DOC2A

Summary

DOC2A (double C2 domain alpha, HGNC:2985) is a protein-coding gene on chromosome 16p11.2, encoding Double C2-like domain-containing protein alpha (Q14183). Calcium sensor which most probably regulates fusion of vesicles with membranes.

There are at least two protein isoforms of the Double C2 protein, namely alpha (DOC2A) and beta (DOC2B), which contain two C2-like domains. DOC2A and DOC2B are encoded by different genes; these genes are at times confused with the unrelated DAB2 gene which was initially named DOC-2. DOC2A is mainly expressed in brain and is suggested to be involved in Ca(2+)-dependent neurotransmitter release. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 8448 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_003586

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2985
Approved symbol	DOC2A
Name	double C2 domain alpha
Location	16p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000149927
Ensembl biotype	protein_coding
OMIM	604567
Entrez	8448

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 45 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000350119, ENST00000561671, ENST00000563125, ENST00000563378, ENST00000564075, ENST00000564233, ENST00000564357, ENST00000564944, ENST00000564979, ENST00000565273, ENST00000566310, ENST00000566456, ENST00000567332, ENST00000567824, ENST00000570194, ENST00000572637, ENST00000574405, ENST00000616445, ENST00000861623, ENST00000861624, ENST00000861625, ENST00000861626, ENST00000861627, ENST00000861628, ENST00000861629, ENST00000861630, ENST00000861631, ENST00000861632, ENST00000861633, ENST00000934550, ENST00000934551, ENST00000934552, ENST00000934553, ENST00000934554, ENST00000934555, ENST00000934556, ENST00000934557, ENST00000934558, ENST00000934559, ENST00000934560, ENST00000934561, ENST00000934562, ENST00000970451, ENST00000970452, ENST00000970453, ENST00000970454, ENST00000970455, ENST00000970456, ENST00000970457, ENST00000970458, ENST00000970459, ENST00000970460, ENST00000970461, ENST00000970462

RefSeq mRNA: 4 — MANE Select: NM_003586 NM_001282062, NM_001282063, NM_001282068, NM_003586

CCDS: CCDS10666

Canonical transcript exons

ENST00000350119 — 11 exons

Exon	Start	End
ENSE00000993009	30008996	30009105
ENSE00002581173	30010903	30011027
ENSE00002597008	30005514	30006331
ENSE00003460707	30009202	30009276
ENSE00003553363	30006413	30006509
ENSE00003563566	30006596	30006677
ENSE00003613495	30009478	30009557
ENSE00003628445	30009961	30010235
ENSE00003639511	30007031	30007090
ENSE00003688983	30006785	30006948
ENSE00003784138	30007173	30007299

Expression profiles

Bgee: expression breadth ubiquitous, 179 present calls, max score 97.24.

FANTOM5 (CAGE): breadth broad, TPM avg 3.4412 / max 142.9911, expressed in 556 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156985	1.5508	174
156993	1.1852	465
156990	0.2733	41
156986	0.2194	77
156988	0.0485	23
156987	0.0444	34
156989	0.0397	21
156991	0.0388	30
156992	0.0250	18
156994	0.0131	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.24	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.12	gold quality
cerebellar hemisphere	UBERON:0002245	96.59	gold quality
cerebellar cortex	UBERON:0002129	96.43	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.96	gold quality
left testis	UBERON:0004533	94.77	gold quality
right testis	UBERON:0004534	94.57	gold quality
anterior cingulate cortex	UBERON:0009835	94.39	gold quality
cingulate cortex	UBERON:0003027	94.38	gold quality
cerebellum	UBERON:0002037	94.13	gold quality
prefrontal cortex	UBERON:0000451	93.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.19	gold quality
frontal cortex	UBERON:0001870	91.96	gold quality
neocortex	UBERON:0001950	91.79	gold quality
right uterine tube	UBERON:0001302	90.83	gold quality
amygdala	UBERON:0001876	90.51	gold quality
testis	UBERON:0000473	90.31	gold quality
cerebral cortex	UBERON:0000956	89.94	gold quality
mucosa of transverse colon	UBERON:0004991	88.45	gold quality
telencephalon	UBERON:0001893	86.97	gold quality
temporal lobe	UBERON:0001871	86.47	gold quality
superior frontal gyrus	UBERON:0002661	86.37	gold quality
Ammon’s horn	UBERON:0001954	85.85	gold quality
forebrain	UBERON:0001890	85.71	gold quality
brain	UBERON:0000955	85.44	gold quality
central nervous system	UBERON:0001017	85.11	gold quality
cortical plate	UBERON:0005343	85.01	gold quality
primary visual cortex	UBERON:0002436	84.37	gold quality
caudate nucleus	UBERON:0001873	83.82	gold quality
middle temporal gyrus	UBERON:0002771	83.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.83

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

23 targeting DOC2A, 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-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-448	99.79	72.37	2103
HSA-MIR-3680-3P	99.75	72.51	3095
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4742-3P	98.73	69.82	1803
HSA-MIR-92A-1-5P	98.28	64.51	631
HSA-MIR-2355-3P	96.84	68.54	909
HSA-MIR-1225-5P	96.76	66.85	417
HSA-MIR-3654	96.43	66.55	646
HSA-MIR-4749-3P	96.40	66.24	798

Literature-anchored findings (GeneRIF, showing 3)

• Study analyzed Doc2alpha and Doc2beta and found that Doc2 responds to changes in [Ca2+], with markedly slower kinetics as compared to the cytosolic domain of syt I (syt), and operates on a timescale consistent with asynchronous neurotransmitter release. (PMID:22036572)
• this study, members of the Doc2 family of presynaptic proteins were eliminated, which caused a reduction in spontaneous neurotransmission, whereas action potential-evoked neurotransmission remained relatively normal. (PMID:28539418)
• This study demonstrated that the DOCA2 increase expression in temporal lobe in temporal lobe epilepsy. (PMID:30844661)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	doc2a	ENSDARG00000078736
mus_musculus	Doc2a	ENSMUSG00000052301
rattus_norvegicus	Doc2a	ENSRNOG00000019920

Paralogs (31): SYT7 (ENSG00000011347), SYT13 (ENSG00000019505), SYT1 (ENSG00000067715), RPH3A (ENSG00000089169), SYTL4 (ENSG00000102362), SYT17 (ENSG00000103528), SYT10 (ENSG00000110975), SYT5 (ENSG00000129990), SYT11 (ENSG00000132718), SYT4 (ENSG00000132872), SYT6 (ENSG00000134207), SYTL2 (ENSG00000137501), SYT16 (ENSG00000139973), SYTL1 (ENSG00000142765), SYT14 (ENSG00000143469), SYT2 (ENSG00000143858), SYTL5 (ENSG00000147041), SYT8 (ENSG00000149043), SYTL3 (ENSG00000164674), TC2N (ENSG00000165929), SYT9 (ENSG00000170743), SYT12 (ENSG00000173227), RPH3AL (ENSG00000181031), C2CD4C (ENSG00000183186), C2CD4A (ENSG00000198535), SYT15 (ENSG00000204176), C2CD4B (ENSG00000205502), SYT3 (ENSG00000213023), C2CD4D (ENSG00000225556), DOC2B (ENSG00000272636), SYT15B (ENSG00000277758)

Protein

Protein identifiers

Double C2-like domain-containing protein alpha — Q14183 (reviewed: Q14183)

All UniProt accessions (7): Q14183, H3BNF7, H3BSH4, H3BTI1, H3BU41, I3L194, I3L3P9

UniProt curated annotations — full annotation on UniProt →

Function. Calcium sensor which most probably regulates fusion of vesicles with membranes. Binds calcium and phospholipids. May be involved in calcium dependent neurotransmitter release through the interaction with UNC13A. May be involved in calcium-dependent spontaneous release of neurotransmitter in absence of action potentials in neuronal cells. Regulates Ca(2+)-dependent secretory lysosome exocytosis in mast cells.

Subunit / interactions. Interacts (via N-terminus) with UNC13A. Interacts with cytoplasmic dynein light chain DYNLT1. Interacts with UNC13D.

Subcellular location. Lysosome. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Synapse. Synaptosome.

Tissue specificity. Predominantly expressed in brain. Also expressed in testis.

Domain organisation. C2 domain 1 is involved in binding calcium and phospholipids.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14183-1	1	yes
Q14183-2	2

RefSeq proteins (4): NP_001268991, NP_001268992, NP_001268997, NP_003577* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001565	Synaptotagmin	Domain
IPR014638	Doc2	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR043566	Rabphilin/DOC2/Noc2	Family
IPR047022	Rabphilin_Doc2_C2A	Domain

Pfam: PF00168

UniProt features (37 total): binding site 12, strand 8, sequence conflict 4, splice variant 3, helix 3, domain 2, region of interest 2, chain 1, sequence variant 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4MJJ	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14183-F1	79.55	0.61

Functional residue map

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

Ligand- & substrate-binding residues (12): 282; 288; 342; 342; 344; 344; 350; 120; 126; 181; 183; 282

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 175 (showing top): GOBP_REGULATION_OF_VESICLE_FUSION, ACTACCT_MIR196A_MIR196B, MODULE_274, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_DEPENDENT_EXOCYTOSIS, GOBP_VESICLE_ORGANIZATION, GCANCTGNY_MYOD_Q6, AREB6_03, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, CAGCTG_AP4_Q5, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (8): chemical synaptic transmission (GO:0007268), nervous system development (GO:0007399), regulation of calcium ion-dependent exocytosis (GO:0017158), positive regulation of calcium ion-dependent exocytosis (GO:0045956), spontaneous neurotransmitter secretion (GO:0061669), calcium-dependent activation of synaptic vesicle fusion (GO:0099502), exocytosis (GO:0006887), synaptic vesicle exocytosis (GO:0016079)

GO Molecular Function (3): calcium-dependent phospholipid binding (GO:0005544), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (8): lysosome (GO:0005764), neuron projection (GO:0043005), synapse (GO:0045202), extrinsic component of synaptic vesicle membrane (GO:0098850), glutamatergic synapse (GO:0098978), membrane (GO:0016020), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcium-ion regulated exocytosis	2
neurotransmitter secretion	2
anterograde trans-synaptic signaling	1
system development	1
regulation of regulated secretory pathway	1
regulation of calcium ion-dependent exocytosis	1
positive regulation of regulated secretory pathway	1
spontaneous synaptic transmission	1
synaptic vesicle exocytosis	1
positive regulation of synaptic vesicle fusion to presynaptic active zone membrane	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
regulated exocytosis	1
establishment of localization in cell	1
presynapse	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
phospholipid binding	1
cation binding	1
binding	1
lytic vacuole	1
plasma membrane bounded cell projection	1
cell junction	1
synaptic vesicle membrane	1
extrinsic component of organelle membrane	1
synapse	1
cellular anatomical structure	1
synaptic vesicle	1
exocytic vesicle membrane	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

944 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOC2A	UNC13B	O14795	826
DOC2A	SNAP25	P13795	752
DOC2A	UNC13A	Q9UPW8	697
DOC2A	HIRIP3	Q9BW71	696
DOC2A	SEZ6L2	Q6UXD5	675
DOC2A	ASPHD1	Q5U4P2	673
DOC2A	KCTD13	Q8WZ19	671
DOC2A	MLF2	Q15773	649
DOC2A	RAB27A	P51159	639
DOC2A	FIMP1	Q96LL3	626
DOC2A	SCGN	O76038	618
DOC2A	TAOK2	Q9UL54	606
DOC2A	KIF22	Q14807	605
DOC2A	C16orf54	Q6UWD8	600
DOC2A	YPEL3	P61236	597

IntAct

18 interactions, top by confidence:

A	B	Type	Score
DOC2A	UBASH3B	psi-mi:“MI:0915”(physical association)	0.800
UBASH3B	DOC2A	psi-mi:“MI:0915”(physical association)	0.800
SCGN	SNAP23	psi-mi:“MI:0914”(association)	0.550
SETMAR	HSPA8	psi-mi:“MI:0914”(association)	0.530
DOC2A	DOC2B	psi-mi:“MI:0914”(association)	0.530
GPR137B	DOC2A	psi-mi:“MI:0914”(association)	0.530
DOC2A	VDAC1	psi-mi:“MI:0915”(physical association)	0.400
DOC2A	RAP1GDS1	psi-mi:“MI:0915”(physical association)	0.370
SCGN	SNAP23	psi-mi:“MI:0914”(association)	0.350
GPR137B	SMC2	psi-mi:“MI:0914”(association)	0.350
SCGN	CNOT1	psi-mi:“MI:0914”(association)	0.350
TRNT1	H1-3	psi-mi:“MI:0914”(association)	0.350
DOC2A	MVK	psi-mi:“MI:0914”(association)	0.350
SLC22A23	MVK	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): DOC2A (Affinity Capture-MS), DOC2A (Affinity Capture-MS), TTC21B (Affinity Capture-MS), DOC2B (Affinity Capture-MS), UBASH3B (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), DOC2B (Affinity Capture-MS), TTC21B (Affinity Capture-MS), KCTD21 (Affinity Capture-MS), DOC2A (Affinity Capture-MS), UBASH3B (Affinity Capture-MS), DOC2A (Affinity Capture-MS), DOC2A (Affinity Capture-MS), UBASH3B (Two-hybrid), DOC2A (Proximity Label-MS)

ESM2 similar proteins: A0FGR8, A0FGR9, O00445, O08835, O35681, O75038, P05129, P10688, P10829, P10895, P21579, P21707, P21709, P24505, P24506, P29101, P40748, P41823, P46096, P46097, P47861, P48018, P51178, P54760, P63318, P63319, P70611, Q06418, Q14183, Q3TZZ7, Q3U7R1, Q4R4U2, Q5DTI8, Q5FWL4, Q5M7N9, Q5R4J5, Q5RAG2, Q60HC0, Q7TNF0, Q8K2J0

Diamond homologs: A0A075F932, A0FGR8, A4IJ05, K8FE10, O00445, O00750, O08625, O08835, O35681, O43581, P04409, P05128, P05129, P05130, P05696, P10102, P10829, P13677, P17252, P20444, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

1604 predictions. Top by Δscore:

Variant	Effect	Δscore
16:30006406:C:A	donor_gain	1.0000
16:30006407:CCTCA:C	donor_loss	1.0000
16:30006408:CTCA:C	donor_loss	1.0000
16:30006409:TCA:T	donor_loss	1.0000
16:30006410:CACCA:C	donor_loss	1.0000
16:30006411:A:AC	donor_gain	1.0000
16:30006411:A:AG	donor_loss	1.0000
16:30006412:C:CC	donor_gain	1.0000
16:30006412:C:CG	donor_loss	1.0000
16:30006507:CTC:C	acceptor_gain	1.0000
16:30006586:T:TA	donor_gain	1.0000
16:30006592:GTACC:G	donor_loss	1.0000
16:30006593:TACCT:T	donor_loss	1.0000
16:30006595:CCT:C	donor_gain	1.0000
16:30006597:T:TA	donor_gain	1.0000
16:30006675:TAC:T	acceptor_gain	1.0000
16:30006676:AC:A	acceptor_gain	1.0000
16:30006677:CC:C	acceptor_gain	1.0000
16:30006677:CCT:C	acceptor_loss	1.0000
16:30006678:C:CA	acceptor_loss	1.0000
16:30006678:C:CC	acceptor_gain	1.0000
16:30006684:G:C	acceptor_gain	1.0000
16:30006684:G:GC	acceptor_gain	1.0000
16:30006779:GCTCA:G	donor_loss	1.0000
16:30006780:CTCA:C	donor_loss	1.0000
16:30006781:TCAC:T	donor_loss	1.0000
16:30006782:CACG:C	donor_loss	1.0000
16:30006783:A:AC	donor_gain	1.0000
16:30006783:ACGT:A	donor_gain	1.0000
16:30006783:ACGTC:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000037841 (16:30010428 G>T), RS1000108327 (16:30019114 T>C), RS1000241646 (16:30021255 G>A,T), RS1000318863 (16:30024907 C>T), RS1000516839 (16:30007096 G>A,C), RS1001003157 (16:30014981 G>A), RS1001010704 (16:30009587 G>A), RS1001118452 (16:30008355 T>G), RS1001378835 (16:30005553 C>A,T), RS1001399239 (16:30023561 C>G,T), RS1001441936 (16:30009410 G>A,T), RS1001455259 (16:30011359 C>A,T), RS1001459423 (16:30013803 C>T), RS1001604345 (16:30006051 C>T), RS1001648775 (16:30007640 T>C)

Disease associations

OMIM: gene MIM:604567 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST002539_82	Schizophrenia	5.000000e-11
GCST004521_236	Autism spectrum disorder or schizophrenia	4.000000e-10
GCST004946_142	Schizophrenia	8.000000e-13
GCST006803_23	Schizophrenia	6.000000e-13
GCST007293_15	Body fat distribution (arm fat ratio)	6.000000e-06
GCST007293_81	Body fat distribution (arm fat ratio)	4.000000e-08
GCST007611_22	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7.000000e-09
GCST008163_270	Height	1.000000e-06
GCST010703_269	Brain morphology (MOSTest)	4.000000e-13

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution
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

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Resveratrol	decreases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, decreases methylation	2
Smoke	decreases expression, increases abundance, increases expression	2
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
sodium arsenite	decreases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	decreases methylation	1
2-palmitoylglycerol	increases expression	1
entinostat	affects cotreatment, increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression	1
MT19c compound	decreases expression	1
Air Pollutants	increases expression, increases abundance	1
Atrazine	increases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Methapyrilene	decreases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	increases expression, decreases expression	1

Clinical trials (associated diseases)

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