D	0.989
X:79362653:G:C	C160W	0.988
X:79362639:A:T	L165H	0.987
X:79361376:C:T	C219Y	0.986
X:79362952:T:C	D144G	0.985
X:79362961:A:T	I141N	0.985
X:79362654:C:T	C160Y	0.984
X:79361375:G:C	C219W	0.983
X:79362655:A:G	C160R	0.983
X:79362949:A:G	F145S	0.983
X:79362624:A:T	V170D	0.982
X:79361099:C:G	C261S	0.981
X:79361100:A:T	C261S	0.981
X:79362682:C:G	A151P	0.981
X:79362961:A:C	I141S	0.981
X:79361377:A:G	C219R	0.980
X:79362952:T:G	D144A	0.980
X:79362956:G:C	H143D	0.980
X:79363013:C:G	A124P	0.979
X:79363457:C:T	G70D	0.979
X:79361132:A:C	F250C	0.978
X:79361398:C:G	G212R	0.978

dbSNP variants (sampled 300 via entrez): RS1000351665 (X:79361666 C>A), RS1000398592 (X:79361328 C>A), RS1000610725 (X:79367996 C>T), RS1001860265 (X:79367762 C>T), RS1002527820 (X:79363812 C>T), RS1002704635 (X:79364256 G>A), RS1002834225 (X:79367873 AT>A,ATT), RS1003075651 (X:79367589 A>G), RS1003413182 (X:79365435 G>A), RS1003531460 (X:79366204 A>G), RS1003631522 (X:79366008 C>T), RS1003709623 (X:79366603 C>G,T), RS1004651980 (X:79366996 A>G,T), RS1005912134 (X:79364647 G>C), RS1006583159 (X:79360783 G>A)

Disease associations

OMIM: gene MIM:300222 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000175_29	Height	3.000000e-06
GCST001984_4	Graves’ disease	2.000000e-33
GCST003999_20	Nose size	2.000000e-07
GCST008362_134	Birth weight	3.000000e-12
GCST008365_10	Thyrotoxic hypokalemic periodic paralysis and Graves disease	6.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004344	birth weight

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects expression, affects cotreatment	7
methylmercuric chloride	decreases expression	3
Arsenic Trioxide	decreases expression, affects cotreatment	3
trichostatin A	increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases expression	2
Diethylhexyl Phthalate	increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Silicon Dioxide	increases expression, decreases expression	2
Tretinoin	affects cotreatment, decreases expression, increases expression	2
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	increases expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
3-nitrobenzanthrone	affects 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’,5-brominated diphenyl ether	decreases expression	1
nutlin 3	affects cotreatment, increases expression	1
belinostat	increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
Sunitinib	decreases expression	1
Vorinostat	increases expression	1
Bexarotene	increases expression	1
Panobinostat	affects cotreatment, increases expression	1
Acetaminophen	affects expression	1
Aldehydes	increases expression	1
Camptothecin	increases expression	1

Clinical trials (associated diseases)

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