REG3A

Summary

REG3A (regenerating family member 3 alpha, HGNC:8601) is a protein-coding gene on chromosome 2p12, encoding Regenerating islet-derived protein 3-alpha (Q06141). Bactericidal C-type lectin which acts exclusively against Gram-positive bacteria and mediates bacterial killing by binding to surface-exposed carbohydrate moieties of peptidoglycan.

This gene encodes a pancreatic secretory protein that may be involved in cell proliferation or differentiation. It has similarity to the C-type lectin superfamily. The enhanced expression of this gene is observed during pancreatic inflammation and liver carcinogenesis. The mature protein also functions as an antimicrobial protein with antibacterial activity. Alternate splicing results in multiple transcript variants that encode the same protein.

Source: NCBI Gene 5068 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 33 total
• MANE Select transcript: NM_002580

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:8601
Approved symbol	REG3A
Name	regenerating family member 3 alpha
Location	2p12
Locus type	gene with protein product
Status	Approved
Aliases	HIP, REG-III, REG3, PBCGF, PAP1
Ensembl gene	ENSG00000172016
Ensembl biotype	protein_coding
OMIM	167805
Entrez	5068

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 4 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000305165, ENST00000393878, ENST00000409839, ENST00000464746, ENST00000490901, ENST00000673909

RefSeq mRNA: 3 — MANE Select: NM_002580 NM_002580, NM_138937, NM_138938

CCDS: CCDS1965

Canonical transcript exons

ENST00000305165 — 6 exons

Exon	Start	End
ENSE00001195316	79159728	79159753
ENSE00001314777	79159330	79159439
ENSE00001843312	79157006	79157293
ENSE00002432019	79158651	79158769
ENSE00002453892	79157572	79157698
ENSE00002497430	79158326	79158463

Expression profiles

Bgee: expression breadth ubiquitous, 150 present calls, max score 99.93.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.7395 / max 1451.4061, expressed in 15 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
29332	1.7360	15
29331	0.0035	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.93	gold quality
jejunal mucosa	UBERON:0000399	99.88	gold quality
duodenum	UBERON:0002114	99.80	gold quality
body of pancreas	UBERON:0001150	99.29	gold quality
pancreatic ductal cell	CL:0002079	99.21	gold quality
islet of Langerhans	UBERON:0000006	99.12	gold quality
type B pancreatic cell	CL:0000169	98.02	gold quality
pancreas	UBERON:0001264	97.78	gold quality
small intestine	UBERON:0002108	96.67	gold quality
small intestine Peyer’s patch	UBERON:0003454	96.54	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.78	gold quality
pylorus	UBERON:0001166	91.37	gold quality
gall bladder	UBERON:0002110	89.62	gold quality
epithelial cell of pancreas	CL:0000083	89.03	gold quality
cardia of stomach	UBERON:0001162	89.03	gold quality
jejunum	UBERON:0002115	88.92	gold quality
body of stomach	UBERON:0001161	77.72	gold quality
right adrenal gland	UBERON:0001233	75.54	gold quality
stomach	UBERON:0000945	74.76	gold quality
right adrenal gland cortex	UBERON:0035827	72.80	gold quality
apex of heart	UBERON:0002098	72.35	gold quality
left adrenal gland	UBERON:0001234	71.17	gold quality
left adrenal gland cortex	UBERON:0035825	70.83	gold quality
adrenal cortex	UBERON:0001235	70.62	gold quality
caecum	UBERON:0001153	70.31	gold quality
fundus of stomach	UBERON:0001160	69.96	gold quality
vermiform appendix	UBERON:0001154	68.56	gold quality
parotid gland	UBERON:0001831	66.74	gold quality
intestine	UBERON:0000160	64.79	gold quality
cerebellar vermis	UBERON:0004720	64.78	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	72271.83
E-MTAB-5061	yes	48276.20
E-HCAD-31	yes	14788.51
E-GEOD-81547	yes	20.34
E-GEOD-125970	yes	16.84
E-GEOD-83139	no	3.34
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, ATF1, ISL1, JUN, NEUROD1, NEUROG3, NKX2-2, PAX4, PAX6, PDX1, STAT3, TCF3

miRNA regulators (miRDB)

16 targeting REG3A, 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-590-3P	99.96	74.34	6478
HSA-MIR-1236-3P	99.94	68.04	1695
HSA-MIR-137-3P	99.87	74.74	2401
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-4499	99.62	67.29	1470
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-7854-3P	99.08	66.26	1117
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-4709-3P	98.88	68.04	1594
HSA-MIR-323A-5P	98.59	65.13	651
HSA-MIR-4665-5P	97.91	67.69	1536
HSA-MIR-873-3P	96.84	66.09	786
HSA-MIR-2277-3P	91.94	62.27	299
HSA-MIR-1295A	85.69	62.42	75

Literature-anchored findings (GeneRIF, showing 40)

• HIP/PAP stimulates liver regeneration after partial hepatectomy and combines mitogenic and anti-apoptotic functions through the protein kinase A signaling pathway. (PMID:12890698)
• In transgenic mice, HIP/PAP is a promising candidate for the prevention and treatment of liver failure. (PMID:16116631)
• findings show that RegIIIgamma and its human counterpart, HIP/PAP, are directly antimicrobial proteins that bind their bacterial targets via interactions with peptidoglycan carbohydrate (PMID:16931762)
• human pancreatitis-associated protein fibrillization is initiated by protein aggregation primarily because of electrostatic interactions (PMID:16963458)
• INGAP and/or related group 3 Reg proteins have a conserved expression in the pancreatic islet. (PMID:17998566)
• Immunoreactivity to INGAP localized to the pancreatic endocrine cells in mouse. INGAP and/or related group 3 Reg proteins have a conserved expression in the pancreatic islet. (PMID:17998566)
• PAP mRNA expression and serum PAP levels are closely related to neoplastic proliferative activity in patients with colorectal carcinoma. (PMID:19051257)
• PAP diminished the expression of MMP-1 and -2 and TIMP-1 and -2 and their concentrations in pancreatic stellate cell supernatants. RECK was detected on the surface of PSCs and its expression was reduced after PAP application (PMID:19077460)
• antibacterial activities of mouse RegIIIgamma and its human ortholog, HIP/PAP, are tightly controlled by an inhibitory N-terminal prosegment that is removed by trypsin in vivo. (PMID:19095652)
• HIP enhanced EXTL3 translocation from the membrane to the nucleus, in support of a model whereby EXTL3 mediates HIP signaling for islet neogenesis. (PMID:19158046)
• N-terminal processing is necessary for the peptidoglycan binding and bacteria-aggregating activity of PAP and that trypsin-processed and elastase-processed forms are functionally equivalent. (PMID:19254208)
• HIP/PAP recognizes the cell wall peptidoglycan carbohydrate backbone in a calcium-independent manner via a conserved “EPN” motif that is critical for bacterial killing. (PMID:20382864)
• The Reg3a can serve as novel target in diabetes mellitus genetic therapy. (PMID:20536387)
• Data suggest that PAP I may contribute to endogenous protective mechanisms relevant under harmful conditions like oxidative stress, brain injury, or neurodegeneration. (PMID:21643999)
• REG3A may mediate the epidermal hyperproliferation observed in normal wound repair and in psoriasis. (PMID:22727489)
• HIP/PAP was abundantly expressed in bladder cancer, and the urinary levels of HIP/PAP could be a novel biomarker for detection of bladder cancer. (PMID:22943287)
• The INGAP-pp may facilitate the differentiation of hUCMSCs into IPCs. However, the IPCs are not as mature as normal human islet beta cells. (PMID:23388332)
• Immunohistochemistry against known cell-type markers on serial sections has localised the expression of REGs to metaplastic Paneth cells (REG1A, REG1B and REG3A) and enteroendocrine cells (REG4), with a marked expansion of expression during inflammation. (PMID:23519454)
• Cells transfected with REG III exhibited significantly lower cell proliferation. (PMID:23743605)
• Both live and heat-inactivated Bifidobacterium breve induced the expression of REGIII-alpha, the human ortholog and homolog of REGIII-gamma, in human colonic epithelial cells (Caco-2). (PMID:24096422)
• human RegIIIalpha (also known as HIP/PAP) binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore (PMID:24256734)
• Reg3A overexpression promoted cell growth in pancreatic cancer. SOCS3 is a key target in cancer by inhibiting cell growth and inducing apoptosis. SOCS3 negatively regulated Reg3A-mediated cell growth in pancreatic cancer. (PMID:24996521)
• Serum regenerating islet-derived 3-alpha is a biomarker of mucosal enteropathies (PMID:25112824)
• Reg3beta-dependent accumulation of macrophages in the ischemic heart has a role in myocardial healing (PMID:25751817)
• Reg3alpha is an extracellular matrix-targeted reactive oxygen species scavenger that binds the fibrin scaffold resulting from hepatocyte death during acute liver failure. (PMID:25938566)
• Serum REG3alpha is not an accurate diagnostic and predictive biomarker in Crohn’s disease patients undergoing hemopoetic stem cell transplantation. (PMID:26278889)
• our findings reveal a dual and contextual pathophysiologic role for REG3beta during pancreatitis and pancreatic ductal adenocarcinoma initiation (PMID:26404002)
• Up-regulation of REG3A correlates with colorectal cancer risk. (PMID:26646797)
• Regulation network analysis confirmed the cell growth related differentially expressed genes, and further uncovered three transcription factor families with immune functions regulated by REG3A (PMID:26719042)
• Data show that regenerating family member 3 alpha protein (REG3A) can modulate specific cutaneous inflammatory responses and that the decrease in cutaneous REG3A exacerbates toll-like receptor 3 (TLR3)-mediated inflammation in diabetic skin wounds. (PMID:27830702)
• Data show that interleukin-2 receptor alpha, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-alpha were significantly associated with non-relapse mortality. (PMID:28126963)
• The pancreas reacts to remote lesions and septic insults in mice and rats with increased PSP synthesis, while PAP is selectively responsive to septic events. Furthermore, our results suggest that serum PSP in septic patients is predominantly derived through an acute phase response of the pancreas. (PMID:28415799)
• Results show that REG3beta binds the surface of extracellular vesicles (EVs), through its lectin domain, thereby interfering with the internalization of EVs by target cells and compromising their functionality. This mechanism could be important in pancreatic ductal adenocarcinoma (PDAC), since we detected REG3beta+ EVs in blood from PDAC patients. (PMID:28600520)
• Patients with high levels of PAP/REG3A had overall shorter survival as well as poor surgical outcomes with reduced disease-free survival. (PMID:28656348)
• skin injury increases IL-36gamma via the activation of TLR3-SLUG-VDR axis and IL-36gamma induces REG3A to promote wound healing (PMID:28774595)
• Association between a SNP in the REG3A gene, rs7588571, located upstream of the REG3A gene, and bone marrow transplant outcomes including the incidence of chronic GVHD. Since REG proteins control intestinal microbiota, and since intestinal dysbiosis is in part responsible for the development of GVHD, findings lead to the concept that REG3A could have some protective effect through the regulation of gut microbiota. (PMID:28945764)
• Mice with hepatocytes that express hREG3A, which travels to the intestinal lumen, are less sensitive to colitis than control mice. Suggest reduced oxidative stress preserves the gut microbiota and its ability to prevent inflammation. (PMID:29133078)
• Data found that REG3A was significantly downregulated in Gastric cancer and closely related with patient prognoses. REG3A overexpression suppressed the invasion and proliferation promoting apoptosis of GC cells. While REG3A knockdown promoted the invasion, and proliferation suppressing (PMID:29512686)
• REG3A SNP was not associated with aGVHD (PMID:30004111)
• Survival signal REG3alpha prevents crypt apoptosis to control acute gastrointestinal graft-versus-host disease. (PMID:30106382)

Cross-species orthologs

19 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-125e6.11	ENSDARG00000025783
danio_rerio	zgc:172053	ENSDARG00000038321
danio_rerio	si:dkey-241l7.6	ENSDARG00000041248
danio_rerio	si:dkey-9i23.4	ENSDARG00000051993
danio_rerio	lectin	ENSDARG00000055833
danio_rerio	si:ch211-125e6.5	ENSDARG00000069381
danio_rerio	si:dkey-241l7.3	ENSDARG00000086956
danio_rerio	si:dkey-241l7.5	ENSDARG00000088989
danio_rerio	si:dkey-241l7.4	ENSDARG00000089478
danio_rerio	si:ch211-125e6.12	ENSDARG00000092090
danio_rerio	si:dkey-9i23.5	ENSDARG00000092459
danio_rerio	si:ch211-125e6.14	ENSDARG00000094183
danio_rerio	si:ch211-125e6.13	ENSDARG00000094370
danio_rerio	si:dkey-241l7.2	ENSDARG00000105335
caenorhabditis_elegans		WBGENE00012621
caenorhabditis_elegans		WBGENE00016912
caenorhabditis_elegans		WBGENE00019328
caenorhabditis_elegans		WBGENE00019914
caenorhabditis_elegans		WBGENE00020585

Paralogs (5): REG1A (ENSG00000115386), REG4 (ENSG00000134193), REG3G (ENSG00000143954), REG1B (ENSG00000172023), CLEC19A (ENSG00000261210)

Protein

Protein identifiers

Regenerating islet-derived protein 3-alpha — Q06141 (reviewed: Q06141)

Alternative names: Hepatointestinal pancreatic protein, Human proislet peptide, Pancreatitis-associated protein 1, Regenerating islet-derived protein III-alpha

All UniProt accessions (3): Q06141, A0A669KAZ1, Q53S56

UniProt curated annotations — full annotation on UniProt →

Function. Bactericidal C-type lectin which acts exclusively against Gram-positive bacteria and mediates bacterial killing by binding to surface-exposed carbohydrate moieties of peptidoglycan. Binds membrane phospholipids and kills bacteria by forming a hexameric membrane-permeabilizing oligomeric pore. Acts as a hormone in response to different stimuli like anti-inflammatory signals, such as IL17A, or gut microbiome. Secreted by different cell types to activate its receptor EXTL3 and induce cell specific signaling pathways. Induced by IL17A in keratinocytes, regulates keratinocyte proliferation and differentiation after skin injury via activation of EXTL3-PI3K-AKT signaling pathway. In parallel, inhibits skin inflammation through the inhibition of inflammatory cytokines such as IL6 and TNF. In pancreas, is able to permealize beta-cells membrane and stimulate their proliferation. Has bacteriostatic activity.

Subunit / interactions. Forms a hexameric membrane-permeabilizing oligomeric pore on membrane phospholipids. The hexamer is formed by three dimers related by helical symmetry. Forms filaments, filamentation traps pore complexes and limits damage to host cells. Interacts with EXTL3.

Subcellular location. Secreted.

Tissue specificity. Expressed by keratinocytes. Highly expressed in epidermal keratinocytes of psoriasis patients (at protein level). Constitutively expressed in intestine. Low expression is found in healthy pancreas. Overexpressed during the acute phase of pancreatitis and in some patients with chronic pancreatitis.

Post-translational modifications. Proteolytic processing by trypsin removes an inhibitory N-terminal propeptide and is essential for peptidoglycan binding and antibacterial activity.

Activity regulation. Lipopolysaccharide inhibits pore-forming activity, explaining why is bactericidal for Gram-positive but not Gram-negative bacteria.

Domain organisation. The EPN motif is essential for recognition of the peptidoglycan carbohydrate backbone and for efficient bacterial killing with Glu-114 playing a key role in peptidoglycan binding and bactericidal activity.

Induction. Appears in pancreatic juice after induction of pancreatic inflammation. Induced by IL17A and IL33 during skin inflammation.

RefSeq proteins (3): NP_002571, NP_620354, NP_620355 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001304	C-type_lectin-like	Domain
IPR016186	C-type_lectin-like/link_sf	Homologous_superfamily
IPR016187	CTDL_fold	Homologous_superfamily
IPR018378	C-type_lectin_CS	Conserved_site
IPR050111	C-type_lectin/snaclec_domain	Family

Pfam: PF00059

UniProt features (35 total): strand 9, mutagenesis site 5, binding site 4, helix 4, disulfide bond 3, chain 2, turn 2, signal peptide 1, sequence conflict 1, propeptide 1, domain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4MTH	X-RAY DIFFRACTION	1.47
1UV0	X-RAY DIFFRACTION	1.78
9WTD	ELECTRON MICROSCOPY	2.21
2GO0	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q06141-F1	89.16	0.76

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 (4): 145; 50; 107; 121

Disulfide bonds (3): 40–51, 68–171, 146–163

Mutagenesis-validated functional residues (5):

Position	Phenotype
93	reduces binding to phospholipids and membrane toxicity. loss of filament formation.
93	no effect on binding to phospholipids and membrane toxicity.
114	reduces peptidoglycan binding and antibacterial activity. no effect on binding to phospholipids and membrane toxicity. n
118	reduces antibacterial activity but no effect on peptidoglycan binding.
166	reduces membrane toxicity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6803157	Antimicrobial peptides

MSigDB gene sets: 130 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_ANTIMICROBIAL_HUMORAL_RESPONSE, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GRUETZMANN_PANCREATIC_CANCER_DN, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_INFLAMMATORY_RESPONSE, YAO_HOXA10_TARGETS_VIA_PROGESTERONE_UP, GOBP_REGULATION_OF_EPIDERMIS_DEVELOPMENT, PEREZ_TP63_TARGETS, GOBP_KERATINOCYTE_PROLIFERATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, GOMF_GROWTH_FACTOR_ACTIVITY, GOBP_REGULATION_OF_EPITHELIAL_CELL_DIFFERENTIATION

GO Biological Process (17): acute-phase response (GO:0006953), heterophilic cell-cell adhesion (GO:0007157), positive regulation of cell population proliferation (GO:0008284), response to symbiotic bacterium (GO:0009609), response to wounding (GO:0009611), positive regulation of keratinocyte proliferation (GO:0010838), response to peptide hormone (GO:0043434), negative regulation of keratinocyte differentiation (GO:0045617), antimicrobial humoral immune response mediated by antimicrobial peptide (GO:0061844), positive regulation of wound healing (GO:0090303), negative regulation of inflammatory response to wounding (GO:0106015), positive regulation of detection of glucose (GO:2000972), inflammatory response (GO:0006954), phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0043491), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), inflammatory response to wounding (GO:0090594), positive regulation of cytokine production involved in inflammatory response (GO:1900017)

GO Molecular Function (7): hormone activity (GO:0005179), carbohydrate binding (GO:0030246), signaling receptor activity (GO:0038023), identical protein binding (GO:0042802), peptidoglycan binding (GO:0042834), oligosaccharide binding (GO:0070492), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
acute inflammatory response	1
cell-cell adhesion	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to symbiont	1
response to bacterium	1
response to stress	1
regulation of keratinocyte proliferation	1
keratinocyte proliferation	1
positive regulation of epithelial cell proliferation	1
response to hormone	1
response to nitrogen compound	1
response to oxygen-containing compound	1
keratinocyte differentiation	1
negative regulation of epidermal cell differentiation	1
regulation of keratinocyte differentiation	1
negative regulation of multicellular organismal process	1
antimicrobial humoral response	1
wound healing	1
regulation of wound healing	1
positive regulation of response to wounding	1
negative regulation of inflammatory response	1
inflammatory response to wounding	1
regulation of inflammatory response to wounding	1
negative regulation of response to wounding	1
positive regulation of response to stimulus	1
detection of glucose	1
regulation of detection of glucose	1
defense response	1
intracellular signaling cassette	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
inflammatory response	1
response to wounding	1
positive regulation of cytokine production	1
cytokine production involved in inflammatory response	1

Protein interactions and networks

STRING

802 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
REG3A	DEFA6	Q01524	739
REG3A	DEFA5	Q01523	695
REG3A	EXTL3	O43909	654
REG3A	TNFRSF1A	P19438	616
REG3A	IL22	Q9GZX6	596
REG3A	DUOXA2	Q1HG44	542
REG3A	ZC3H12A	Q5D1E8	541
REG3A	HGF	P14210	535
REG3A	MYD88	P78397	533
REG3A	PI3	P19957	526
REG3A	CXCL8	P10145	514
REG3A	MUC1	P13931	503
REG3A	TLR4	O00206	494
REG3A	DUOX2	Q9NRD8	493
REG3A	LYPD8	Q6UX82	448

IntAct

9 interactions, top by confidence:

A	B	Type	Score
MDFI	REG3A	psi-mi:“MI:0915”(physical association)	0.560
REG3A	MDFI	psi-mi:“MI:0915”(physical association)	0.560
REG3A	ACTB	psi-mi:“MI:0914”(association)	0.530
REG3A	REG3A	psi-mi:“MI:0407”(direct interaction)	0.520
REG3A	SERPINB8	psi-mi:“MI:0914”(association)	0.350

BioGRID (16): REG3A (Two-hybrid), ACTB (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), REG3A (Synthetic Lethality), ACTC1 (Affinity Capture-MS), ACTB (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), CMAS (Affinity Capture-MS), SDC2 (Reconstituted Complex), FN1 (Reconstituted Complex), KLHL22 (Affinity Capture-MS), SERPINB8 (Affinity Capture-MS), CMSS1 (Affinity Capture-MS)

ESM2 similar proteins: A1XXJ9, A3FM55, A7X3Z4, A7X3Z7, A7X413, B4XSY7, B4XSZ1, B4XT00, B4XT01, B4XT02, B4XT03, B4XT08, D1MGU0, E2DQZ6, I7JUQ0, J3S3U6, O09037, O09049, P0DM38, P10758, P23132, P23807, P25031, P35230, P35231, P42854, P43137, Q06141, Q08731, Q09GJ8, Q09GK0, Q38L02, Q5FZI6, Q696W1, Q6T7B5, Q6T7B7, Q6TPH0, Q6UW15, Q71RQ7, Q71RR1

Diamond homologs: A7X3W1, A7X3W6, A7X3Z4, A7X3Z7, B0VXV2, B4XSY4, B4XSY5, B4XSY6, B4XSY9, B4XSZ0, B4XSZ2, B4XSZ4, B4XSZ5, B4XSZ7, B4XSZ8, B4XSZ9, D2YVK5, D2YW39, J3SBP0, O09037, O09049, O60449, P05451, P0DJL4, P10758, P23132, P25031, P35230, P35231, P42854, P43137, P48304, P49259, P81111, P81112, P81115, Q06141, Q08731, Q13018, Q29191

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	8
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

901 predictions. Top by Δscore:

Variant	Effect	Δscore
2:79158650:CAT:C	donor_gain	1.0000
2:79158649:A:AC	donor_gain	0.9900
2:79158650:C:CC	donor_gain	0.9900
2:79158707:AGG:A	donor_gain	0.9900
2:79158769:CCTG:C	acceptor_loss	0.9900
2:79158771:T:A	acceptor_loss	0.9900
2:79158466:T:C	acceptor_gain	0.9800
2:79159418:T:C	acceptor_gain	0.9800
2:79158645:ACT:A	donor_loss	0.9700
2:79158647:T:TG	donor_loss	0.9700
2:79158649:A:C	donor_loss	0.9700
2:79158650:C:A	donor_loss	0.9700
2:79158775:G:GC	acceptor_gain	0.9700
2:79159331:TTGA:T	donor_gain	0.9700
2:79159332:TGA:T	donor_gain	0.9700
2:79158466:T:TC	acceptor_gain	0.9600
2:79158770:C:CC	acceptor_gain	0.9600
2:79158474:A:T	acceptor_gain	0.9500
2:79159640:C:CA	donor_gain	0.9500
2:79158617:CCGG:C	donor_gain	0.9400
2:79158643:CCACT:C	donor_loss	0.9400
2:79158644:CACTC:C	donor_loss	0.9400
2:79158767:CAC:C	acceptor_gain	0.9400
2:79158775:G:C	acceptor_gain	0.9400
2:79159440:C:CC	acceptor_gain	0.9400
2:79158461:CAG:C	acceptor_gain	0.9300
2:79158461:CAGCT:C	acceptor_gain	0.9300
2:79158463:GCT:G	acceptor_loss	0.9300
2:79158465:T:A	acceptor_loss	0.9300
2:79159089:TTCCC:T	donor_gain	0.9300

AlphaMissense

1135 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:79157280:C:A	W158C	0.999
2:79157280:C:G	W158C	0.999
2:79157633:C:A	W133C	0.999
2:79157633:C:G	W133C	0.999
2:79157666:C:A	W122C	0.998
2:79157666:C:G	W122C	0.998
2:79157672:C:A	W120C	0.998
2:79157672:C:G	W120C	0.998
2:79158663:C:A	W61C	0.998
2:79158663:C:G	W61C	0.998
2:79158350:C:A	W103C	0.997
2:79158350:C:G	W103C	0.997
2:79157282:A:G	W158R	0.996
2:79157282:A:T	W158R	0.996
2:79157595:C:G	C146S	0.996
2:79157596:A:T	C146S	0.996
2:79158456:C:G	C68S	0.996
2:79158456:C:T	C68Y	0.996
2:79158457:A:T	C68S	0.996
2:79158656:C:G	A64P	0.996
2:79157242:C:G	C171S	0.995
2:79157243:A:T	C171S	0.995
2:79157668:A:G	W122R	0.994
2:79157668:A:T	W122R	0.994
2:79158455:G:C	C68W	0.994
2:79157242:C:T	C171Y	0.993
2:79157245:A:T	V170D	0.993
2:79157266:C:G	C163S	0.993
2:79157267:A:T	C163S	0.993
2:79158352:A:G	W103R	0.992

dbSNP variants (sampled 300 via entrez): RS1000304866 (2:79160886 C>T), RS1000866442 (2:79159323 A>G), RS1001329113 (2:79156528 C>T), RS1002243112 (2:79157504 A>C), RS1002337856 (2:79157867 G>A), RS1002753001 (2:79159039 T>C), RS1003215097 (2:79158863 G>A,C), RS1004171623 (2:79157963 G>A,C), RS1005097312 (2:79159257 A>G,T), RS1005805415 (2:79156604 C>T), RS1006600389 (2:79161050 A>C,G), RS1007602256 (2:79159589 A>T), RS1008234513 (2:79156789 G>A), RS1009181305 (2:79160011 C>A,T), RS1009463817 (2:79156755 G>A)

Disease associations

OMIM: gene MIM:167805 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002783_115	Body mass index	7.000000e-06
GCST002783_132	Body mass index	5.000000e-06
GCST002783_315	Body mass index	6.000000e-06
GCST011743_70	HDL cholesterol levels in HIV infection	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	increases expression	1
5-iodotubercidin	decreases expression	1
daphnetin	decreases reaction, increases expression, decreases expression, increases cleavage, increases phosphorylation (+1 more)	1
CGP 52608	affects binding, increases reaction	1
Zoledronic Acid	increases expression	1
Gemcitabine	decreases expression	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases reaction, increases expression, decreases expression, increases cleavage, increases phosphorylation (+1 more)	1
Antirheumatic Agents	increases expression	1

Clinical trials (associated diseases)

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