CSN2

Summary

CSN2 (casein beta, HGNC:2447) is a protein-coding gene on chromosome 4q13.3, encoding Beta-casein (P05814). Important role in determination of the surface properties of the casein micelles.

This gene is a member of the beta casein family. There are two types of casein protein, beta (encoded by this gene) and kappa, both of which are secreted in human milk. Beta casein is the principal protein in human milk and the primary source of essential amino acids for a suckling infant. Beta and kappa casein proteins acting together form spherical micelles which bind within them important dietary minerals, such as calcium and phosphorous. In addition, the C-terminal 14 aa of the protein has antimicrobial activity, especially in preterm milk, displaying antibacterial activity against S. aureus and Y. enterocolitica. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 1447 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 46 total
• MANE Select transcript: NM_001891

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2447
Approved symbol	CSN2
Name	casein beta
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135222
Ensembl biotype	protein_coding
OMIM	115460
Entrez	1447

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000353151

RefSeq mRNA: 3 — MANE Select: NM_001891 NM_001302770, NM_001385731, NM_001891

CCDS: CCDS3532

Canonical transcript exons

ENST00000353151 — 8 exons

Exon	Start	End
ENSE00000865215	69958909	69958953
ENSE00001024573	69960945	69961007
ENSE00001024574	69960053	69960079
ENSE00001024575	69959049	69959069
ENSE00001024576	69957274	69957804
ENSE00001076574	69956314	69956355
ENSE00001395695	69955256	69955592
ENSE00003935595	69965681	69965728

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 98.48.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	98.48	gold quality
tonsil	UBERON:0002372	48.77	gold quality
saliva-secreting gland	UBERON:0001044	46.44	gold quality
minor salivary gland	UBERON:0001830	43.70	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	42.08	gold quality
sural nerve	UBERON:0015488	38.02	gold quality
islet of Langerhans	UBERON:0000006	37.34	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
bone marrow cell	CL:0002092	36.16	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
smooth muscle tissue	UBERON:0001135	34.85	gold quality
placenta	UBERON:0001987	33.81	silver quality
muscle tissue	UBERON:0002385	33.72	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
hindlimb stylopod muscle	UBERON:0004252	32.15	gold quality
bone marrow	UBERON:0002371	31.74	gold quality
urinary bladder	UBERON:0001255	30.10	silver quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
prefrontal cortex	UBERON:0000451	29.04	gold quality
pancreas	UBERON:0001264	28.45	gold quality
monocyte	CL:0000576	28.16	gold quality
duodenum	UBERON:0002114	28.14	gold quality
leukocyte	CL:0000738	28.11	gold quality
liver	UBERON:0002107	28.04	gold quality
lymph node	UBERON:0000029	27.57	gold quality
muscle of leg	UBERON:0001383	27.00	silver quality
vermiform appendix	UBERON:0001154	26.42	gold quality
gastrocnemius	UBERON:0001388	26.25	silver quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-10855	yes	109800.98
E-MTAB-10885	yes	94569.26
E-MTAB-9841	yes	75448.36
E-ANND-3	no	2.29

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BCL6, CEBPA, CEBPB, CEBPG, DDIT3, ESR1, ESR2, FOS, HNF4A, ID4, MYC, NCOA1, NFKB1, NFKB, NR0B2, NR3C1, NR3C2, NRG1, PGR, POU2F1, POU2F2, PPARA, PPARG, RELA, RUNX2, SMAD2, SMAD3, SMAD4, STAT1, STAT3, STAT5A, STAT5B, STAT6, TP53, TP63, TSC22D3, YY1, ZNF335

miRNA regulators (miRDB)

48 targeting CSN2, 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-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-4307	99.82	70.45	3374
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-5580-3P	99.70	69.41	2052
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-190A-5P	99.54	71.45	933

Literature-anchored findings (GeneRIF, showing 9)

• New functions of lactoferrin and beta-casein in mammalian milk as cysteine protease inhibitors. They might play a role in antiseptic and antiinfectious functions due to cysteine protease inhibition of bacteria and viruses. (PMID:12788072)
• The RCM-kappa does form concentration-dependent micelles. Also, beta-CN phosphorylation level influences micelle formation. Complexes were low-temperature reversible and RCM-kappa fibrils were seen. (PMID:16947075)
• a negative cross talk between PR and Stat5a/GR may contribute to the physiological role of progesterone to repress lactogenic hormone induction of the beta-casein gene (PMID:16973758)
• derivatives of peptide fragment (54-59) exhibit immunosuppressant activity (PMID:19463972)
• Milk congestion gives rise to higher levels of beta-casomorphin-8 in milk and plasma than in lactating women without problems. (PMID:24189037)
• The acidic fragment of human Abeta (Abeta1-11) and a phosphorylated fragment of beta-Casein induced tau fibrillization in vitro. (PMID:24364857)
• Exogenous 5-HT decreased beta-casein expression in MCF-12A human mammary epithelial cells and was responsible for inhibiting phosphorylation of STAT5, resulting in a decline in lactational function. (PMID:25087955)
• Data suggest that neurogenesis in neuronal stem cells is differentially affected by human and bovine beta-casein-derived opioid peptides BCM7 and BCM9; such neurogenic changes are accompanied by changes in glutathione/glutathione disulfide ratio and in S-adenosylmethionine/S-adenosylhomocysteine ratio, indicative of changes in redox and methylation states (including DNA methylation). (PMID:27611101)
• The PDC213 peptide derived from CSN2 displays antimicrobial activity against S. aureus and Y. enterocolitica. (PMID:28093229)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Csn2	ENSMUSG00000063157
rattus_norvegicus	Csn2	ENSRNOG00000039326

Protein

Protein identifiers

Beta-casein — P05814 (reviewed: P05814)

All UniProt accessions (2): P05814, W5RWE1

UniProt curated annotations — full annotation on UniProt →

Function. Important role in determination of the surface properties of the casein micelles.

Subcellular location. Secreted.

Tissue specificity. Mammary gland specific. Secreted in milk.

Post-translational modifications. Form 1-P is phosphorylated once; half of the molecules are phosphorylated on Ser-24, half on Ser-25.

Similarity. Belongs to the beta-casein family.

RefSeq proteins (3): NP_001289699, NP_001372660, NP_001882* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001588	Casein	Family
IPR016345	Casein_beta	Family
IPR031305	Casein_CS	Conserved_site

Pfam: PF00363

UniProt features (19 total): sequence conflict 12, modified residue 5, signal peptide 1, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05814-F1	60.09	0.04

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 (5): 18, 21, 23, 24, 25

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-9927426	Developmental Lineage of Mammary Gland Alveolar Cells
R-HSA-1236394	Signaling by ERBB4
R-HSA-162582	Signal Transduction
R-HSA-9006934	Signaling by Receptor Tyrosine Kinases

MSigDB gene sets: 109 (showing top): PID_REG_GR_PATHWAY, GOBP_MONOATOMIC_CATION_TRANSPORT, chr4q13, CATTTCA_MIR203, WTGAAAT_UNKNOWN, GOBP_SECRETION, GOBP_MAMMARY_GLAND_DEVELOPMENT, MCBRYAN_PUBERTAL_BREAST_5_6WK_UP, GOBP_BODY_FLUID_SECRETION, GATA4_Q3, GOBP_REGULATION_OF_BODY_FLUID_LEVELS, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP, GOBP_LACTATION, NAKAMURA_TUMOR_ZONE_PERIPHERAL_VS_CENTRAL_UP, GOMF_PEPTIDASE_REGULATOR_ACTIVITY

GO Biological Process (2): calcium ion transport (GO:0006816), lactation (GO:0007595)

GO Molecular Function (4): enzyme inhibitor activity (GO:0004857), cysteine-type endopeptidase inhibitor activity (GO:0004869), calcium ion binding (GO:0005509), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Signaling by ERBB4	1
Developmental Lineages of the Mammary Gland	1
Signaling by Receptor Tyrosine Kinases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
metal ion transport	1
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
catalytic activity	1
enzyme regulator activity	1
molecular function inhibitor activity	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
metal ion binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

888 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSN2	CSN1S1	P47710	999
CSN2	CSN3	P07498	998
CSN2	LALBA	P00709	970
CSN2	ALB	P02768	896
CSN2	LTF	P02788	882
CSN2	PRL	P01236	881
CSN2	PRLR	P16471	802
CSN2	STAT5A	P42229	691
CSN2	MB	P02144	690
CSN2	BICD2	Q8TD16	673
CSN2	HTRA1	Q92743	662
CSN2	BTN1A1	Q13410	660
CSN2	STAT5B	P51692	653
CSN2	NEK9	Q8TD19	651
CSN2	NEK6	Q9HC98	636

IntAct

28 interactions, top by confidence:

A	B	Type	Score
CSN2	FHL2	psi-mi:“MI:0915”(physical association)	0.670
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
CSN2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
CSN2	PPP3CC	psi-mi:“MI:0914”(association)	0.530
CSN2	CRYBB3	psi-mi:“MI:0914”(association)	0.530
FAM20C	CSN2	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
ACE2	CSN2	psi-mi:“MI:0570”(protein cleavage)	0.440
htrA	CSN2	psi-mi:“MI:0194”(cleavage reaction)	0.440
ARRB1		psi-mi:“MI:0914”(association)	0.350
ARRB2		psi-mi:“MI:0914”(association)	0.350
ARHGAP36	HAX1	psi-mi:“MI:0914”(association)	0.350
PIPOX	LALBA	psi-mi:“MI:0914”(association)	0.350
CSN2	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
CSN2	FHL2	psi-mi:“MI:0915”(physical association)	0.000
UBQLN2	CSN2	psi-mi:“MI:0915”(physical association)	0.000
CSN2	CDC42	psi-mi:“MI:0915”(physical association)	0.000
CSN2	GRB2	psi-mi:“MI:0915”(physical association)	0.000
CSN2	NFYC	psi-mi:“MI:0915”(physical association)	0.000
CSN2	RAC1	psi-mi:“MI:0915”(physical association)	0.000
TOLLIP	CSN2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (40): FHL2 (Two-hybrid), CSN2 (Biochemical Activity), CORO2A (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), CSN2 (Affinity Capture-MS), CSN2 (Affinity Capture-MS), CSN2 (Affinity Capture-MS), CSN2 (Two-hybrid), UBQLN2 (Two-hybrid), CSN2 (Affinity Capture-MS), CORO2A (Affinity Capture-MS), CRYBB3 (Affinity Capture-MS), PPP3CC (Affinity Capture-MS), PPP3R1 (Affinity Capture-MS), CSN2 (Affinity Capture-MS)

ESM2 similar proteins: B3A0Q1, C0HLZ9, C0HM00, H2A0K6, H2A0K7, H2A0M5, H2KYS8, J7M3T1, J7M799, O17389, O76192, P05814, P07182, P07183, P08798, P0CU45, P0CU47, P0CU48, P0CU50, P13428, P13673, P17110, P17111, P27780, P29695, P46504, P50418, P80675, P82187, P86947, P86948, Q17282, Q196U1, Q26416, Q27022, Q27952, Q4WUL0, Q57081, Q6GB43, Q6R7C3

Diamond homologs: P02665, P02666, P05814, P09116, P10598, P11839, P33048, P39037, P86273, Q9GKK3, Q9TSI0, Q9TVD0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	8
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

838 predictions. Top by Δscore:

Variant	Effect	Δscore
4:69958894:T:C	donor_gain	1.0000
4:69957650:T:TA	donor_gain	0.9900
4:69958893:AT:A	donor_gain	0.9900
4:69960947:C:A	donor_gain	0.9900
4:69958905:TTACC:T	donor_loss	0.9800
4:69958906:TAC:T	donor_loss	0.9800
4:69958907:ACC:A	donor_loss	0.9800
4:69958908:C:CA	donor_loss	0.9800
4:69960943:ACCTC:A	donor_gain	0.9800
4:69960944:CCTCC:C	donor_gain	0.9800
4:69955593:C:CC	acceptor_gain	0.9700
4:69956497:T:C	acceptor_gain	0.9700
4:69957638:G:C	donor_gain	0.9700
4:69957651:C:A	donor_gain	0.9700
4:69958893:A:AC	donor_gain	0.9700
4:69958912:T:A	donor_gain	0.9700
4:69959067:TTCC:T	acceptor_loss	0.9700
4:69959068:TCC:T	acceptor_loss	0.9700
4:69959070:CTACA:C	acceptor_loss	0.9700
4:69959071:T:A	acceptor_loss	0.9700
4:69960946:T:TA	donor_gain	0.9700
4:69956499:G:C	acceptor_gain	0.9600
4:69956499:G:GC	acceptor_gain	0.9600
4:69957605:A:AC	donor_gain	0.9600
4:69958908:CCT:C	donor_gain	0.9600
4:69958909:C:T	donor_loss	0.9500
4:69960940:CATA:C	donor_loss	0.9500
4:69960941:ATACC:A	donor_loss	0.9500
4:69960942:TA:T	donor_loss	0.9500
4:69960943:A:AG	donor_loss	0.9500

AlphaMissense

1463 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:69960974:A:G	C8R	0.981
4:69960976:G:T	A7D	0.900
4:69960964:G:T	A11D	0.895
4:69960961:A:G	L12P	0.880
4:69960970:A:G	L9P	0.876
4:69960959:C:G	A13P	0.840
4:69960967:A:T	V10E	0.839
4:69960972:G:C	C8W	0.839
4:69960958:G:T	A13D	0.833
4:69960953:C:G	A15P	0.832
4:69960982:A:T	I5N	0.827
4:69960979:A:T	L6H	0.819
4:69960952:G:T	A15E	0.807
4:69960955:A:G	L14P	0.803
4:69960982:A:G	I5T	0.799
4:69960979:A:C	L6R	0.796
4:69960973:C:T	C8Y	0.794
4:69957745:G:C	F68L	0.773
4:69957745:G:T	F68L	0.773
4:69957747:A:G	F68L	0.773
4:69960990:C:A	K2N	0.770
4:69960990:C:G	K2N	0.770
4:69960982:A:C	I5S	0.769
4:69960952:G:A	A15V	0.764
4:69960965:C:G	A11P	0.755
4:69960979:A:G	L6P	0.743
4:69960985:A:T	L4H	0.730
4:69960991:T:A	K2M	0.730
4:69960961:A:T	L12H	0.725
4:69960985:A:G	L4P	0.724

dbSNP variants (sampled 300 via entrez): RS1000022566 (4:69960244 C>T), RS1000030034 (4:69965172 C>T), RS1000319750 (4:69955222 G>A), RS1000325488 (4:69958582 T>C), RS1000472350 (4:69959742 A>G), RS1000756362 (4:69955405 T>C), RS1000986041 (4:69963754 A>G), RS1001190826 (4:69965031 A>C,G), RS1001249055 (4:69957865 G>T), RS1001326320 (4:69956448 C>T), RS1001357777 (4:69956709 C>A,T), RS1001626875 (4:69961896 A>G), RS1001997657 (4:69965704 G>A), RS10021394 (4:69957013 G>A), RS1002557809 (4:69960826 A>G)

Disease associations

OMIM: gene MIM:115460 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
linalool	increases expression	1
Rosiglitazone	increases expression	1
Benzo(a)pyrene	affects methylation	1
Tobacco Smoke Pollution	increases expression	1

Clinical trials (associated diseases)

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