CSN3

Summary

CSN3 (casein kappa, HGNC:2446) is a protein-coding gene on chromosome 4q13.3, encoding Kappa-casein (P07498). Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk.

Involved in lactation and protein stabilization. Located in extracellular space.

Source: NCBI Gene 1448 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_001394997

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2446
Approved symbol	CSN3
Name	casein kappa
Location	4q13.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171209
Ensembl biotype	protein_coding
OMIM	601695
Entrez	1448

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000304954, ENST00000689459

RefSeq mRNA: 2 — MANE Select: NM_001394997 NM_001394997, NM_005212

CCDS: CCDS3538

Canonical transcript exons

ENST00000304954 — 5 exons

Exon	Start	End
ENSE00001138964	70248998	70249493
ENSE00001138970	70244812	70244873
ENSE00001171071	70251262	70251432
ENSE00001171080	70247818	70247850
ENSE00001171087	70242597	70242665

Expression profiles

Bgee: expression breadth broad, 76 present calls, max score 86.30.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0362 / max 22.0090, expressed in 9 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
47912	0.0362	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	86.30	silver quality
minor salivary gland	UBERON:0001830	82.64	gold quality
saliva-secreting gland	UBERON:0001044	78.59	gold quality
mouth mucosa	UBERON:0003729	77.47	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	66.39	gold quality
nasal cavity mucosa	UBERON:0001826	53.32	gold quality
tendon of biceps brachii	UBERON:0008188	52.94	gold quality
nephron tubule	UBERON:0001231	50.47	gold quality
lower esophagus mucosa	UBERON:0035834	50.03	gold quality
tonsil	UBERON:0002372	49.97	gold quality
metanephric glomerulus	UBERON:0004736	49.64	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
kidney epithelium	UBERON:0004819	49.28	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	49.14	gold quality
renal glomerulus	UBERON:0000074	49.07	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
myocardium	UBERON:0002349	48.87	gold quality
type B pancreatic cell	CL:0000169	48.83	gold quality
vastus lateralis	UBERON:0001379	48.55	gold quality
cardiac muscle of right atrium	UBERON:0003379	48.55	gold quality
CA1 field of hippocampus	UBERON:0003881	48.50	gold quality
cervix epithelium	UBERON:0004801	48.42	gold quality
epithelial cell of pancreas	CL:0000083	48.41	gold quality
left ventricle myocardium	UBERON:0006566	48.24	gold quality
orbitofrontal cortex	UBERON:0004167	48.20	gold quality
oviduct epithelium	UBERON:0004804	48.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-10885	yes	24964.91
E-MTAB-10855	yes	24182.97
E-MTAB-9841	yes	22566.48
E-ANND-3	no	2.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting CSN3, 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-574-5P	100.00	66.01	989
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-5002-5P	99.76	70.84	1763
HSA-MIR-4428	99.73	66.41	1733
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4677-5P	99.70	70.09	1940
HSA-MIR-29B-2-5P	99.67	68.98	1726
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-3160-3P	99.07	64.78	955
HSA-MIR-5701	98.97	69.54	1502
HSA-MIR-3145-3P	98.85	69.07	2031
HSA-MIR-3136-5P	98.53	67.68	793
HSA-MIR-4439	98.53	67.53	793
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-1267	98.24	69.05	837
HSA-MIR-5187-3P	97.28	67.10	1037
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-3193	92.99	64.93	116

Literature-anchored findings (GeneRIF, showing 3)

• The recombinant Caseinomacropeptide (hCMP)has been produced as a secretory product in yeast and was estimated to be 7.0kDa by SDS-PAGE, and showed a lower glycosylation than the natural bovine CMP. (PMID:15866733)
• human milk plasma protein exterts an apoptotic effect on MCF-7 adenocarcinoma cells. (PMID:18505157)
• CSN3 was found to contain an interesting coding polymorphism as well as containing excess rare variation as compared with the other genes evaluated in cerebral ischemia patients. (PMID:22536414)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Csn3	ENSMUSG00000001622
rattus_norvegicus	Csn3	ENSRNOG00000001951

Protein

Protein identifiers

Kappa-casein — P07498 (reviewed: P07498)

All UniProt accessions (1): P07498

UniProt curated annotations — full annotation on UniProt →

Function. Kappa-casein stabilizes micelle formation, preventing casein precipitation in milk.

Subunit / interactions. Heteromultimers composed of alpha-s1 casein and kappa casein linked by disulfide bonds.

Subcellular location. Secreted.

Tissue specificity. Mammary gland specific. Secreted in milk.

Post-translational modifications. The N-terminus is blocked.

Similarity. Belongs to the kappa-casein family.

RefSeq proteins (2): NP_001381926, NP_005203 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000117	Casein_kappa	Family

Pfam: PF00997

UniProt features (21 total): glycosylation site 8, sequence conflict 6, sequence variant 3, signal peptide 1, chain 1, site 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07498-F1	58.12	0.00

Functional residue map

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

Catalytic / active sites (1): 117–118 (cleavage; by chymosin/rennin)

Post-translational modifications (1): 157

Glycosylation sites (8): 169, 178, 133, 143, 148, 151, 157, 167

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events
R-HSA-382551	Transport of small molecules

MSigDB gene sets: 70 (showing top): MCBRYAN_PUBERTAL_TGFB1_TARGETS_DN, chr4q13, GCM_PRKCG, GCM_RING1, KOYAMA_SEMA3B_TARGETS_UP, GOBP_PROTEIN_STABILIZATION, GCM_FCGR2B, MCBRYAN_PUBERTAL_BREAST_3_4WK_UP, GOBP_SECRETION, GOBP_MAMMARY_GLAND_DEVELOPMENT, GOBP_REGULATION_OF_PROTEIN_STABILITY, JECHLINGER_EPITHELIAL_TO_MESENCHYMAL_TRANSITION_UP, GOBP_BODY_FLUID_SECRETION, ZAMORA_NOS2_TARGETS_UP, GCM_CDH5

GO Biological Process (2): lactation (GO:0007595), protein stabilization (GO:0050821)

GO Molecular Function (1): protein binding (GO:0005515)

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

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
body fluid secretion	1
mammary gland development	1
milk ejection reflex	1
regulation of protein stability	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSN3	CSN1S1	P47710	998
CSN3	CSN2	P05814	998
CSN3	LALBA	P00709	981
CSN3	KCNN4	O15554	912
CSN3	ALB	P02768	835
CSN3	KCNN3	Q9UGI6	832
CSN3	CALM1	P02593	722
CSN3	KRT76	Q01546	722
CSN3	NME2	P22392	721
CSN3	KCNMA1	Q12791	720
CSN3	KCNN1	Q92952	718
CSN3	TRPV4	Q9HBA0	705
CSN3	KCNN2	Q9H2S1	697
CSN3	PLG	P00747	688
CSN3	LTF	P02788	678

IntAct

30 interactions, top by confidence:

A	B	Type	Score
RBPMS	CSN3	psi-mi:“MI:0915”(physical association)	0.670
CSN3	RBPMS	psi-mi:“MI:0915”(physical association)	0.670
MILR1	INPPL1	psi-mi:“MI:0914”(association)	0.640
CSN3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.560
CSN3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.560
VENTX	CSN3	psi-mi:“MI:0915”(physical association)	0.560
	CSN3	psi-mi:“MI:0915”(physical association)	0.560
CSN3	ZNF76	psi-mi:“MI:0915”(physical association)	0.560
LIN7C	ABLIM1	psi-mi:“MI:0914”(association)	0.530
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
DMRTB1	CSN3	psi-mi:“MI:0915”(physical association)	0.370
Caskin1	CSN3	psi-mi:“MI:0915”(physical association)	0.370
ARHGAP36	HAX1	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
SYNGAP1	POTEF	psi-mi:“MI:0914”(association)	0.350
LIN7B	ABLIM1	psi-mi:“MI:0914”(association)	0.350
CSN3	UBQLN1	psi-mi:“MI:0915”(physical association)	0.000
CSN3	UBQLN2	psi-mi:“MI:0915”(physical association)	0.000
VENTX	CSN3	psi-mi:“MI:0915”(physical association)	0.000
	CSN3	psi-mi:“MI:0915”(physical association)	0.000
ZNF76	CSN3	psi-mi:“MI:0915”(physical association)	0.000
PRNP	CSN3	psi-mi:“MI:0407”(direct interaction)	0.000

BioGRID (19): RBPMS (Two-hybrid), CSN3 (Affinity Capture-Western), CSN3 (Affinity Capture-MS), CSN3 (Two-hybrid), CSN3 (Two-hybrid), CSN3 (Two-hybrid), CSN3 (Two-hybrid), UBQLN2 (Two-hybrid), CSN3 (Affinity Capture-MS), CSN3 (Two-hybrid), CSN3 (Affinity Capture-Western), CSN3 (Negative Genetic), CSN3 (Affinity Capture-Western), CSN3 (Reconstituted Complex), MAPRE1 (Co-localization)

ESM2 similar proteins: A0A0G2K6Z9, A0A1D0BN92, A0A411D538, A1YQ92, B3A0Q4, D5L5Q8, H2A0M0, K9N4Q4, O08546, O15946, O35979, O35985, O36359, P06796, P07498, P0DMD3, P0DMD4, P11841, P13432, P15450, P18897, P34468, P54684, P55796, P79139, P81058, P81059, P83055, P83474, P86735, Q01493, Q09283, Q17RF5, Q28441, Q28451, Q28794, Q29135, Q29137, Q61900, Q7T6X1

Diamond homologs: P02668, P02669, P02670, P04468, P06796, P07498, P11840, P11841, P19442, P33618, P42155, P42156, P42157, P50420, P50421, P50422, P50423, P50424, P50425, P79139, P82187, Q27952, Q28400, Q28417, Q28441, Q28451, Q28794, Q29135, Q29137, Q29150, Q95146, Q95147, Q95149, Q95177, Q95184, Q95191, Q95199, Q95224, Q95225, Q95227

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	1
Likely pathogenic	0
Uncertain significance	29
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
57091	GRCh38/hg38 4q13.2-13.3(chr4:66842408-70831557)x1	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1171 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:70249259:T:C	F117L	0.806
4:70249261:T:A	F117L	0.806
4:70249261:T:G	F117L	0.806
4:70244854:C:A	A12E	0.750
4:70244842:T:A	V8D	0.742
4:70244846:T:A	N9K	0.737
4:70244846:T:G	N9K	0.737
4:70244868:T:C	F17L	0.735
4:70244870:T:A	F17L	0.735
4:70244870:T:G	F17L	0.735
4:70244851:T:C	L11P	0.714
4:70244851:T:G	L11R	0.712
4:70244829:T:C	F4L	0.710
4:70244831:T:A	F4L	0.710
4:70244831:T:G	F4L	0.710
4:70244839:T:A	V7D	0.703
4:70244863:T:C	L15P	0.673
4:70249260:T:G	F117C	0.664
4:70244851:T:A	L11Q	0.635
4:70244825:G:C	K2N	0.621
4:70244825:G:T	K2N	0.621
4:70249412:A:C	S168R	0.602
4:70249414:C:A	S168R	0.602
4:70249414:C:G	S168R	0.602
4:70249266:C:A	A119D	0.586
4:70244857:T:C	L13S	0.584
4:70249022:T:C	F38L	0.582
4:70249024:C:A	F38L	0.582
4:70249024:C:G	F38L	0.582
4:70249260:T:C	F117S	0.577

dbSNP variants (sampled 300 via entrez): RS1000872162 (4:70236568 T>C), RS1000965362 (4:70240766 G>A,T), RS1001119941 (4:70246966 G>A,C), RS1001300702 (4:70247221 A>C), RS1001305828 (4:70243260 T>G), RS1001546123 (4:70236423 C>G), RS1001756632 (4:70242234 T>C), RS1001976958 (4:70246225 C>T), RS1002121746 (4:70246509 T>A,C), RS1002209120 (4:70241872 G>A,T), RS1002297927 (4:70246235 T>C), RS1002520656 (4:70236807 G>A), RS1002520709 (4:70251366 C>T), RS1002623531 (4:70245074 C>T), RS1002623613 (4:70244848 C>T)

Disease associations

OMIM: gene MIM:601695 | 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: yes

ChEMBL targets (1): CHEMBL3621024 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

5 total (human), top 5 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
pirinixic acid	affects binding, decreases expression, increases activity	1
CGP 52608	affects binding, increases reaction	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation	1
Permethrin	decreases expression	1

ChEMBL screening assays

14 unique, capped per target: 14 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3624236	Binding	Inhibition of CASK (unknown origin) at 10 uM	Discovery, Development, and SAR of Aminothiazoles as LIMK Inhibitors with Cellular Anti-Invasive Properties. — J Med Chem

Clinical trials (associated diseases)

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