CILP2

Summary

CILP2 (cartilage intermediate layer protein 2, HGNC:24213) is a protein-coding gene on chromosome 19p13.11, encoding Cartilage intermediate layer protein 2 (Q8IUL8). May play a role in cartilage scaffolding.

Located in extracellular exosome.

Source: NCBI Gene 148113 — RefSeq curated summary.

At a glance

• GWAS associations: 44
• Clinical variants (ClinVar): 238 total
• MANE Select transcript: NM_153221

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24213
Approved symbol	CILP2
Name	cartilage intermediate layer protein 2
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	MGC45771
Ensembl gene	ENSG00000160161
Ensembl biotype	protein_coding
OMIM	612419
Entrez	148113

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000291495, ENST00000586018, ENST00000588333, ENST00000862972

RefSeq mRNA: 1 — MANE Select: NM_153221 NM_153221

CCDS: CCDS12405

Canonical transcript exons

ENST00000291495 — 8 exons

Exon	Start	End
ENSE00001050196	19542864	19542972
ENSE00001050200	19543248	19543405
ENSE00001050201	19542375	19542650
ENSE00001121436	19539679	19539777
ENSE00001237510	19540204	19540476
ENSE00001237532	19543681	19546659
ENSE00003603072	19541091	19541246
ENSE00003702834	19538265	19538413

Expression profiles

Bgee: expression breadth ubiquitous, 124 present calls, max score 91.82.

FANTOM5 (CAGE): breadth broad, TPM avg 1.2428 / max 86.5563, expressed in 494 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
174813	1.2428	494

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cartilage tissue	UBERON:0002418	91.82	gold quality
tendon of biceps brachii	UBERON:0008188	84.21	gold quality
calcaneal tendon	UBERON:0003701	82.00	gold quality
tendon	UBERON:0000043	80.42	gold quality
tibia	UBERON:0000979	78.01	gold quality
layer of synovial tissue	UBERON:0007616	72.77	gold quality
trabecular bone tissue	UBERON:0002483	72.75	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	72.39	gold quality
myocardium	UBERON:0002349	68.15	gold quality
left testis	UBERON:0004533	68.09	gold quality
right testis	UBERON:0004534	67.68	gold quality
testis	UBERON:0000473	66.35	gold quality
superficial temporal artery	UBERON:0001614	64.33	gold quality
gall bladder	UBERON:0002110	64.12	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	62.51	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	61.46	gold quality
stromal cell of endometrium	CL:0002255	60.75	gold quality
lower lobe of lung	UBERON:0008949	59.78	silver quality
sperm	CL:0000019	58.93	gold quality
synovial joint	UBERON:0002217	58.21	silver quality
mucosa of paranasal sinus	UBERON:0005030	58.00	silver quality
vena cava	UBERON:0004087	57.81	gold quality
bone marrow cell	CL:0002092	57.46	gold quality
upper leg skin	UBERON:0004262	57.41	silver quality
mammalian vulva	UBERON:0000997	57.11	silver quality
right ovary	UBERON:0002118	57.03	gold quality
trachea	UBERON:0003126	56.82	silver quality
right lobe of thyroid gland	UBERON:0001119	55.80	gold quality
dorsal root ganglion	UBERON:0000044	55.11	gold quality
left lobe of thyroid gland	UBERON:0001120	54.79	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

26 targeting CILP2, 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-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-498-3P	99.91	71.27	1114
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-4422	99.72	72.07	2908
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-516B-5P	99.56	66.33	1495
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-4434	99.10	67.01	1984
HSA-MIR-5703	99.10	67.09	2053
HSA-MIR-6814-5P	99.03	66.68	1273
HSA-MIR-3196	98.96	63.91	326
HSA-MIR-3132	97.96	67.91	711
HSA-MIR-197-5P	97.23	68.10	596
HSA-MIR-4286	97.20	64.37	1587
HSA-MIR-345-5P	96.40	66.43	663
HSA-MIR-4522	95.76	66.23	742
HSA-MIR-1231	95.10	65.63	663

Literature-anchored findings (GeneRIF, showing 9)

• Data show no differences in triglyceride or total cholesterol levels in relation to any allelic variants of ANGPTL3, CILP2, or TRIB1 SNPs. (PMID:21691831)
• Cartilage intermediate layer protein 2 (CILP-2) is expressed in articular and meniscal cartilage and down-regulated in experimental osteoarthritis. (PMID:21880736)
• Sex (male)-specific association of rs16996148 SNP in the NCAN/CILP2/PBX4 and serum lipid levels is observed both the Mulao and Han ethnic groups. (PMID:22208664)
• The minor T allele of CILP2 gene and I allele of ACE gene have a protective effect. (PMID:24350279)
• This study aims to analyze the influences of single-nucleotide polymorphism in the NCAN-CILP2 region on non-alcoholic fatty liver disease and plasma lipid levels in the Asian and Pacific ethnic groups. (PMID:26758378)
• Circulating Levels of CILP2 Are Elevated in Coronary Heart Disease and Associated with Atherosclerosis. (PMID:33204392)
• Expression of CILP-2 and DDR2 and ultrastructural changes in the articular cartilage of patients with knee osteoarthritis undergoing total knee arthroplasty: a pilot morphological study. (PMID:36370214)
• CILP2 promotes hypertrophic scar through Snail acetylation by interaction with ACLY. (PMID:38670440)
• CILP2 is a potential biomarker for the prediction and therapeutic target of peritoneal metastases in colorectal cancer. (PMID:38816545)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	cilp2	ENSDARG00000013687
mus_musculus	Cilp2	ENSMUSG00000044006
rattus_norvegicus	Cilp2	ENSRNOG00000020622

Paralogs (1): CILP (ENSG00000138615)

Protein

Protein identifiers

Cartilage intermediate layer protein 2 — Q8IUL8 (reviewed: Q8IUL8)

All UniProt accessions (2): Q8IUL8, K7EPJ4

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in cartilage scaffolding.

Subcellular location. Secreted. Extracellular space. Extracellular matrix.

Tissue specificity. Expressed in articular chondrocytes but not in knee meniscal cartilage cells. Localizes to the intermediate to deep zone of articular cartilage.

Post-translational modifications. May be cleaved into 2 chains possibly by a furin-like protease upon or preceding secretion.

RefSeq proteins (1): NP_694953* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000884	TSP1_rpt	Repeat
IPR003598	Ig_sub2	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR008969	CarboxyPept-like_regulatory	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR025155	WxxW_domain	Domain
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR036383	TSP1_rpt_sf	Homologous_superfamily
IPR039675	CILP1/CILP2	Family
IPR056255	CILP-1/2_dom	Domain
IPR056256	CILP-1/2_b-sand_dom2	Domain
IPR056257	CILP-1/2_8th	Domain
IPR056258	CILP-1/2_C	Domain

Pfam: PF00090, PF13330, PF13620, PF13927, PF23591, PF23599, PF23708, PF23730

UniProt features (15 total): disulfide bond 4, chain 3, glycosylation site 3, domain 2, signal peptide 1, sequence conflict 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IUL8-F1	80.47	0.35

Functional residue map

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

Disulfide bonds (4): 158–191, 162–196, 173–181, 313–359

Glycosylation sites (3): 276, 308, 329

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 45 (showing top): ZIC1_01, chr19p13, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ESTER_BONDS, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_ACID_ANHYDRIDES, GOMF_PHOSPHORIC_ESTER_HYDROLASE_ACTIVITY, GOMF_DINUCLEOTIDE_PHOSPHATASE_ACTIVITY, GOMF_PHOSPHATASE_ACTIVITY, NABA_ECM_GLYCOPROTEINS, ZNF592_TARGET_GENES, MIR95_5P, MIR4422, MIR4516, MIR5703, MIR4434, MIR498_3P

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (3): obsolete extracellular space (GO:0005615), extracellular exosome (GO:0070062), extracellular region (GO:0005576)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
extracellular vesicle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CILP2	PBX4	Q9BYU1	823
CILP2	FURIN	P09958	668
CILP2	NCAN	O14594	581
CILP2	TM6SF2	Q9BZW4	581
CILP2	TRIB1	Q96RU8	580
CILP2	GALNT2	Q10471	579
CILP2	PSRC1	Q6PGN9	544
CILP2	CELSR2	Q9HCU4	526
CILP2	ANGPTL3	Q9Y5C1	524
CILP2	MMAB	Q96EY8	478
CILP2	YJEFN3	A6XGL0	476
CILP2	SORT1	Q99523	475
CILP2	APOA5	Q6Q788	447
CILP2	KLHL42	Q9P2K6	447
CILP2	MATN3	O15232	445
CILP2	MLXIPL	Q9NP71	445

IntAct

33 interactions, top by confidence:

A	B	Type	Score
KLHL22	METTL15	psi-mi:“MI:0914”(association)	0.640
VWCE	ZNF316	psi-mi:“MI:0914”(association)	0.530
DEFA5	NUDT19	psi-mi:“MI:0914”(association)	0.530
DEFA1	MANBA	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
MATN4	MATN1	psi-mi:“MI:0914”(association)	0.350
FBLN5	ZNF320	psi-mi:“MI:0914”(association)	0.350
NOTCH2	ZNF320	psi-mi:“MI:0914”(association)	0.350
CCL3	KRBA1	psi-mi:“MI:0914”(association)	0.350
CCL4L1	QSOX1	psi-mi:“MI:0914”(association)	0.350
FEM1A	RNF113A	psi-mi:“MI:0914”(association)	0.350
MATN4	HSPA5	psi-mi:“MI:0914”(association)	0.350
TMEM106A	TMEM131L	psi-mi:“MI:0914”(association)	0.350
BTNL2	TMEM131L	psi-mi:“MI:0914”(association)	0.350
SFTPC	TMEM131L	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
NCR3	POTEF	psi-mi:“MI:0914”(association)	0.350
CFC1	POTEF	psi-mi:“MI:0914”(association)	0.350
EDN3	POTEF	psi-mi:“MI:0914”(association)	0.350
PI15		psi-mi:“MI:0914”(association)	0.350
ISLR		psi-mi:“MI:0914”(association)	0.350
MFAP4	QSOX1	psi-mi:“MI:0914”(association)	0.350
PRG2	QSOX1	psi-mi:“MI:0914”(association)	0.350
CRLF1	MANBA	psi-mi:“MI:0914”(association)	0.350
FEM1A	LAD1	psi-mi:“MI:0914”(association)	0.350
OIT3	WNT10B	psi-mi:“MI:0914”(association)	0.350
SIRPD	ADAM10	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-RNA), CILP2 (Affinity Capture-RNA), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS), CILP2 (Affinity Capture-MS)

ESM2 similar proteins: A0JNK3, A2RT60, A4IHA1, A6YFB5, A9JRB3, B3LVG7, B3P3J9, B4G316, B4HEM8, B4JTT7, B4K835, B4LY58, B4N937, B4PST0, B4QZU6, D3ZA76, D3ZKF5, E1BJW1, F1N152, F4J3G5, O22609, O23614, O43464, P14543, P38935, P73940, P83105, P83110, Q14689, Q14703, Q297U2, Q3U213, Q5SNQ7, Q5XIL0, Q6GMI0, Q852K0, Q8BMS2, Q8IUL8, Q8IZJ1, Q91XF4

Diamond homologs: D3Z7H8, O15394, O19112, O35136, O75339, P20241, P70193, P98167, Q66K08, Q6PDN3, Q8IUL8, Q8WZ42, A2AAJ9, A2ABU4, O94898, P0C6S8, P18460, P18461, P21803, P22455, P22607, P29294, P29317, P35969, P53767, P54755, Q03145, Q04589, Q1KL86, Q2EY13, Q2EY14, Q2EY15, Q2VWP7, Q2VWP9, Q3UQ28, Q52KR2, Q589G5, Q5STE3, Q5VTT5, Q61851

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Extracellular matrix organization	5	9.9×	9e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	224
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1199 predictions. Top by Δscore:

Variant	Effect	Δscore
19:19539664:A:AG	acceptor_gain	1.0000
19:19539665:C:G	acceptor_gain	1.0000
19:19539671:A:AG	acceptor_gain	1.0000
19:19539672:C:G	acceptor_gain	1.0000
19:19539676:CAGAC:C	acceptor_loss	1.0000
19:19539677:A:AG	acceptor_gain	1.0000
19:19539677:AGA:A	acceptor_loss	1.0000
19:19539678:G:GA	acceptor_gain	1.0000
19:19539678:GAC:G	acceptor_gain	1.0000
19:19539773:GGAAG:G	donor_gain	1.0000
19:19539774:GAAG:G	donor_gain	1.0000
19:19539774:GAAGG:G	donor_gain	1.0000
19:19539775:AAGG:A	donor_loss	1.0000
19:19539778:G:GG	donor_gain	1.0000
19:19539779:T:A	donor_loss	1.0000
19:19542364:T:G	acceptor_gain	1.0000
19:19542642:A:G	donor_gain	1.0000
19:19542646:GTTGG:G	donor_gain	1.0000
19:19542647:T:G	donor_gain	1.0000
19:19542647:TTGG:T	donor_gain	1.0000
19:19542649:GG:G	donor_gain	1.0000
19:19542650:GG:G	donor_gain	1.0000
19:19542651:G:GG	donor_gain	1.0000
19:19542651:GTAAG:G	donor_loss	1.0000
19:19542652:T:A	donor_loss	1.0000
19:19542862:A:AG	acceptor_gain	1.0000
19:19542863:G:GG	acceptor_gain	1.0000
19:19542863:GA:G	acceptor_gain	1.0000
19:19542863:GAGAA:G	acceptor_gain	1.0000
19:19543403:TTGG:T	donor_loss	1.0000

AlphaMissense

7404 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:19540217:G:C	W59C	0.998
19:19540217:G:T	W59C	0.998
19:19540226:G:C	W62C	0.998
19:19540226:G:T	W62C	0.998
19:19540407:T:A	C123S	0.998
19:19540408:G:C	C123S	0.998
19:19545783:T:A	C1080S	0.998
19:19545783:T:C	C1080R	0.998
19:19545784:G:C	C1080S	0.998
19:19540224:T:A	W62R	0.997
19:19540224:T:C	W62R	0.997
19:19540402:T:C	F121S	0.997
19:19540440:T:A	C134S	0.997
19:19540441:G:C	C134S	0.997
19:19540462:T:C	F141S	0.997
19:19545332:G:C	W929C	0.997
19:19545332:G:T	W929C	0.997
19:19545528:T:C	C995R	0.997
19:19545785:C:G	C1080W	0.997
19:19540228:T:C	F63S	0.996
19:19540407:T:C	C123R	0.996
19:19540409:C:G	C123W	0.996
19:19545362:C:G	C939W	0.996
19:19545474:A:C	S977R	0.996
19:19545476:T:A	S977R	0.996
19:19545476:T:G	S977R	0.996
19:19545513:T:C	C990R	0.996
19:19545514:G:A	C990Y	0.996
19:19545528:T:A	C995S	0.996
19:19545529:G:C	C995S	0.996

dbSNP variants (sampled 300 via entrez): RS1001042490 (19:19541920 A>G), RS1001434526 (19:19537832 A>G), RS1001830420 (19:19536738 G>A), RS1002156629 (19:19537251 G>C,T), RS1002589236 (19:19541546 T>C), RS1002662651 (19:19541343 T>G), RS1003111560 (19:19536531 T>C), RS1003184931 (19:19536359 C>A), RS1003390344 (19:19545939 G>A), RS1003673220 (19:19539897 G>T), RS1003708722 (19:19542528 C>T), RS1003938125 (19:19546739 C>T), RS1003972336 (19:19546555 C>A), RS1003979630 (19:19542595 C>T), RS1004000371 (19:19536553 C>G,T)

Disease associations

OMIM: gene MIM:612419 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

44 associations (top):

Study	Trait	p-value
GCST000132_3	LDL cholesterol	3.000000e-09
GCST000134_2	LDL cholesterol	3.000000e-08
GCST000138_9	Triglycerides	4.000000e-09
GCST000139_9	Triglycerides	3.000000e-09
GCST000286_11	Triglycerides	4.000000e-11
GCST000287_4	LDL cholesterol	2.000000e-08
GCST000758_7	Triglycerides	2.000000e-29
GCST000759_15	LDL cholesterol	7.000000e-22
GCST000760_8	Cholesterol, total	3.000000e-38
GCST000807_10	LDL cholesterol	1.000000e-11
GCST000809_4	Triglycerides	4.000000e-08
GCST002149_11	Schizophrenia	3.000000e-09
GCST002216_23	Triglycerides	1.000000e-69
GCST002221_14	Cholesterol, total	4.000000e-77
GCST002222_24	LDL cholesterol	3.000000e-54
GCST002539_89	Schizophrenia	4.000000e-10
GCST002896_33	Cholesterol, total	8.000000e-29
GCST002897_34	Triglycerides	2.000000e-25
GCST002898_36	LDL cholesterol	3.000000e-23
GCST004233_8	LDL cholesterol levels	6.000000e-51
GCST004235_13	Total cholesterol levels	5.000000e-75
GCST004237_26	Triglyceride levels	5.000000e-71
GCST004541_2	Low density lipoprotein cholesterol levels	3.000000e-11
GCST004548_2	Total cholesterol levels	8.000000e-11
GCST004550_3	Triglyceride levels	2.000000e-08
GCST004621_161	Red cell distribution width	2.000000e-15
GCST004759_3	Very low density lipoprotein cholesterol levels	1.000000e-08
GCST004894_26	Type 2 diabetes	9.000000e-13
GCST004894_84	Type 2 diabetes	4.000000e-09
GCST005047_58	Type 2 diabetes	7.000000e-09

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0009188	Red cell distribution width
EFO:0005763	pulse pressure measurement
EFO:0004341	body fat distribution
EFO:0009963	bipolar I disorder
EFO:0009964	bipolar II disorder
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression, increases methylation	4
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
Estradiol	increases expression	2
Phenylmercuric Acetate	decreases expression, affects cotreatment	2
aristolochic acid I	increases expression	1
sulforaphane	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, increases expression	1
entinostat	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression, affects cotreatment	1
Resveratrol	affects cotreatment, decreases expression	1
Cisplatin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects cotreatment, increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	increases expression	1
Smoke	decreases expression	1
Thimerosal	decreases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	increases expression	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1
Acrylamide	increases expression	1

Clinical trials (associated diseases)

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