ANTXR2

Summary

ANTXR2 (ANTXR cell adhesion molecule 2, HGNC:21732) is a protein-coding gene on chromosome 4q21.21, encoding Anthrax toxin receptor 2 (P58335). Necessary for cellular interactions with laminin and the extracellular matrix.

This gene encodes a receptor for anthrax toxin. The protein binds to collagen IV and laminin, suggesting that it may be involved in extracellular matrix adhesion. Mutations in this gene cause juvenile hyaline fibromatosis and infantile systemic hyalinosis. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 118429 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hyaline fibromatosis syndrome (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 20
• Clinical variants (ClinVar): 329 total — 17 pathogenic, 20 likely-pathogenic
• Phenotypes (HPO): 59
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_058172

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21732
Approved symbol	ANTXR2
Name	ANTXR cell adhesion molecule 2
Location	4q21.21
Locus type	gene with protein product
Status	Approved
Aliases	CMG2, CMG-2, FLJ31074
Ensembl gene	ENSG00000163297
Ensembl biotype	protein_coding
OMIM	608041
Entrez	118429

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 18 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000307333, ENST00000346652, ENST00000403729, ENST00000404191, ENST00000449651, ENST00000482406, ENST00000491345, ENST00000506286, ENST00000514959, ENST00000679571, ENST00000680913, ENST00000681115, ENST00000681710, ENST00000875744, ENST00000875745, ENST00000958986, ENST00000958987, ENST00000958988, ENST00000958989, ENST00000958990, ENST00000958991, ENST00000958992, ENST00000958993

RefSeq mRNA: 4 — MANE Select: NM_058172 NM_001145794, NM_001286780, NM_001286781, NM_058172

CCDS: CCDS47085, CCDS47086, CCDS68733

Canonical transcript exons

ENST00000403729 — 17 exons

Exon	Start	End
ENSE00001123400	80031623	80031692
ENSE00001123410	80033472	80033570
ENSE00001123421	80035972	80036032
ENSE00001123430	80054272	80054352
ENSE00001553494	79901146	79907467
ENSE00001564420	80072409	80073229
ENSE00003468790	79978007	79978174
ENSE00003496721	79977621	79977701
ENSE00003521794	80055932	80056013
ENSE00003546933	80055150	80055218
ENSE00003567370	80071583	80071654
ENSE00003568297	80055360	80055467
ENSE00003577690	80069436	80069507
ENSE00003589625	79984819	79984863
ENSE00003593368	80008521	80008616
ENSE00003620192	80018898	80018976
ENSE00003678077	79983878	79983970

Expression profiles

Bgee: expression breadth ubiquitous, 243 present calls, max score 99.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 25.9753 / max 341.4609, expressed in 1657 samples.

FANTOM5 promoters (19 alternative TSS)

Promoter ID	TPM avg	Samples expressed
52759	9.5317	1444
52756	6.7312	1357
52751	3.1854	1266
52750	1.1890	683
52753	1.1741	781
52764	0.8669	257
52762	0.5112	262
52757	0.4004	211
52758	0.3991	184
52766	0.3782	91

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of stomach	UBERON:0001199	99.05	gold quality
decidua	UBERON:0002450	98.93	gold quality
smooth muscle tissue	UBERON:0001135	98.84	gold quality
stromal cell of endometrium	CL:0002255	98.79	gold quality
cauda epididymis	UBERON:0004360	98.55	gold quality
calcaneal tendon	UBERON:0003701	98.53	gold quality
myometrium	UBERON:0001296	97.98	gold quality
lower esophagus muscularis layer	UBERON:0035833	97.94	gold quality
lower esophagus	UBERON:0013473	97.86	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	97.86	gold quality
body of uterus	UBERON:0009853	97.70	gold quality
gall bladder	UBERON:0002110	97.39	gold quality
muscle layer of sigmoid colon	UBERON:0035805	97.39	gold quality
colonic epithelium	UBERON:0000397	97.32	gold quality
urinary bladder	UBERON:0001255	97.27	gold quality
ileal mucosa	UBERON:0000331	96.96	gold quality
synovial joint	UBERON:0002217	96.94	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.71	gold quality
seminal vesicle	UBERON:0000998	96.65	gold quality
tendon	UBERON:0000043	96.44	gold quality
rectum	UBERON:0001052	96.33	gold quality
left ventricle myocardium	UBERON:0006566	96.31	gold quality
layer of synovial tissue	UBERON:0007616	96.30	gold quality
placenta	UBERON:0001987	96.29	gold quality
prostate gland	UBERON:0002367	96.25	gold quality
epithelial cell of pancreas	CL:0000083	96.20	gold quality
right ovary	UBERON:0002118	96.11	gold quality
saphenous vein	UBERON:0007318	96.11	gold quality
urethra	UBERON:0000057	96.09	gold quality
left ovary	UBERON:0002119	95.94	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	22.81
E-MTAB-7249	no	868.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

268 targeting ANTXR2, 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-5011-5P	100.00	83.46	5820
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4533	100.00	69.48	2758
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• identification and characterization of juvenile hyaline fibromatosis and infantile systemic hyalinosis disease-causing mutations in the capillary morphogenesis factor-2 gene (PMID:12973667)
• identification of 15 different mutations in the gene encoding capillary morphogenesis protein 2 in 17 families with juvenile hyaline fibromatosis or infantile systemic hyalinosis (PMID:14508707)
• structures provide a template to begin probing the high-affinity capillary morphogenesis protein 2-protective antigen interaction and may facilitate understanding of toxin assembly/internalization (PMID:15079089)
• crystal structure of the complex with anthrax toxin (PMID:15243628)
• Data show that cells expressing palmitoylation-defective mutant receptors are less sensitive to anthrax toxin due to a lower number of surface receptors as well as premature internalization of protective antigen without a requirement for heptamerization. (PMID:16401723)
• Molecular dynamics simulations explain the great strength that the protective antigen-capillary morphogenesis gene 2 complex achieves through extraordinary coordination of a divalent cation. (PMID:16473908)
• Divalent metal ion coordination by residue T118 of anthrax toxin receptor 2 is not essential for protective antigen binding. (PMID:17183731)
• Results suggest that, in vivo, slow folding, rather than misfolding, is responsible for ER retention, and that systemic hyalinosis can be qualified as a conformational disease. (PMID:19191226)
• Cytoplasmic delivery of lethal factor by anthrax toxin receptor 2 was mediated by cathepsin B. (PMID:19858192)
• the molecular basis (spectrum of ANTXR2 mutations) of infantile systemic hyalinosis and juvenile hyaline fibromatosis in two unrelated Egyptian families (PMID:20331448)
• ANTXR2 and IL-1R2 polymorphisms are not associated with ankylosing spondylitis in Chinese Han population. (PMID:20652271)
• Missense mutations in the extracellular von Willebrand domain of CMG2 lead to protein folding defects. (PMID:21328543)
• ANTXR2 might not be a susceptibility gene of Ankylosing Spondylitis in Chinese Han. (PMID:22118297)
• results reveal extensive diversity in cell lethality dependent on anthrax toxin PA-mediated toxin binding and uptake, and identify individual differences in CMG2 expression level as a determinant of this diversity (PMID:22315420)
• 2 novel ANTXR2 mutations were identified in patients with hyaline fibromatosis syndrome (PMID:22383261)
• Investigated the kinetics of binding as a function of pH to the full-length monomeric anthrax protective antigen(PA)and to two variants to CMG2. Results suggest that for the full-length PA, low pH increases the binding affinity. (PMID:22855243)
• Fused the ANTXR2 ectodomain to the C-terminus of bacterial Trigger Factor (TF), and the fusion protein was overly expressed as a dominant soluble protein in E coli. (PMID:24380801)
• A protective antigen mutation increases the pH threshold of anthrax toxin receptor 2-mediated pore formation (PMID:24641616)
• Loss of CMG2 expression is associated with breast cancer progression. (PMID:24667935)
• Silencing CMG2 using targeted siRNAs provided almost complete protection against anthrax lethal toxin-induced cytotoxicity and death in murine and human macrophages. (PMID:24742682)
• data suggested that cellular cholesterol regulated ANTXR2-dependent activation of MMP-2 via ERK1/2 phosphorylation in neuroglioma U251 cell. (PMID:24924630)
• Results show that CMG2 has been shown to be able to regulate the proliferation and tubule formation of endothelial cells, but not the migration. (PMID:24993339)
• Ankylosing spondylitis is associated with the anthrax toxin receptor 2 gene. (PMID:25169729)
• miR-124 might induce autophagy to participate in AS by targeting ANTXR2, which might be implicated in pathological process of AS. (PMID:25736362)
• CMG2 glycosylation provides a buffer towards genetic variation by promoting folding of the protein in the ER lumen. (PMID:25781883)
• The disulfide bond Cys255-Cys279 in the immunoglobulin-like domain of ANTXR2 is required for membrane insertion of anthrax protective antigen pore. (PMID:26107617)
• The association between ANTXR2 rs4333130 and ankylosing spondylitis was independent of HLA-B27 status. Clinical disease severity scores (BASDAI and BASFI) and pain score were higher in ANTXR2 rs4333130 CT genotype. (PMID:26590821)
• Anthrax Susceptibility: Human Genetic Polymorphisms Modulating ANTXR2 Expression (PMID:26703731)
• This study reports a novel association between ANTXR2 and ankylosing spondylitis in the Han Chinese. (PMID:26728147)
• Roles of Anthrax Toxin Receptor 2 in Anthrax Toxin Membrane Insertion and Pore Formation (PMID:26805886)
• Case Report: systemic hyalinosis with a heterozygous mutation in CMG2. (PMID:26885603)
• expression does not affect cytotoxicity to anthrax toxin (PMID:27170489)
• study examines 4 cases with clinical features of hyaline fibromatosis syndrome; identified a previously unreported splice junction mutation (c.946-2A–>G in intron 11) and a recurrent founder mutation ( c.1074delT) (PMID:27174544)
• Stability of domain 4 of the anthrax toxin protective antigen and the effect of the VWA domain of CMG2 on stability (PMID:27874231)
• Results identified Gly116Val mutation in ANTXR2 associated with hyaline fibromatosis syndrome. (PMID:28103792)
• A decreased CMG2 expression is a negative prognostic factor for soft tissue sarcoma patients. (PMID:29215551)
• CMG2 is an indicator of poor prognosis of glioma patients and also a stimulator of cell cycle progression in cultured glioma cells. (PMID:29473166)
• CMG2 promotes GC progression by maintaining GCSLCs and can serve as a new prognostic indicator and a target for human GC therapy. (PMID:29662192)
• Results from hyaline fibromatosis syndrome (HFS) patients with consanguineous background identified a novel homozygous frameshift deletion c.969del (p.Ile323Metfs*14), a previously reported mutation c.134 T > C (p.Leu45Pro) and a recurrent homozygous frameshift mutation c.1073dup (p.Ala359Cysfs*13). These findings improves the understanding of a recurrent mutation in HFS. (PMID:29801470)
• Study provides evidence to reinforce the previous hypothesis that missense mutations in exons 1-12 in ANTXR2 and mutations leading to a premature stop codon lead to the severe form of the disease, while missense pathogenic variants in exons 13-17 lead to the mild form of hyaline fibromatosis syndrome. [review] (PMID:30176098)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	antxr2b	ENSDARG00000063011
danio_rerio	antxr2a	ENSDARG00000104118
mus_musculus	Antxr2	ENSMUSG00000029338
rattus_norvegicus	Antxr2	ENSRNOG00000000081

Paralogs (2): ANTXR1 (ENSG00000169604), ANTXRL (ENSG00000274209)

Protein

Protein identifiers

Anthrax toxin receptor 2 — P58335 (reviewed: P58335)

Alternative names: Capillary morphogenesis gene 2 protein

All UniProt accessions (6): A0A0C4DG84, A0A7P0T8H3, A0A7P0TAR4, P58335, A0A7P0Z4A8, J3KPY9

UniProt curated annotations — full annotation on UniProt →

Function. Necessary for cellular interactions with laminin and the extracellular matrix. (Microbial infection) Receptor for the protective antigen (PA) of B.anthracis. Binding of PA leads to heptamerization of the receptor-PA complex. Upon binding of the PA of B.anthracis, the complex moves to glycosphingolipid-rich lipid rafts, where it is internalized via a clathrin-dependent pathway. In the endosomal membrane, at pH under 7, the complex then rearranges and forms a pore allowing the other components of anthrax toxin to escape to the cytoplasm.

Subunit / interactions. Binds laminin, and possibly also collagen type IV. (Microbial infection) Interacts (via VWFA domain) with the protective antigen (PA) of B.anthracis.

Subcellular location. Cell membrane Endoplasmic reticulum membrane Secreted.

Tissue specificity. Expressed in prostate, thymus, ovary, testis, pancreas, colon, heart, kidney, lung, liver, peripheral blood leukocytes, placenta, skeletal muscle, small intestine and spleen.

Disease relevance. Hyaline fibromatosis syndrome (HFS) [MIM:228600] An autosomal recessive syndrome characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Disease severity is variable. Some individuals manifest symptoms in infancy and have additional visceral or systemic involvement. Hyaline deposits in multiple organs, recurrent infections and intractable diarrhea often lead to early death. Surviving children may suffer from severely reduced mobility due to joint contractures. Other patients have later onset of a milder disorder affecting only the face and digits. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Similarity. Belongs to the ATR family.

Isoforms (4)

UniProt ID	Names	Canonical?
P58335-1	1	yes
P58335-2	2
P58335-3	3
P58335-4	4

RefSeq proteins (4): NP_001139266, NP_001273709, NP_001273710, NP_477520* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002035	VWF_A	Domain
IPR008399	Anthrax_toxin_rcpt_C	Domain
IPR008400	Anthrax_toxin_rcpt_extracel	Domain
IPR017360	Anthrax_toxin_rcpt	Family
IPR036465	vWFA_dom_sf	Homologous_superfamily

Pfam: PF00092, PF05586, PF05587

UniProt features (41 total): helix 9, sequence variant 8, strand 6, splice variant 4, binding site 3, glycosylation site 2, topological domain 2, signal peptide 1, chain 1, modified residue 1, disulfide bond 1, transmembrane region 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
9DOC	X-RAY DIFFRACTION	1.19
1SHU	X-RAY DIFFRACTION	1.5
8FT8	X-RAY DIFFRACTION	1.6
1SHT	X-RAY DIFFRACTION	1.81
8FZU	X-RAY DIFFRACTION	1.9
8FZ4	X-RAY DIFFRACTION	2.19
1T6B	X-RAY DIFFRACTION	2.5
9YKB	X-RAY DIFFRACTION	2.5
9RT2	ELECTRON MICROSCOPY	2.6
9RT4	ELECTRON MICROSCOPY	2.6
8FT6	X-RAY DIFFRACTION	2.62
7N1O	X-RAY DIFFRACTION	2.77
8FZV	X-RAY DIFFRACTION	3.29
1TZN	X-RAY DIFFRACTION	4.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P58335-F1	71.75	0.25

Functional residue map

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

Ligand- & substrate-binding residues (3): 52; 54; 118

Post-translational modifications (1): 147

Disulfide bonds (1): 39–218

Glycosylation sites (2): 250, 260

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5210891	Uptake and function of anthrax toxins

MSigDB gene sets: 384 (showing top): GOBP_SINGLE_FERTILIZATION, AGGAAGC_MIR5163P, GOBP_COLLAGEN_FIBRIL_ORGANIZATION, GOLDRATH_IMMUNE_MEMORY, GOCC_CELL_SURFACE, CHANDRAN_METASTASIS_DN, GTGCCTT_MIR506, GOBP_REPRODUCTIVE_SYSTEM_DEVELOPMENT, CCTGTGA_MIR513, BROWN_MYELOID_CELL_DEVELOPMENT_UP, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, SENESE_HDAC1_TARGETS_UP, GOBP_FERTILIZATION, GRYDER_PAX3FOXO1_ENHANCERS_IN_TADS, TGCCTTA_MIR124A

GO Biological Process (3): single fertilization (GO:0007338), collagen fibril organization (GO:0030199), uterus development (GO:0060065)

GO Molecular Function (4): transmembrane signaling receptor activity (GO:0004888), metal ion binding (GO:0046872), protein binding (GO:0005515), signaling receptor activity (GO:0038023)

GO Cellular Component (8): extracellular region (GO:0005576), endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), endosome membrane (GO:0010008), endoplasmic reticulum (GO:0005783), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Uptake and actions of bacterial toxins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
fertilization	1
extracellular matrix organization	1
animal organ development	1
reproductive structure development	1
signaling receptor activity	1
cation binding	1
binding	1
molecular transducer activity	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
plasma membrane	1
cell surface	1
side of membrane	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1220 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ANTXR2	LRP6	O75581	833
ANTXR2	VWF	P04275	791
ANTXR2	ERAP1	Q9NZ08	769
ANTXR2	FURIN	P09958	663
ANTXR2	IL1R2	P27930	659
ANTXR2	LRFN5	Q96NI6	601
ANTXR2	CCDC71	Q8IV32	593
ANTXR2	FZD1	Q9UP38	552
ANTXR2	DKK2	Q9UBU2	549
ANTXR2	IL23R	Q5VWK5	549
ANTXR2	PI4K2A	Q9BTU6	513
ANTXR2	DYRK2	Q92630	511
ANTXR2	SOST	Q9BQB4	508
ANTXR2	TJP2	Q9UDY2	505
ANTXR2	PTH1R	Q03431	491

IntAct

19 interactions, top by confidence:

A	B	Type	Score
ANTXR2	pagA	psi-mi:“MI:0407”(direct interaction)	0.790
pagA	ANTXR2	psi-mi:“MI:0407”(direct interaction)	0.790
ANTXR2	pagA	psi-mi:“MI:0915”(physical association)	0.790
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
IL13RA2	METTL15	psi-mi:“MI:0914”(association)	0.530
ANTXR2	CFTR	psi-mi:“MI:0915”(physical association)	0.520
LRP6	ANTXR2	psi-mi:“MI:0915”(physical association)	0.460
ANTXR2	LRP6	psi-mi:“MI:0403”(colocalization)	0.460
SMAD2	ANTXR2	psi-mi:“MI:0915”(physical association)	0.370
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
ANTXR2	HS1BP3	psi-mi:“MI:0914”(association)	0.350
ANTXR2	ALOX12B	psi-mi:“MI:0914”(association)	0.350
IGSF8	HIP1R	psi-mi:“MI:0914”(association)	0.350
KCNK3	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (31): TCEB3 (Affinity Capture-MS), HS1BP3 (Affinity Capture-MS), IKBIP (Affinity Capture-MS), ANKRD13D (Affinity Capture-MS), ANTXR2 (Proximity Label-MS), ANTXR2 (Proximity Label-MS), HS1BP3 (Affinity Capture-MS), SPTBN4 (Affinity Capture-MS), ANTXR2 (Affinity Capture-MS), ANKRD13D (Affinity Capture-MS), ALOX12B (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS), SDR9C7 (Affinity Capture-MS), ANTXR2 (Affinity Capture-MS), ANTXR2 (Affinity Capture-MS)

ESM2 similar proteins: A5PKI3, A7E2Z9, A8MWY0, B0BLS9, D4A1F2, F1MF74, O94851, P58335, P58499, P97259, P97675, P97805, Q04499, Q08834, Q09328, Q0ZHH6, Q2M146, Q3UZV7, Q58D72, Q5EBA1, Q5I598, Q5R4P1, Q60HD2, Q6DD88, Q6DDW2, Q6DFX2, Q6DYE8, Q6GQC1, Q6NVG7, Q6PA06, Q6PST4, Q7ZYY4, Q80YD1, Q810F4, Q8BH66, Q8BML1, Q8IYB8, Q8K1B9, Q8NHH9, Q8R4G6

Diamond homologs: A6NF34, P58335, Q0PMD2, Q4R7B7, Q6DFX2, Q8BVM2, Q9CZ52, Q9H6X2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	20
Uncertain significance	163
Likely benign	43
Benign	61

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1332786	NM_058172.6(ANTXR2):c.1073del (p.Pro358fs)	Pathogenic
1879605	NM_058172.6(ANTXR2):c.1268_1269del (p.Glu423fs)	Pathogenic
209132	NM_058172.6(ANTXR2):c.1305del (p.Thr436fs)	Pathogenic
2581430	NM_058172.6(ANTXR2):c.1294C>T (p.Arg432Ter)	Pathogenic
2585639	NM_058172.6(ANTXR2):c.1139del (p.Tyr380fs)	Pathogenic
2598	NM_058172.6(ANTXR2):c.1179G>A (p.Glu393=)	Pathogenic
2599	NM_058172.6(ANTXR2):c.1142A>G (p.Tyr381Cys)	Pathogenic
2600	NM_058172.6(ANTXR2):c.314G>A (p.Gly105Asp)	Pathogenic
2601	NM_058172.6(ANTXR2):c.986T>G (p.Leu329Arg)	Pathogenic
2602	NM_058172.6(ANTXR2):c.658G>T (p.Glu220Ter)	Pathogenic
2603	NM_058172.6(ANTXR2):c.566T>C (p.Ile189Thr)	Pathogenic
2604	NM_058172.6(ANTXR2):c.1073dup (p.Ala359fs)	Pathogenic
419342	NM_058172.6(ANTXR2):c.1074del (p.Ala359fs)	Pathogenic
4277999	NM_058172.6(ANTXR2):c.1347+1G>T	Pathogenic
446525	NM_058172.6(ANTXR2):c.903dup (p.Ser302fs)	Pathogenic
687488	GRCh37/hg19 4q21.21-21.22(chr4:80199183-84074906)x1	Pathogenic
982062	NM_058172.6(ANTXR2):c.1069del (p.Ala357fs)	Pathogenic
1323915	NM_058172.6(ANTXR2):c.297-2del	Likely pathogenic
1723454	NM_058172.6(ANTXR2):c.496_497del (p.Ser166fs)	Likely pathogenic
209133	NM_058172.6(ANTXR2):c.241T>C (p.Ser81Pro)	Likely pathogenic
2431432	NM_058172.6(ANTXR2):c.1287_1288del (p.Arg429fs)	Likely pathogenic
2431563	NM_058172.6(ANTXR2):c.487-2A>G	Likely pathogenic
2434220	NM_058172.6(ANTXR2):c.297-1G>A	Likely pathogenic
2445864	NM_058172.6(ANTXR2):c.1087-1G>A	Likely pathogenic
2585304	NM_058172.6(ANTXR2):c.211del (p.Glu71fs)	Likely pathogenic
2635528	NM_058172.6(ANTXR2):c.697+1G>A	Likely pathogenic
3393145	NM_058172.6(ANTXR2):c.698-2A>G	Likely pathogenic
3591243	NM_058172.6(ANTXR2):c.1179+1G>C	Likely pathogenic
3591244	NM_058172.6(ANTXR2):c.1114_1115dup (p.Trp373fs)	Likely pathogenic
383749	NM_058172.6(ANTXR2):c.134T>G (p.Leu45Arg)	Likely pathogenic

SpliceAI

3085 predictions. Top by Δscore:

Variant	Effect	Δscore
4:79978004:TA:T	donor_loss	1.0000
4:79978005:A:AC	donor_gain	1.0000
4:79978006:C:CC	donor_gain	1.0000
4:79978006:C:G	donor_loss	1.0000
4:79978170:CGAAC:C	acceptor_gain	1.0000
4:79978171:GAAC:G	acceptor_gain	1.0000
4:79978172:AAC:A	acceptor_gain	1.0000
4:79978173:AC:A	acceptor_gain	1.0000
4:79978174:CC:C	acceptor_gain	1.0000
4:79978175:C:CC	acceptor_gain	1.0000
4:79978176:T:G	acceptor_loss	1.0000
4:79978177:G:C	acceptor_gain	1.0000
4:79978183:C:CT	acceptor_gain	1.0000
4:79981698:A:C	donor_gain	1.0000
4:80008520:CCA:C	donor_gain	1.0000
4:80008617:C:CC	acceptor_gain	1.0000
4:80018889:TTTAC:T	donor_loss	1.0000
4:80018890:TTAC:T	donor_loss	1.0000
4:80018891:TACTT:T	donor_loss	1.0000
4:80018892:ACTTA:A	donor_loss	1.0000
4:80018894:TT:T	donor_loss	1.0000
4:80018895:T:TG	donor_loss	1.0000
4:80018896:A:AC	donor_gain	1.0000
4:80018897:C:CC	donor_gain	1.0000
4:80018897:C:CG	donor_loss	1.0000
4:80018897:CA:C	donor_gain	1.0000
4:80018897:CACA:C	donor_gain	1.0000
4:80018897:CACAT:C	donor_gain	1.0000
4:80018972:GAGTT:G	acceptor_gain	1.0000
4:80018974:GTT:G	acceptor_gain	1.0000

AlphaMissense

3136 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:79978166:C:A	W396C	0.999
4:79978166:C:G	W396C	0.999
4:79978168:A:G	W396R	0.999
4:79978168:A:T	W396R	0.999
4:79983938:C:A	W373C	0.998
4:79983938:C:G	W373C	0.998
4:79983940:A:G	W373R	0.998
4:79983940:A:T	W373R	0.998
4:80069477:A:C	F85L	0.998
4:80069477:A:T	F85L	0.998
4:80069479:A:G	F85L	0.998
4:79978131:A:G	L408P	0.997
4:80054299:A:C	F203L	0.997
4:80054299:A:T	F203L	0.997
4:80054301:A:G	F203L	0.997
4:80055409:A:G	L146P	0.997
4:80071630:C:A	W59C	0.997
4:80071630:C:G	W59C	0.997
4:79978167:C:G	W396S	0.996
4:80054300:A:C	F203C	0.996
4:80055178:A:T	V176D	0.996
4:79978141:C:G	G405R	0.995
4:79983891:A:G	I389T	0.995
4:80054339:G:T	A190D	0.995
4:80055218:C:G	A163P	0.994
4:80055943:C:G	G123R	0.994
4:80055943:C:T	G123R	0.994
4:80071632:A:G	W59R	0.994
4:80071632:A:T	W59R	0.994
4:80071652:G:A	S52F	0.994

dbSNP variants (sampled 300 via entrez): RS1000033392 (4:79900716 A>C), RS10000339 (4:79957426 C>A,G,T), RS1000044305 (4:79973004 G>A,C), RS10000471 (4:80022534 C>A,T), RS1000066051 (4:80054416 C>G,T), RS1000097161 (4:80004611 A>C), RS10001066 (4:79973528 A>G), RS1000112156 (4:80010624 G>A), RS1000115463 (4:79953954 TC>T), RS1000147430 (4:80029044 G>A,T), RS1000147467 (4:79927417 A>G), RS1000149529 (4:80004836 C>T), RS1000180438 (4:79927633 T>G), RS1000181365 (4:79952188 T>A), RS1000199876 (4:80028311 A>G,T)

Disease associations

OMIM: gene MIM:608041 | disease phenotypes: MIM:228600, MIM:616640, MIM:117000

GenCC curated gene-disease

Disease	Classification	Inheritance
hyaline fibromatosis syndrome	Definitive	Autosomal recessive
juvenile hyaline fibromatosis	Definitive	Autosomal recessive
infantile systemic hyalinosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hyaline fibromatosis syndrome	Definitive	AR

Mondo (5): hyaline fibromatosis syndrome (MONDO:0009229), early-onset Lafora body disease (MONDO:0014717), central core myopathy (MONDO:0007294), juvenile hyaline fibromatosis (MONDO:0016071), infantile systemic hyalinosis (MONDO:0016331)

Orphanet (4): Juvenile hyaline fibromatosis (Orphanet:2028), Hyaline fibromatosis syndrome (Orphanet:498474), PRDM8-related progressive myoclonus epilepsy (Orphanet:324290), Central core disease (Orphanet:597)

HPO phenotypes

59 total (30 of 59 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000147	Polycystic ovaries
HP:0000169	Gingival fibromatosis
HP:0000212	Gingival overgrowth
HP:0000256	Macrocephaly
HP:0000271	Abnormality of the face
HP:0000275	Narrow face
HP:0000280	Coarse facial features
HP:0000369	Low-set ears
HP:0000470	Short neck
HP:0000834	Abnormality of the adrenal glands
HP:0000929	Abnormal skull morphology
HP:0000938	Osteopenia
HP:0000939	Osteoporosis
HP:0000940	Abnormal diaphysis morphology
HP:0000953	Hyperpigmentation of the skin
HP:0001004	Lymphedema
HP:0001025	Urticaria
HP:0001072	Thickened skin
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001371	Flexion contracture
HP:0001387	Joint stiffness
HP:0001482	Subcutaneous nodule
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001522	Death in infancy
HP:0001595	Abnormal hair morphology
HP:0002014	Diarrhea

GWAS associations

20 associations (top):

Study	Trait	p-value
GCST000563_9	Ankylosing spondylitis	9.000000e-08
GCST001149_5	Ankylosing spondylitis	9.000000e-08
GCST002815_4	Bipolar disorder (inflammation and infection response interaction)	4.000000e-06
GCST003997_43	Myopia	3.000000e-15
GCST004162_28	Carotid plaque burden	3.000000e-06
GCST004627_58	Lymphocyte count	7.000000e-23
GCST004632_106	Lymphocyte percentage of white cells	2.000000e-14
GCST004633_48	Neutrophil percentage of white cells	7.000000e-12
GCST005537_17	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	2.000000e-08
GCST005830_65	Hand grip strength	3.000000e-09
GCST006291_36	Spherical equivalent or myopia (age of diagnosis)	2.000000e-12
GCST008361_8	Response to cognitive-behavioural therapy in major depressive disorder	5.000000e-06
GCST010002_9	Refractive error	2.000000e-65
GCST010463_7	Childhood ALL/LBL (acute lymphoblastic leukemia/lymphoblastic lymphoma) treatment-related venous thromboembolism	3.000000e-07
GCST010774_5	Essential hypertension (time to event)	1.000000e-07
GCST010988_218	Adult body size	6.000000e-10
GCST90002388_344	Lymphocyte count	3.000000e-47
GCST90002389_49	Lymphocyte percentage of white cells	5.000000e-28
GCST90002399_376	Neutrophil percentage of white cells	5.000000e-19
GCST90002407_437	White blood cell count	2.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0007050	HSV1 seropositivity
EFO:0006501	carotid plaque build
EFO:0004587	lymphocyte count
EFO:0007993	lymphocyte percentage of leukocytes
EFO:0007990	neutrophil percentage of leukocytes
EFO:0006941	grip strength measurement
EFO:0004847	age at onset
EFO:0007820	cognitive behavioural therapy
EFO:0004918	age at diagnosis

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020512	Myopathy, Central Core	C05.651.575.300; C10.668.491.550.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296326 (SINGLE PROTEIN)

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

ChEMBL bioactivities

10 potent at pChembl≥5 of 11 total, top 10 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.24	IC50	58	nM	CHEMBL377052
7.00	IC50	100	nM	CHEMBL383306
6.88	IC50	132	nM	CHEMBL4557794
6.78	IC50	167	nM	CHEMBL4469305
6.52	IC50	300	nM	PENTAGALLOYL GLUCOSE
6.30	IC50	500	nM	CHEMBL2070828
6.22	IC50	600	nM	CHEMBL559789
6.22	IC50	607	nM	PENTAGALLOYL GLUCOSE
5.93	IC50	1164	nM	CHEMBL4440070
5.47	IC50	3420	nM	CHEMBL4474868

PubChem BioAssay actives

10 with measured affinity, of 34 total; 9 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
[(2R,3R,4S,5S,6S)-3,4,5,6-tetrakis[(3,4,5-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 3,4,5-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	0.0580	uM
[(2R,3R,4S,5S,6R)-3,4,5,6-tetrakis[(3,4,5-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 3,4,5-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	0.1000	uM
[(2R,3R,4S,5S,6S)-3,4,5,6-tetrakis[(2,3,4-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 2,3,4-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	0.1320	uM
[(2R,3S,4S,5R)-6-hydroxy-3,4,5-tris[(3,4,5-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 3,4,5-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	0.1670	uM
[(2R,3R,4S,5R,6S)-3,4,5,6-tetrakis[(3,4,5-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 3,4,5-trihydroxybenzoate	725981: Inhibition of CMG2 (40 to 217) C175A and R40C double mutant (unknown origin) interaction to full length PA E733C mutant expressed in Escherichia coli by FRET assay	ic50	0.3000	uM
6-hydroxy-7-methoxy-3-methylbenzo[h]chromen-2-one	678674: Inhibition of AF546-tagged CMG2 R40C mutant binding to AF488-tagged PA E733C mutant incubated for 1 to 3 hrs prior to AF488-tagged PA E733C addition measured after 3 to 4 hrs by FRET assay	ic50	0.5000	uM
6,8-dihydroxy-3-methylisochromen-1-one	678674: Inhibition of AF546-tagged CMG2 R40C mutant binding to AF488-tagged PA E733C mutant incubated for 1 to 3 hrs prior to AF488-tagged PA E733C addition measured after 3 to 4 hrs by FRET assay	ic50	0.6000	uM
[(2R,3R,4S,5R,6S)-4,5,6-tris[(2,3,4-trihydroxybenzoyl)oxy]-3-[(2R,3R,4S,5R,6R)-3,4,5-tris[(2,3,4-trihydroxybenzoyl)oxy]-6-[(2,3,4-trihydroxybenzoyl)oxymethyl]oxan-2-yl]oxyoxan-2-yl]methyl 2,3,4-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	1.1640	uM
[(2R,3R,4S,5R)-3,4,5,6-tetrakis[(2,3,4-trihydroxybenzoyl)oxy]oxan-2-yl]methyl 2,3,4-trihydroxybenzoate	1589753: Inhibition of AF488-labelled PA binding to AF546- labelled GST-tagged CMG2 R40C/C178A double mutant (unknown origin) expressed in Escherichia coli BL21 DE3 measured after 4 hrs by FRET assay	ic50	3.4200	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Estradiol	affects expression, affects cotreatment, decreases expression, increases expression	3
Valproic Acid	decreases expression, increases expression	3
nickel sulfate	decreases expression, increases expression	2
entinostat	decreases expression, affects cotreatment	2
Air Pollutants	increases abundance, increases expression, decreases expression	2
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Smoke	decreases expression, increases expression	2
Cyclosporine	affects expression, increases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
bisphenol F	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	increases expression	1
3,4-dichloroaniline	increases expression	1
mono-(2-ethylhexyl)phthalate	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
benzo(e)pyrene	increases methylation	1
cupric chloride	increases expression	1
1-nitropyrene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2071924	Binding	Inhibition of AF546-tagged CMG2 R40C mutant binding to AF488-tagged PA E733C mutant incubated for 1 to 3 hrs prior to AF488-tagged PA E733C addition measured after 3 to 4 hrs by FRET assay	Phenolic compounds as antiangiogenic CMG2 inhibitors from Costa Rican endophytic fungi. — Bioorg Med Chem Lett

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SC65	HAP1 ANTXR2 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05327751	PHASE3	UNKNOWN	Possible Protective Effect of Celecoxib Against Capecitabine Induced Hand and Foot Syndrome in Patients With Colorectal Cancer
NCT07501442	Not specified	NOT_YET_RECRUITING	Clinical Trial Evaluating the Efficacy and Safety of Uracil 0,5% Plasters in Oncology Patients Affected by Hand-foot Syndrome (HFS)
NCT03196115	Not specified	WITHDRAWN	Biomarker for Hyaline Fibromatosis Syndrome (BioHFS)
NCT07173010	Not specified	NOT_YET_RECRUITING	Pediatric Arthropathy Beyond Inflammation: Clinical Spectrum and Diagnostic Approach at Assiut University Children Hospital
NCT00272883	Not specified	RECRUITING	Molecular and Genetic Studies of Congenital Myopathies
NCT06157268	Not specified	RECRUITING	The Natural History and Muscle Fatigability of Patients With Congenital Myopathies.
NCT06791369	Not specified	NOT_YET_RECRUITING	The Prevalence of RYR1-related Disease