C2CD2L

Summary

C2CD2L (C2CD2 like, HGNC:29000) is a protein-coding gene on chromosome 11q23.3, encoding Phospholipid transfer protein C2CD2L (O14523). Lipid-binding protein that transports phosphatidylinositol, the precursor of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), from its site of synthesis in the endoplasmic reticulum to the cell membrane.

Enables phosphatidylinositol binding activity and phosphatidylinositol transfer activity. Involved in positive regulation of insulin secretion involved in cellular response to glucose stimulus. Located in cortical endoplasmic reticulum; cytoplasmic side of apical plasma membrane; and endoplasmic reticulum-plasma membrane contact site.

Source: NCBI Gene 9854 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 128 total
• MANE Select transcript: NM_001290474

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29000
Approved symbol	C2CD2L
Name	C2CD2 like
Location	11q23.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0285
Ensembl gene	ENSG00000172375
Ensembl biotype	protein_coding
OMIM	617582
Entrez	9854

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 20 protein_coding, 5 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000336702, ENST00000525598, ENST00000527854, ENST00000528271, ENST00000528586, ENST00000529600, ENST00000529874, ENST00000529885, ENST00000533458, ENST00000534024, ENST00000648610, ENST00000861314, ENST00000861315, ENST00000861316, ENST00000861317, ENST00000861318, ENST00000861319, ENST00000861320, ENST00000861321, ENST00000861322, ENST00000938387, ENST00000938388, ENST00000945176, ENST00000945177, ENST00000945178, ENST00000945179, ENST00000945180, ENST00000945181

RefSeq mRNA: 5 — MANE Select: NM_001290474 NM_001290474, NM_001382611, NM_001382612, NM_001382613, NM_014807

CCDS: CCDS8413, CCDS91609

Canonical transcript exons

ENST00000648610 — 14 exons

Exon	Start	End
ENSE00001127740	119114080	119114365
ENSE00001195641	119110104	119110199
ENSE00001258016	119113611	119113712
ENSE00001258025	119112700	119112874
ENSE00001786076	119113855	119113988
ENSE00002154561	119116045	119118544
ENSE00003502381	119111263	119111374
ENSE00003506165	119110561	119110680
ENSE00003508820	119112482	119112609
ENSE00003535223	119110847	119110957
ENSE00003557125	119112328	119112392
ENSE00003568879	119111052	119111168
ENSE00003656608	119111521	119111629
ENSE00003834653	119107344	119108095

Expression profiles

Bgee: expression breadth ubiquitous, 235 present calls, max score 92.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.1018 / max 348.8806, expressed in 1747 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
117095	10.5172	1726
117093	0.3947	175
117094	0.1899	57

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	92.45	gold quality
prefrontal cortex	UBERON:0000451	92.08	gold quality
granulocyte	CL:0000094	91.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	90.75	gold quality
nucleus accumbens	UBERON:0001882	90.60	gold quality
caudate nucleus	UBERON:0001873	90.25	gold quality
cerebellar hemisphere	UBERON:0002245	89.97	gold quality
cerebellar cortex	UBERON:0002129	89.85	gold quality
putamen	UBERON:0001874	89.55	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	89.41	gold quality
cerebellum	UBERON:0002037	88.44	gold quality
frontal cortex	UBERON:0001870	88.31	gold quality
cingulate cortex	UBERON:0003027	88.27	gold quality
right uterine tube	UBERON:0001302	88.11	gold quality
anterior cingulate cortex	UBERON:0009835	88.01	gold quality
neocortex	UBERON:0001950	87.93	gold quality
pituitary gland	UBERON:0000007	87.90	gold quality
adenohypophysis	UBERON:0002196	87.75	gold quality
telencephalon	UBERON:0001893	87.16	gold quality
amygdala	UBERON:0001876	87.13	gold quality
mucosa of transverse colon	UBERON:0004991	87.00	gold quality
forebrain	UBERON:0001890	86.98	gold quality
cerebral cortex	UBERON:0000956	86.93	gold quality
cortical plate	UBERON:0005343	86.84	gold quality
brain	UBERON:0000955	86.52	gold quality
central nervous system	UBERON:0001017	86.35	gold quality
leukocyte	CL:0000738	85.78	gold quality
monocyte	CL:0000576	85.75	gold quality
hypothalamus	UBERON:0001898	85.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.28

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

65 targeting C2CD2L, 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-6127	100.00	66.76	2188
HSA-MIR-150-5P	99.99	66.69	1976
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-605-3P	99.88	69.22	1833
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-4465	99.71	72.56	2096
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-186-3P	99.51	66.24	1685
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-5697	99.39	67.74	1249
HSA-MIR-4311	99.31	70.47	3041
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119

Literature-anchored findings (GeneRIF, showing 4)

• Paper describes the tissue distribution, interaction partners and pathway where this protein functions. This paper shows that C2CD2L (TMEM24) interacts with insulin and plays a role in Glucose stimulated insulin secretion in pancreatic islets. Also, at protein level shows enrichment for expression in pancreatic islets and brain. (PMID:24012759)
• In the absence of TMEM24, calcium oscillations are abolished, leading to a defect in triggered insulin release. (PMID:28209843)
• Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24. (PMID:33479206)
• A complex of the lipid transport ER proteins TMEM24 and C2CD2 with band 4.1 at cell-cell contacts. (PMID:39158698)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	c2cd2l	ENSDARG00000061066
mus_musculus	C2cd2l	ENSMUSG00000032120
rattus_norvegicus	C2cd2l	ENSRNOG00000009719
drosophila_melanogaster	CG10737	FBGN0034420
caenorhabditis_elegans		WBGENE00020012

Paralogs (1): C2CD2 (ENSG00000157617)

Protein

Protein identifiers

Phospholipid transfer protein C2CD2L — O14523 (reviewed: O14523)

Alternative names: C2 domain-containing protein 2-like, Transmembrane protein 24

All UniProt accessions (2): E9PK05, O14523

UniProt curated annotations — full annotation on UniProt →

Function. Lipid-binding protein that transports phosphatidylinositol, the precursor of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), from its site of synthesis in the endoplasmic reticulum to the cell membrane. It thereby maintains the pool of cell membrane phosphoinositides, which are degraded during phospholipase C (PLC) signaling. Plays a key role in the coordination of Ca(2+) and phosphoinositide signaling: localizes to sites of contact between the endoplasmic reticulum and the cell membrane, where it tethers the two bilayers. In response to elevation of cytosolic Ca(2+), it is phosphorylated at its C-terminus and dissociates from the cell membrane, abolishing phosphatidylinositol transport to the cell membrane. Positively regulates insulin secretion in response to glucose: phosphatidylinositol transfer to the cell membrane allows replenishment of PI(4,5)P2 pools and calcium channel opening, priming a new population of insulin granules.

Subunit / interactions. Homodimer. Interacts (via the SMP-LBD and C2 domains) with phosphorylated alt-RPL36, a protein produced by an alternative reading frame of the RPL36 gene; the interaction is required for localization of alt-RPL36 to the endoplasmic reticulum and inhibits C2CD2L-dependent transport of phosphatidylinositol from the endoplasmic reticulum to the cell membrane.

Subcellular location. Endoplasmic reticulum membrane. Cell membrane.

Post-translational modifications. Phosphorylation at the C-terminus acidifies the protein and leads to disassociation from the acidic cell membrane. Reassociates with the cell membrane upon dephosphorylation.

Domain organisation. The SMP-LBD domain is a lipid transport module, which binds glycerolipids with a preference for phosphatidylinositol (PI).

Isoforms (2)

UniProt ID	Names	Canonical?
O14523-1	1	yes
O14523-2	2

RefSeq proteins (5): NP_001277403, NP_001369540, NP_001369541, NP_001369542, NP_055622 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR039934	C2CD2/C2CD2L	Family
IPR040885	SMP_C2CD2L	Domain

Pfam: PF00168, PF18696

UniProt features (46 total): modified residue 18, strand 7, region of interest 5, compositionally biased region 4, helix 3, topological domain 2, domain 2, chain 1, transmembrane region 1, splice variant 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5TOD	X-RAY DIFFRACTION	2.96

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O14523-F1	64.75	0.17

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 (18): 59, 358, 374, 411, 417, 419, 428, 464, 468, 470, 613, 619, 621, 623, 638, 660, 662, 674

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (4): positive regulation of insulin secretion involved in cellular response to glucose stimulus (GO:0035774), lipid transport (GO:0006869), phospholipid transport (GO:0015914), intermembrane lipid transfer (GO:0120009)

GO Molecular Function (5): phosphatidylinositol transfer activity (GO:0008526), phosphatidylinositol binding (GO:0035091), insulin binding (GO:0043559), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (7): endoplasmic reticulum membrane (GO:0005789), plasma membrane (GO:0005886), cortical endoplasmic reticulum (GO:0032541), endoplasmic reticulum-plasma membrane contact site (GO:0140268), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), cytoplasmic side of apical plasma membrane (GO:0098592)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
lipid transport	2
binding	2
positive regulation of insulin secretion	1
insulin secretion involved in cellular response to glucose stimulus	1
regulation of insulin secretion involved in cellular response to glucose stimulus	1
transport	1
lipid localization	1
organophosphate ester transport	1
membrane organization	1
phosphatidylinositol binding	1
lipid transfer activity	1
anion binding	1
protein binding	1
peptide hormone binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
cell cortex	1
endoplasmic reticulum tubular network	1
organelle membrane contact site	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
cellular anatomical structure	1
cytoplasmic side of plasma membrane	1
apical plasma membrane	1

Protein interactions and networks

STRING

686 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C2CD2L	ESYT1	Q9BSJ8	621
C2CD2L	ESYT2	A0FGR8	584
C2CD2L	PITPNM1	O00562	582
C2CD2L	OSBPL5	Q9H0X9	571
C2CD2L	OSBPL8	Q9BZF1	516
C2CD2L	PITPNM2	Q9BZ72	473
C2CD2L	TMEM217	Q8N7C4	469
C2CD2L	PDZD8	Q8NEN9	451
C2CD2L	OSBP	P22059	448
C2CD2L	TEX2	Q8IWB9	447
C2CD2L	SEC22B	O75396	444
C2CD2L	ESYT3	A0FGR9	431
C2CD2L	PRRT2	Q7Z6L0	408
C2CD2L	VAPA	Q9P0L0	407
C2CD2L	GRAMD2A	Q8IUY3	400

IntAct

178 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
C2CD2L	BIK	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	TMEM88	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	AMIGO1	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	TMEM248	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	LEPROTL1	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	ZDHHC15	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	TMEM14B	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	AQP6	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	REEP2	psi-mi:“MI:0915”(physical association)	0.560
C2CD2L	TMX2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (162): C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS), C2CD2L (Affinity Capture-MS)

ESM2 similar proteins: A1L3I3, A2A699, A2AEV7, A5PKW4, A8MVW0, D3ZG83, F1MUS9, O14511, O14523, O14559, O35182, O43541, O94983, P46062, P56974, Q02779, Q2THW8, Q2THX0, Q3B8N7, Q3KP66, Q53LP3, Q5BJT1, Q5DTT2, Q5DU25, Q5JU85, Q5RBI7, Q5RD34, Q5VUB5, Q63HR2, Q66H43, Q66L42, Q69YU3, Q69ZH9, Q6PDH0, Q6R6L0, Q7TN12, Q80VC9, Q80Y50, Q80YF9, Q86VZ4

Diamond homologs: E9Q3C1, O14523, Q80X80, Q9Y426

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	102
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2513 predictions. Top by Δscore:

Variant	Effect	Δscore
11:119108091:ACGGG:A	donor_gain	1.0000
11:119108092:CGGG:C	donor_gain	1.0000
11:119108093:GGG:G	donor_gain	1.0000
11:119108093:GGGG:G	donor_gain	1.0000
11:119108094:GG:G	donor_gain	1.0000
11:119108094:GGG:G	donor_gain	1.0000
11:119108095:GG:G	donor_gain	1.0000
11:119108096:G:GA	donor_loss	1.0000
11:119108096:G:GG	donor_gain	1.0000
11:119108097:T:A	donor_loss	1.0000
11:119110556:CTCA:C	acceptor_loss	1.0000
11:119110557:TCAG:T	acceptor_loss	1.0000
11:119110558:CAG:C	acceptor_loss	1.0000
11:119110676:CACAG:C	donor_loss	1.0000
11:119110679:AGGTA:A	donor_loss	1.0000
11:119110680:GG:G	donor_loss	1.0000
11:119110681:G:GA	donor_loss	1.0000
11:119110682:T:A	donor_loss	1.0000
11:119110844:TAGTT:T	acceptor_loss	1.0000
11:119110845:A:AG	acceptor_gain	1.0000
11:119110845:AGTT:A	acceptor_gain	1.0000
11:119110846:G:GC	acceptor_gain	1.0000
11:119110846:GTT:G	acceptor_gain	1.0000
11:119110846:GTTG:G	acceptor_gain	1.0000
11:119110953:GGGAG:G	donor_gain	1.0000
11:119110954:GGAGG:G	donor_gain	1.0000
11:119111047:T:TA	acceptor_gain	1.0000
11:119111047:TGCAG:T	acceptor_gain	1.0000
11:119111049:CAG:C	acceptor_gain	1.0000
11:119111049:CAGAG:C	acceptor_gain	1.0000

AlphaMissense

4514 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:119112824:T:A	V446D	1.000
11:119113972:T:A	I536N	1.000
11:119112833:T:A	V449D	0.999
11:119113912:T:C	L516P	0.999
11:119113966:T:C	L534P	0.999
11:119113972:T:C	I536T	0.999
11:119113972:T:G	I536S	0.999
11:119113900:C:A	A512E	0.998
11:119113966:T:A	L534H	0.998
11:119111610:T:A	W334R	0.997
11:119111610:T:C	W334R	0.997
11:119112815:G:T	G443V	0.997
11:119113903:T:A	I513N	0.997
11:119113903:T:C	I513T	0.997
11:119112797:G:C	R437P	0.996
11:119113899:G:C	A512P	0.996
11:119113903:T:G	I513S	0.996
11:119113969:T:A	I535N	0.996
11:119110895:T:A	W207R	0.995
11:119110895:T:C	W207R	0.995
11:119112780:G:C	K431N	0.995
11:119112780:G:T	K431N	0.995
11:119112824:T:G	V446G	0.995
11:119113912:T:A	L516Q	0.995
11:119113959:A:C	S532R	0.995
11:119113961:C:A	S532R	0.995
11:119113961:C:G	S532R	0.995
11:119113969:T:C	I535T	0.995
11:119113969:T:G	I535S	0.995
11:119111612:G:C	W334C	0.994

dbSNP variants (sampled 300 via entrez): RS1000033841 (11:119115759 T>C), RS1000060882 (11:119106781 G>A), RS1000088629 (11:119106598 T>C), RS1000213032 (11:119102476 T>C,G), RS1000265564 (11:119102674 T>C), RS1000565819 (11:119109423 C>G), RS1000694241 (11:119118288 C>T), RS1000723207 (11:119118477 G>A), RS1001062263 (11:119105035 C>A,T), RS1001285168 (11:119107081 T>G), RS1001327979 (11:119110012 C>T), RS1001356607 (11:119111685 T>G), RS1001491821 (11:119116517 C>A), RS1001569587 (11:119107286 T>C,G), RS1001610741 (11:119110349 T>A,C,G)

Disease associations

OMIM: gene MIM:617582 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST006979_228	Heel bone mineral density	1.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, increases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	affects cotreatment, increases expression	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
Air Pollutants	affects expression, increases abundance	1
Caffeine	affects phosphorylation	1
Catechin	affects cotreatment, decreases expression	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Lead	affects expression	1
Ozone	affects expression, increases abundance	1
Phthalic Acids	decreases methylation	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	increases expression	1
Valproic Acid	increases expression, increases methylation	1

Clinical trials (associated diseases)

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