CNN2

Summary

CNN2 (calponin 2, HGNC:2156) is a protein-coding gene on chromosome 19p13.3, encoding Calponin-2 (Q99439). Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction.

The protein encoded by this gene, which can bind actin, calmodulin, troponin C, and tropomyosin, may function in the structural organization of actin filaments. The encoded protein could play a role in smooth muscle contraction and cell adhesion. Several pseudogenes of this gene have been identified, and are present on chromosomes 1, 2, 3, 6, 9, 11, 13, 15, 16, 21 and 22. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 1265 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 67 total — 2 pathogenic
• GTEx eGene: eQTL in 36 tissues, sQTL in 39 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.01 (unconstrained)
• MANE Select transcript: NM_004368
• Interaction hub: 1,778 STRING partners (top 10% of genes corpus-wide)
• Notable: 67 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2156
Approved symbol	CNN2
Name	calponin 2
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000064666
Ensembl biotype	protein_coding
OMIM	602373
Entrez	1265

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 30 protein_coding, 8 nonsense_mediated_decay, 2 retained_intron

MANE Select: ENST00000263097

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2, TSL 2: 4, TSL 3: 1, TSL 4: 1, TSL 5: 2

ENST00000263097, ENST00000348419, ENST00000562015, ENST00000562075, ENST00000562958, ENST00000564572, ENST00000565096, ENST00000566695, ENST00000568865, ENST00000569352, ENST00000606983, ENST00000607102, ENST00000865315, ENST00000865316, ENST00000926772, ENST00000926773, ENST00000926774, ENST00000926775, ENST00000926776, ENST00000926777, ENST00000926778, ENST00000926779, ENST00000997382, ENST00000997383, ENST00001030732, ENST00001030734, ENST00001030735, ENST00001030736, ENST00001030737, ENST00001030739, ENST00001030740, ENST00001082750, ENST00001082751, ENST00001097880, ENST00001097881, ENST00001097882, ENST00001097883, ENST00001123262, ENST00001130880, ENST00001142641

RefSeq mRNA: 4 — MANE Select: NM_004368 NM_001303499, NM_001303501, NM_004368, NM_201277

CCDS: CCDS12053, CCDS12054, CCDS77204, CCDS77205

Canonical transcript exons

ENST00000263097 — 7 exons

Exon	Start	End
ENSE00003695062	1031071	1031192
ENSE00003695886	1036416	1036562
ENSE00003696727	1032559	1032696
ENSE00003698662	1026608	1026724
ENSE00003736499	1032392	1032458
ENSE00003739803	1036130	1036246
ENSE00003850190	1037625	1039065

Expression profiles

Bgee: expression breadth ubiquitous, 246 present calls, max score 98.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 188.3678 / max 1613.7939, expressed in 1819 samples.

Highest expression (Bgee): granulocyte, stromal cell of endometrium, ovary, lung, lower esophagus mucosa.

Genetic regulation across tissues (GTEx eQTL / sQTL)

CNN2 is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 36 tissues and its splicing (sQTL) in 39 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 75 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	6.0e-172	+1.23	19:1036019:G:A
Whole Blood	sqtl	2.3e-154	+0.91	19:1036019:G:A
Artery Tibial	sqtl	5.0e-137	+1.04	19:1036019:G:A
Skin Not Sun Exposed Suprapubic	sqtl	5.4e-124	+1.01	19:1036019:G:A
Esophagus Mucosa	sqtl	3.5e-121	+1.11	19:1036019:G:A
Skin Sun Exposed Lower leg	sqtl	4.6e-113	+0.97	19:1036019:G:A
Artery Aorta	sqtl	6.3e-110	+1.16	19:1036019:G:A
Thyroid	sqtl	2.3e-105	+0.95	19:1036019:G:A
Esophagus Muscularis	sqtl	3.4e-101	+1.08	19:1036019:G:A
Adipose Visceral Omentum	sqtl	1.4e-98	+0.98	19:1036019:G:A
Breast Mammary Tissue	sqtl	8.1e-95	+1.07	19:1036019:G:A
Nerve Tibial	sqtl	1.3e-94	+0.99	19:1036019:G:A
Whole Blood	eqtl	5.0e-89	-0.39	19:1038290:A:C
Lung	sqtl	6.2e-78	+0.79	19:1036019:G:A
Colon Transverse	sqtl	6.8e-67	+1.03	19:1036019:G:A
Colon Sigmoid	sqtl	4.0e-63	+1.09	19:1036019:G:A
Cells EBV-transformed lymphocytes	sqtl	1.2e-57	+0.97	19:1036019:G:A
Heart Atrial Appendage	sqtl	1.4e-57	+0.85	19:1036019:G:A
Esophagus Gastroesophageal Junction	sqtl	3.7e-53	+1.11	19:1036019:G:A
Stomach	sqtl	1.1e-48	+0.86	19:1036019:G:A

FANTOM5 promoters

6 alternative TSS:

Promoter ID	TPM avg	Samples expressed
172832	183.4851	1819
172837	3.4100	1146
208626	0.5740	367
172830	0.4114	246
172831	0.2706	128
172835	0.2168	61

Top tissues by expression

showing 100 of 277 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.61	gold quality
stromal cell of endometrium	CL:0002255	98.43	gold quality
right ovary	UBERON:0002118	98.27	gold quality
right lung	UBERON:0002167	98.17	gold quality
lower esophagus mucosa	UBERON:0035834	98.11	gold quality
left ovary	UBERON:0002119	98.10	gold quality
left uterine tube	UBERON:0001303	98.09	gold quality
blood	UBERON:0000178	97.91	gold quality
upper lobe of left lung	UBERON:0008952	97.88	gold quality
right coronary artery	UBERON:0001625	97.85	gold quality
ascending aorta	UBERON:0001496	97.67	gold quality
thoracic aorta	UBERON:0001515	97.67	gold quality
upper lobe of lung	UBERON:0008948	97.49	gold quality
aorta	UBERON:0000947	97.32	gold quality
gall bladder	UBERON:0002110	97.29	gold quality
body of uterus	UBERON:0009853	97.22	gold quality
popliteal artery	UBERON:0002250	97.18	gold quality
tibial artery	UBERON:0007610	97.18	gold quality
ectocervix	UBERON:0012249	97.06	gold quality
spleen	UBERON:0002106	97.02	gold quality
descending thoracic aorta	UBERON:0002345	97.02	gold quality
buccal mucosa cell	CL:0002336	97.01	gold quality
left coronary artery	UBERON:0001626	96.92	gold quality
esophagus mucosa	UBERON:0002469	96.81	gold quality
mucosa of stomach	UBERON:0001199	96.76	gold quality
lymph node	UBERON:0000029	96.75	gold quality
minor salivary gland	UBERON:0001830	96.70	gold quality
leukocyte	CL:0000738	96.69	gold quality
monocyte	CL:0000576	96.67	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.64	gold quality
mononuclear cell	CL:0000842	96.49	gold quality
body of stomach	UBERON:0001161	96.44	gold quality
endocervix	UBERON:0000458	96.42	gold quality
ovary	UBERON:0000992	96.37	gold quality
bone marrow cell	CL:0002092	96.30	gold quality
esophagus	UBERON:0001043	96.25	gold quality
left lobe of thyroid gland	UBERON:0001120	96.23	gold quality
olfactory bulb	UBERON:0002264	96.23	silver quality
coronary artery	UBERON:0001621	96.20	gold quality
vagina	UBERON:0000996	96.14	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.03	gold quality
smooth muscle tissue	UBERON:0001135	96.00	gold quality
lower esophagus	UBERON:0013473	95.80	gold quality
thyroid gland	UBERON:0002046	95.78	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.78	gold quality
right lobe of thyroid gland	UBERON:0001119	95.77	gold quality
skin of leg	UBERON:0001511	95.70	gold quality
saliva-secreting gland	UBERON:0001044	95.67	gold quality
muscle layer of sigmoid colon	UBERON:0035805	95.66	gold quality
skin of abdomen	UBERON:0001416	95.54	gold quality
omental fat pad	UBERON:0010414	95.46	gold quality
peritoneum	UBERON:0002358	95.42	gold quality
vermiform appendix	UBERON:0001154	95.40	gold quality
prostate gland	UBERON:0002367	95.39	gold quality
type B pancreatic cell	CL:0000169	95.22	gold quality
mouth mucosa	UBERON:0003729	95.19	gold quality
metanephros cortex	UBERON:0010533	95.18	gold quality
stomach	UBERON:0000945	95.12	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.96	gold quality
mucosa of transverse colon	UBERON:0004991	94.88	gold quality
right atrium auricular region	UBERON:0006631	94.77	gold quality
body of pancreas	UBERON:0001150	94.76	gold quality
tibial nerve	UBERON:0001323	94.34	gold quality
transverse colon	UBERON:0001157	94.19	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.09	gold quality
subcutaneous adipose tissue	UBERON:0002190	93.67	gold quality
zone of skin	UBERON:0000014	93.62	gold quality
tonsil	UBERON:0002372	93.49	gold quality
calcaneal tendon	UBERON:0003701	93.38	gold quality
caecum	UBERON:0001153	93.34	gold quality
lower lobe of lung	UBERON:0008949	92.97	gold quality
adipose tissue	UBERON:0001013	92.79	gold quality
cardiac atrium	UBERON:0002081	92.73	gold quality
lung	UBERON:0002048	92.61	gold quality
bone marrow	UBERON:0002371	92.55	gold quality
connective tissue	UBERON:0002384	92.48	gold quality
fundus of stomach	UBERON:0001160	92.40	gold quality
small intestine	UBERON:0002108	92.36	gold quality
apex of heart	UBERON:0002098	92.25	gold quality
heart	UBERON:0000948	92.08	gold quality
heart left ventricle	UBERON:0002084	91.99	gold quality
myometrium	UBERON:0001296	91.98	gold quality
colon	UBERON:0001155	91.94	gold quality
cardiac ventricle	UBERON:0002082	91.73	gold quality
intestine	UBERON:0000160	91.59	gold quality
large intestine	UBERON:0000059	91.53	gold quality
colonic epithelium	UBERON:0000397	91.51	gold quality
rectum	UBERON:0001052	91.42	gold quality
female reproductive system	UBERON:0000474	91.13	gold quality
nasal cavity mucosa	UBERON:0001826	90.81	gold quality
right lobe of liver	UBERON:0001114	90.78	gold quality
urinary bladder	UBERON:0001255	90.55	gold quality
vena cava	UBERON:0004087	90.50	gold quality
uterine cervix	UBERON:0000002	90.37	gold quality
pancreas	UBERON:0001264	90.35	gold quality
right uterine tube	UBERON:0001302	90.31	gold quality
nasal cavity epithelium	UBERON:0005384	90.24	gold quality
pancreatic ductal cell	CL:0002079	90.07	gold quality
parotid gland	UBERON:0001831	89.92	gold quality
bone element	UBERON:0001474	89.89	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	441.49
E-HCAD-10	yes	61.81
E-CURD-122	yes	16.15
E-MTAB-7606	no	1099.59
E-CURD-97	no	1016.32
E-CURD-120	no	10.31
E-ANND-3	no	0.00

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	197.4	not detected
Lymph node	tissue	172.3	medium
Tonsil	tissue	159.2	medium
Appendix	tissue	141.3	low
Ovary	tissue	121.2	not detected
Spleen	tissue	113.4	low
Lung	tissue	90.8	medium
Urinary bladder	tissue	80.8	not detected
Vagina	tissue	77.9	not detected
Gallbladder	tissue	73.8	not detected
Salivary gland	tissue	72.4	not detected
Cervix	tissue	68.8	low
Thyroid gland	tissue	65.9	low
Seminal vesicle	tissue	64.4	not detected
Esophagus	tissue	61.7	not detected
Adipose tissue	tissue	58.9	not detected
Endometrium 1	tissue	56.9	not detected
Choroid plexus	tissue	54.0
Smooth muscle	tissue	52.3	not detected
Prostate	tissue	48.6	low
Thymus	tissue	48.6
Skin 1	tissue	48.1	not detected
Pancreas	tissue	43.7	not detected
Stomach 1	tissue	41.2	low
Heart muscle	tissue	36.2	not detected
Placenta	tissue	35.5	not detected
Colon	tissue	34.0	not detected
Spinal cord	tissue	33.4
Liver	tissue	32.8	not detected
Breast	tissue	31.8	low
Rectum	tissue	31.6	not detected
Fallopian tube	tissue	30.6	not detected
Superior colliculi	tissue	29.4
Small intestine	tissue	28.9	not detected
Duodenum	tissue	24.1	not detected
Kidney	tissue	22.8	not detected
Pituitary gland	tissue	21.8
Epididymis	tissue	18.9	not detected
Adrenal gland	tissue	18.4	not detected
Substantia nigra	tissue	15.4
Medulla oblongata	tissue	13.6
Thalamus	tissue	11.2
Pons	tissue	10.6
Midbrain	tissue	10.3
Hypothalamus	tissue	9.0
Periaqueductal gray	tissue	8.9
Parathyroid gland	tissue	8.1	not detected
Testis	tissue	8.0	not detected
Hippocampal formation	tissue	7.4
Corpus callosum	tissue	7.3
Olfactory bulb	tissue	7.3
Tongue	tissue	7.1
Septum	tissue	7.1
Retina	tissue	7.0
Entorhinal cortex	tissue	7.0
Putamen	tissue	6.0
Cerebral cortex	tissue	5.9	not detected
Motor cortex	tissue	5.9
Skeletal muscle	tissue	5.6	not detected
Temporal cortex	tissue	5.6

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Blood vessel (124.6), Dorsal spinal cord (33.4), Ventral spinal cord (19.4), Angular gyrus (white matter) (18.8), Parieto-temporal junction (white matter) (17.0).

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CTNNB1

miRNA regulators (miRDB)

Targeting CNN2 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 46 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-8082	99.95	67.27	1170
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-3150A-3P	99.76	64.44	1640
HSA-MIR-6763-5P	99.76	64.68	1767
HSA-MIR-3175	99.65	66.30	2031
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-4649-3P	99.56	66.90	1783
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-133A-3P	99.27	71.53	1270
HSA-MIR-133B	99.27	71.53	1270
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-548AS-3P	99.12	69.12	2294
HSA-MIR-625-5P	99.02	68.64	2031
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-143-5P	98.98	68.87	946
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-331-3P	98.76	64.91	793

Functional genomics

gnomAD constraint: pLI 1.01e-05, LOEUF 1.01, missense Z 0.228 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000263097 — one region, missense o/e 0.93.

Literature-anchored findings (GeneRIF, showing 7)

• h2-Calponin gene expression is further affected by the treatment of cells with Notch inhibitor and activator, suggesting an upstream signaling mechanism. (PMID:24285540)
• High Calponin-h2 serum levels are associated with breast cancer. (PMID:25099617)
• our results demonstrated that knockdown of endogenous CNN2 in AGS cells could significantly activate cell apoptosis pathway and therefore suppress cell growth in vitro. The deletion of CNN2 might be a potential therapeutic approach to inhibit aggressive growth of gastric cancer. (PMID:28714360)
• Study in human hepatocellular carcinoma cell line and xenograft mouse model shows that CNN2 plays an important role in tumor growth and metastasis, possibly through MEK1/2-ERK1/2 signaling pathway. (PMID:29333089)
• A rapid degradation of calponin 2 is required for cytokinesis. (PMID:34133238)
• Serum calponin 2 is a novel biomarker of tubal ectopic pregnancy. (PMID:34217487)
• Calponin 2 regulates ketogenesis to mitigate acute kidney injury. (PMID:37751293)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	cnn2	ENSDARG00000035858
mus_musculus	Cnn2	ENSMUSG00000004665
rattus_norvegicus	Cnn2	ENSRNOG00000043044
drosophila_melanogaster	Mp20	FBGN0002789
drosophila_melanogaster	Chd64	FBGN0035499
caenorhabditis_elegans	cpn-1	WBGENE00000777
caenorhabditis_elegans		WBGENE00000778
caenorhabditis_elegans	cpn-3	WBGENE00000779
caenorhabditis_elegans	cpn-4	WBGENE00000780

Paralogs (5): CNN3 (ENSG00000117519), CNN1 (ENSG00000130176), TAGLN3 (ENSG00000144834), TAGLN (ENSG00000149591), TAGLN2 (ENSG00000158710)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:105093) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 9 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased neutrophil cell number	1
decreased monocyte cell number	1
increased bone marrow cell number	1
decreased granulocyte number	1
abnormal immune system cell morphology	1
abnormal macrophage physiology	1
enhanced wound healing	1
increased macrophage cell number	1
abnormal macrophage chemotaxis	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q4R5J4	100.0%	Diamond
Pongo abelii	Q5RFN6	100.0%	Diamond
Sus scrofa	Q08092	99.7%	Diamond
Bos taurus	Q2HJ38	99.7%	Diamond
Ovis aries	Q7YRL2	99.7%	Diamond
Mustela putorius furo	Q9GK38	99.0%	Diamond
Gallus gallus	P26932	98.9%	Diamond
Meleagris gallopavo	P37803	98.9%	Diamond
Xenopus laevis	Q3KQW7	57.5%	Diamond
Echinococcus granulosus	Q24799	51.1%	Diamond
Dictyostelium discoideum	Q55GV9	47.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
RNU6-2	snRNA	103625684
ARHGAP45	protein-coding	23526
GPX4	protein-coding	2879
POLR2E	protein-coding	5434
ABCA7	protein-coding	10347
GRIN3B	protein-coding	116444
WDR18	protein-coding	57418
TMEM259	protein-coding	91304
ARID3A	protein-coding	1820
SBNO2	protein-coding	22904

Protein

Protein identifiers

Calponin-2 — Q99439 (reviewed: Q99439)

Alternative names: Calponin H2, smooth muscle, Neutral calponin

All UniProt accessions (9): A0A087WV51, A0A087X1X5, A0A087X271, B4DDF4, B4DUT8, H3BVI6, K7ES69, Q99439, U3KPS3

UniProt curated annotations — full annotation on UniProt →

Function. Thin filament-associated protein that is implicated in the regulation and modulation of smooth muscle contraction. It is capable of binding to actin, calmodulin and tropomyosin. The interaction of calponin with actin inhibits the actomyosin Mg-ATPase activity.

Tissue specificity. Heart and smooth muscle.

Similarity. Belongs to the calponin family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q99439-1	1	yes
Q99439-2	2

RefSeq proteins (4): NP_001290428, NP_001290430, NP_004359, NP_958434 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000557	Calponin_repeat	Repeat
IPR001715	CH_dom	Domain
IPR001997	Calponin/LIMCH1	Family
IPR003096	SM22_calponin	Family
IPR036872	CH_dom_sf	Homologous_superfamily
IPR050606	Calponin-like	Family

Pfam: PF00307, PF00402

UniProt features (25 total): helix 7, sequence conflict 5, modified residue 4, repeat 3, initiator methionine 1, chain 1, splice variant 1, domain 1, strand 1, region of interest 1

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
1WYN	Solution structure of the CH domain of human calponin-2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99439-F1	68.62	0.18

Human Protein Atlas

Protein class: Predicted intracellular proteins, Plasma proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): actin filaments

Antibody reliability (HPA): IH approved · IF approved

Functional residue map

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

Post-translational modifications (4)

Type	Positions
Phosphoserine	138
N-acetylserine	2
N6-acetyllysine	8, 25

Function

Pathways and Gene Ontology

Reactome pathways

2 curated (TAS) of 8; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

8 pathways:

ID	Pathway	Evidence
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	curated
R-HSA-6798695	Neutrophil degranulation	curated
R-HSA-1280215	Cytokine Signaling in Immune system	—
R-HSA-168256	Immune System	—
R-HSA-168249	Innate Immune System	—
R-HSA-447115	Interleukin-12 family signaling	—
R-HSA-9020591	Interleukin-12 signaling	—
R-HSA-449147	Signaling by Interleukins	—

MSigDB gene sets: 268 (showing top): HORIUCHI_WTAP_TARGETS_DN, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, WWTAAGGC_UNKNOWN, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, BERTUCCI_MEDULLARY_VS_DUCTAL_BREAST_CANCER_DN, GOCC_SECRETORY_GRANULE, GOBP_CELLULAR_RESPONSE_TO_EXTERNAL_STIMULUS, LFA1_Q6, GOBP_NEGATIVE_REGULATION_OF_ENDOCYTOSIS, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, SRF_Q5_01, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (5): cytoskeleton organization (GO:0007010), actin filament organization (GO:0007015), actomyosin structure organization (GO:0031032), regulation of actin filament-based process (GO:0032970), cellular response to mechanical stimulus (GO:0071260)

GO Molecular Function (5): actin binding (GO:0003779), calmodulin binding (GO:0005516), cadherin binding (GO:0045296), actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (9): stress fiber (GO:0001725), extracellular region (GO:0005576), cytoskeleton (GO:0005856), cell-cell junction (GO:0005911), focal adhesion (GO:0005925), actin cytoskeleton (GO:0015629), membrane (GO:0016020), specific granule lumen (GO:0035580), tertiary granule lumen (GO:1904724)

Reactome top-level categories

6 top-level categories:

Category	Pathways
Immune System	2
Innate Immune System	1
Interleukin-12 signaling	1
Signaling by Interleukins	1
Cytokine Signaling in Immune system	1
Interleukin-12 family signaling	1

GO top-level categories

25 GO namespaces:

Category	Terms
actin cytoskeleton organization	2
cellular anatomical structure	2
organelle organization	1
supramolecular fiber organization	1
actin filament-based process	1
regulation of cellular process	1
response to mechanical stimulus	1
cellular response to abiotic stimulus	1
cellular response to external stimulus	1
cytoskeletal protein binding	1
protein binding	1
cell adhesion molecule binding	1
actin binding	1
protein-containing complex binding	1
binding	1
actomyosin	1
contractile actin filament bundle	1
intracellular membraneless organelle	1
anchoring junction	1
cell-substrate junction	1
cytoskeleton	1
secretory granule lumen	1
specific granule	1
intracellular organelle lumen	1
tertiary granule	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 6 of 19 annotations. The rest are phylogenetic / computational / electronic (IEA).

6 experimentally-supported GO terms:

GO term	NS	Evidence
cellular response to mechanical stimulus	BP	direct assay
regulation of actin filament-based process	BP	direct assay
focal adhesion	CC	high-throughput assay
membrane	CC	high-throughput assay
stress fiber	CC	direct assay
cadherin binding	MF	high-throughput assay

Protein interactions and networks

STRING

showing 17 of 1,778 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CNN2	VCL	P18206	646
CNN2	MYH11	P35749	488
CNN2	SRF	P11831	477
CNN2	TGFB1	P01137	468
CNN2	CALD1	Q05682	468
CNN2	FLNA	P21333	466
CNN2	MYOCD	Q8IZQ8	463
CNN2	SMTN	P53814	460
CNN2	MYH9	P35579	444
CNN2	VAV1	P15498	436
CNN2	FLNC	Q14315	429
CNN2	MYH10	P35580	428
CNN2	MYL9	P24844	395
CNN2	PLEK	P08567	370
CNN2	PDGFRB	P09619	370
CNN2	CALB2	P22676	370
CNN2	DST	Q03001	370

IntAct

Human interaction partners of CNN2 in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

1 partners by confidence:

Partner	Interaction type	MIscore	Records
ATE1	association	0.530	3

BioGRID (107 interactions; top human partners by supporting records): ATE1 (Affinity Capture-MS; 3 records), CNN3 (Affinity Capture-MS; 3 records), HSPA8 (Affinity Capture-MS; 3 records), ALAD (Affinity Capture-MS; 2 records), CFTR (Affinity Capture-MS; 2 records), HSPA1A (Affinity Capture-MS; 2 records), NAGK (Affinity Capture-MS; 2 records), AAR2 (Affinity Capture-MS), ABAT (Co-fractionation), ACTA2 (Co-fractionation), ACTB (Proximity Label-MS), ACTC1 (Proximity Label-MS), AKR1C2 (Co-fractionation), ALDH8A1 (Co-fractionation), ANXA1 (Co-fractionation)

Disease & clinical

Genetic variants

Variant evidence for CNN2: 67 ClinVar records (2 pathogenic / likely pathogenic); 16 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	49
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1696851	NM_004368.4(CNN2):c.797G>A (p.Arg266Gln)	Pathogenic	no assertion criteria provided	1
1696852	NM_004368.4(CNN2):c.787G>A (p.Gly263Ser)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore CNN2’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 694):

Position(s)	Effect	Δscore	Sites
19:1026725–1026726	donor_loss	1.0000	5
19:1031069	acceptor_loss	1.0000
19:1032370	acceptor_gain	1.0000
19:1032377	acceptor_gain	1.0000	2
19:1032380	acceptor_gain	1.0000
19:1032390–1032391	acceptor_loss	1.0000	5
19:1032459–1032460	donor_loss	1.0000	5
19:1032546	acceptor_gain	1.0000
19:1032557–1032558	acceptor_loss	1.0000	6
19:1036247–1036248	donor_loss	1.0000	4

AlphaMissense

1,168 missense substitutions predicted likely pathogenic (of 2,040 scored), across 241 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M181	9	0.987	0.999
M170	9	0.980	0.998
M221	9	0.976	0.998
M210	9	0.966	0.997
M249	9	0.913	0.988
D110	8	0.995	0.998
F106	8	0.992	0.999
N87	8	0.986	0.997
D104	8	0.973	0.991
H189	8	0.973	0.995
D202	8	0.972	0.992
N173	8	0.971	0.998
F154	8	0.969	0.999
D192	8	0.957	0.990
N213	8	0.956	0.997
F91	8	0.952	0.998
F50	8	0.939	0.997
N116	8	0.936	0.998
F262	8	0.926	0.992
D232	8	0.923	0.977

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Disease associations

OMIM: gene MIM:602373 | disease phenotypes:

GWAS associations

16 associations:

Study	Trait	p-value
GCST90002407_489	White blood cell count	2e-29
GCST90002393_322	Monocyte count	8e-28
GCST90002382_472	Eosinophil percentage of white cells	1e-24
GCST90002398_171	Neutrophil count	5e-24
GCST90002404_298	Red cell distribution width	5e-22
GCST90002400_706	Plateletcrit	7e-12
GCST004599_81	Mean platelet volume	1e-11
GCST004625_204	Monocyte count	3e-11
GCST90002399_147	Neutrophil percentage of white cells	5e-11
GCST004610_7	White blood cell count	3e-10
GCST004614_18	Granulocyte count	3e-10
GCST90002395_481	Mean platelet volume	5e-10
GCST90002381_634	Eosinophil count	2e-9
GCST90002388_621	Lymphocyte count	2e-9
GCST004617_57	Eosinophil percentage of granulocytes	5e-9
GCST003219_46	Advanced age-related macular degeneration	3e-8

EFO canonical traits (from GWAS)

11 canonical traits:

EFO ID	Trait name
EFO:1001492	atrophic macular degeneration
EFO:0007987	granulocyte count
EFO:0007996	eosinophil percentage of granulocytes
EFO:0005091	monocyte count
EFO:0004842	eosinophil count
EFO:0007991	eosinophil percentage of leukocytes
EFO:0004587	lymphocyte count
EFO:0004833	neutrophil count
EFO:0007990	neutrophil percentage of leukocytes
EFO:0007985	platelet crit
EFO:0009188	Red cell distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295930 (SINGLE PROTEIN)

PharmGKB: 1 entry (CPIC guideline: no)

Binding affinities (BindingDB)

1 measured of 1 human assays (2 total across all organisms); most potent 1 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value
CHEMBL5653589	KD	1440 nM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	3
sodium arsenite	affects cotreatment, decreases expression, increases abundance, increases expression	2
(+)-JQ1 compound	decreases expression	2
Rotenone	increases expression	2
Tretinoin	increases expression	2
1-Methyl-4-phenylpyridinium	increases expression	2
Genistein	decreases expression, increases reaction	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment	2
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
beta-lapachone	decreases expression	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
isobutyl alcohol	decreases expression, increases abundance, affects cotreatment	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
abrine	decreases expression	1
eprenetapopt	affects expression, affects reaction	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Leflunomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118779	Binding	Binding affinity to CNN2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — *Bioorg Med Chem*

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

Predicted chemistry — Sugi Predict

The predicted patent-compound landscape for CNN2 across ~30M SureChEMBL compounds — explore on Sugi Predict.