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): 73 total — 2 pathogenic
• GTEx eGene: eQTL in 31 tissues, sQTL in 6 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 0.97 (unconstrained)
• MANE Select transcript: NM_003586
• Notable: 73 clinical variants but no curated precision-oncology (CIViC) evidence yet

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: 57 — 48 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 2 nonsense_mediated_decay

MANE Select: ENST00000350119

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 3, TSL 3: 3, TSL 4: 4, TSL 5: 5

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, ENST00001051675, ENST00001051676, ENST00001135541

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.

Highest expression (Bgee): frontal lobe, hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex, Brodmann (1909) area 9.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DOC2A is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 31 tissues and its splicing (sQTL) in 6 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 37 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Testis	sqtl	1.4e-12	-0.55	16:30030645:A:G
Colon Transverse	eqtl	4.5e-12	-0.16	16:30027326:A:G
Esophagus Mucosa	eqtl	7.1e-09	-0.20	16:30056216:TCTC:T
Brain Cerebellar Hemisphere	sqtl	7.7e-09	-0.81	16:30003243:C:T
Esophagus Gastroesophageal Junction	eqtl	9.4e-09	-0.24	16:30057148:T:G
Brain Cortex	sqtl	3.0e-08	+0.92	16:29971163:G:A
Brain Frontal Cortex BA9	sqtl	8.7e-08	+0.75	16:30003243:C:T
Thyroid	eqtl	5.1e-07	-0.17	16:30039173:G:A
Spleen	eqtl	1.9e-06	-0.27	16:29959536:C:G
Artery Aorta	eqtl	4.3e-06	-0.25	16:30037232:C:T
Esophagus Muscularis	eqtl	9.6e-06	-0.15	16:30057148:T:G
Heart Atrial Appendage	eqtl	5.6e-05	-0.20	16:30090275:C:A
Small Intestine Terminal Ileum	eqtl	9.8e-05	-0.33	16:30057148:T:G
Adipose Subcutaneous	eqtl	1.3e-04	-0.15	16:30004701:C:T
Brain Cerebellum	eqtl	1.5e-04	+0.29	16:30055011:CCT:C
Stomach	eqtl	3.2e-04	-0.26	16:30007399:C:T
Pancreas	eqtl	3.7e-04	-0.21	16:30030645:A:G
Artery Tibial	eqtl	3.9e-04	-0.17	16:30067171:G:C
Heart Left Ventricle	eqtl	4.2e-04	-0.16	16:30039173:G:A
Adipose Visceral Omentum	eqtl	5.6e-04	-0.11	16:29997323:C:T

FANTOM5 promoters

showing 10 of 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

showing 100 of 292 tissues 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
Brodmann (1909) area 46	UBERON:0006483	82.92	silver quality
nucleus accumbens	UBERON:0001882	82.81	gold quality
Brodmann (1909) area 10	UBERON:0013541	82.68	gold quality
left ovary	UBERON:0002119	82.53	gold quality
orbitofrontal cortex	UBERON:0004167	82.42	silver quality
postcentral gyrus	UBERON:0002581	81.94	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.89	gold quality
entorhinal cortex	UBERON:0002728	81.66	gold quality
hypothalamus	UBERON:0001898	81.60	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	81.27	gold quality
right ovary	UBERON:0002118	80.64	gold quality
parietal lobe	UBERON:0001872	80.11	gold quality
occipital lobe	UBERON:0002021	79.87	gold quality
adenohypophysis	UBERON:0002196	79.39	gold quality
putamen	UBERON:0001874	79.27	gold quality
pituitary gland	UBERON:0000007	78.97	gold quality
transverse colon	UBERON:0001157	78.67	gold quality
Brodmann (1909) area 23	UBERON:0013554	78.47	silver quality
right lung	UBERON:0002167	77.08	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	76.96	gold quality
right adrenal gland cortex	UBERON:0035827	76.95	gold quality
cerebellar vermis	UBERON:0004720	75.93	silver quality
ventricular zone	UBERON:0003053	75.90	gold quality
spinal cord	UBERON:0002240	74.94	gold quality
ovary	UBERON:0000992	74.79	gold quality
right adrenal gland	UBERON:0001233	74.61	gold quality
ganglionic eminence	UBERON:0004023	73.69	gold quality
left adrenal gland cortex	UBERON:0035825	73.36	gold quality
frontal pole	UBERON:0002795	73.10	silver quality
adrenal cortex	UBERON:0001235	73.01	gold quality
left adrenal gland	UBERON:0001234	72.48	gold quality
spleen	UBERON:0002106	72.10	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.41	gold quality
lower esophagus mucosa	UBERON:0035834	71.33	gold quality
paraflocculus	UBERON:0005351	70.48	gold quality
adrenal gland	UBERON:0002369	69.83	gold quality
endometrium epithelium	UBERON:0004811	69.75	gold quality
bronchial epithelial cell	CL:0002328	69.46	silver quality
metanephros cortex	UBERON:0010533	69.46	gold quality
apex of heart	UBERON:0002098	69.36	gold quality
colon	UBERON:0001155	69.18	gold quality
epithelium of bronchus	UBERON:0002031	68.98	silver quality
rectum	UBERON:0001052	68.89	gold quality
large intestine	UBERON:0000059	68.62	gold quality
substantia nigra	UBERON:0002038	68.60	gold quality
small intestine Peyer’s patch	UBERON:0003454	68.60	gold quality
bronchus	UBERON:0002185	68.58	silver quality
omental fat pad	UBERON:0010414	68.39	gold quality
peritoneum	UBERON:0002358	68.36	gold quality
midbrain	UBERON:0001891	67.96	gold quality
prostate gland	UBERON:0002367	67.94	gold quality
intestine	UBERON:0000160	67.69	gold quality
upper lobe of left lung	UBERON:0008952	67.64	gold quality
adipose tissue of abdominal region	UBERON:0007808	67.63	gold quality
adrenal tissue	UBERON:0018303	67.33	gold quality
endocervix	UBERON:0000458	67.08	gold quality
ectocervix	UBERON:0012249	66.94	gold quality
middle frontal gyrus	UBERON:0002702	66.87	gold quality
muscle layer of sigmoid colon	UBERON:0035805	66.68	gold quality
small intestine	UBERON:0002108	66.25	gold quality
lower esophagus	UBERON:0013473	65.87	gold quality
lower esophagus muscularis layer	UBERON:0035833	65.85	gold quality
upper lobe of lung	UBERON:0008948	65.50	gold quality
cortex of kidney	UBERON:0001225	65.47	gold quality
esophagus mucosa	UBERON:0002469	65.31	gold quality
anatomical system	UBERON:0000467	65.25	gold quality
esophagus	UBERON:0001043	65.15	gold quality
adult mammalian kidney	UBERON:0000082	65.13	gold quality
body of uterus	UBERON:0009853	65.13	gold quality
multicellular organism	UBERON:0000468	65.04	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

HPA expression

RNA tissue specificity: Group enriched

showing 60 of 73 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Postcentral gyrus	tissue	63.2
Prefrontal cortex	tissue	43.8
Cerebral cortex	tissue	43.8
Motor cortex	tissue	39.8
Hippocampus	tissue	39.7
Retrosplenial and cingulate cortex	tissue	39.1
Frontal cortex	tissue	34.7
Somatosensory cortex	tissue	33.4
Hippocampal formation	tissue	32.9
Entorhinal cortex	tissue	32.9
Retrosplenial cortex	tissue	32.8
Insular cortex	tissue	32.0
Temporal cortex	tissue	31.6
Occipital cortex	tissue	25.5
Choroid plexus	tissue	21.6
Locus coeruleus	tissue	17.1
Amygdala	tissue	16.4
Nucleus accumbens	tissue	15.5
Testis	tissue	10.6
Pituitary gland	tissue	8.1
Spinal cord	tissue	7.8
Periaqueductal gray	tissue	7.4
Hypothalamus	tissue	6.8
Medulla oblongata	tissue	6.5
Septum	tissue	6.5
Thalamus	tissue	6.2
Olfactory bulb	tissue	6.0
Pons	tissue	5.9
Caudate putamen	tissue	5.4
Superior colliculi	tissue	4.7
Midbrain	tissue	4.6
Corpus callosum	tissue	4.5
Ventral forebrain	tissue	4.5
Cerebellum	tissue	3.8
Substantia nigra	tissue	3.6
Ovary	tissue	3.1
Basal ganglia	tissue	2.3
Lung	tissue	2.1
Vagina	tissue	2.0
Putamen	tissue	2.0
Spleen	tissue	2.0
Fallopian tube	tissue	2.0
Colon	tissue	1.8
Adrenal gland	tissue	1.6
Breast	tissue	1.3
Rectum	tissue	1.2
Prostate	tissue	1.2
Bone marrow	tissue	1.2
Retina	tissue	1.0
Small intestine	tissue	1.0
Parathyroid gland	tissue	0.8
Gallbladder	tissue	0.7
Duodenum	tissue	0.7
Salivary gland	tissue	0.6
Smooth muscle	tissue	0.6
Seminal vesicle	tissue	0.5
Endometrium 1	tissue	0.5
Kidney	tissue	0.5
Cervix	tissue	0.4
Stomach 1	tissue	0.4

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Temporo-occipital transitional zone (105.1), Olfactory area (94.9), Perirhinal gyrus (92.4), Claustrum (86.6), Posterior insular cortex (86.2).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting DOC2A by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

23 miRNAs:

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

Functional genomics

gnomAD constraint: pLI 1.58e-08, LOEUF 0.974, missense Z 1.32 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000350119 — one region, missense o/e 0.86.

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

2 orthologs

Organism	Symbol	Gene ID
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)

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:109446) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 6 distinct phenotype terms.

Mouse phenotype (MP)	Records
reduced long-term potentiation	1
abnormal passive avoidance behavior	1
increased corpus callosum size	1
increased primary motor cortex size	1
increased cingulate cortex size	1
increased secondary somatosensory cortex size	1

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Bos taurus	P48018	99.8%	Diamond
Pongo abelii	Q5R4J5	99.8%	Diamond
Macaca fascicularis	Q60HC0	99.8%	Diamond
Anser cygnoides	A0A075F932	98.8%	Diamond
Gallus gallus	P47191	98.8%	Diamond
Xenopus laevis	Q5FWL4	94.4%	Diamond
Diplobatis ommata	P24505	85.5%	Diamond
Arabidopsis thaliana	Q9LP65	85.0%	Diamond
Xenopus tropicalis	B3DLH6	75.6%	Diamond
Drosophila melanogaster	P21521	75.2%	Diamond
Caenorhabditis elegans	P34693	73.1%	Diamond
Aplysia californica	P41823	70.7%	Diamond
Saccharomyces cerevisiae S288C	P48231	54.8%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
FIMP1	protein-coding	146378
ALDOA	protein-coding	226
INO80E	protein-coding	283899
PPP4C	protein-coding	5531
TBX6	protein-coding	6911
TLCD3B	protein-coding	83723
KCTD13-DT	ncRNA	107984836
TMEM219	protein-coding	124446
KCTD13	protein-coding	253980
HIRIP3	protein-coding	8479
TAOK2	protein-coding	9344

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

Structure

Experimental structures (PDB)

1 structures by resolution:

PDB	Title	Method	Resolution (Å)
4MJJ	Crystal structure of the C2A domain of DOC2A	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

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

Human Protein Atlas

Protein class: Predicted intracellular proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): cell junctions; nucleoli; nucleoplasm

Antibody reliability (HPA): IF approved

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)

Position	Role
282	Ca(2+)
288	Ca(2+)
342	Ca(2+)
344	Ca(2+)
350	Ca(2+)
120	Ca(2+)
126	Ca(2+)
181	Ca(2+)
183	Ca(2+)

Function

Pathways and Gene Ontology

Reactome pathways

0 curated (TAS) of 0; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

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 (7): 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), 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

33 GO namespaces:

Category	Terms
calcium-ion regulated exocytosis	2
anterograde trans-synaptic signaling	1
system development	1
animal gross anatomical part developmental process	1
regulation of regulated secretory pathway	1
regulation of calcium ion-dependent exocytosis	1
positive regulation of regulated secretory pathway	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
neurotransmitter secretion	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

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 1 of 18 annotations. The rest are phylogenetic / computational / electronic (IEA).

1 experimentally-supported GO terms:

GO term	NS	Evidence
regulation of calcium ion-dependent exocytosis	BP	mutant phenotype

Protein interactions and networks

STRING

showing 16 of 900 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DOC2A	HIRIP3	Q9BW71	697
DOC2A	SEZ6L2	Q6UXD5	683
DOC2A	KCTD13	Q8WZ19	666
DOC2A	INO80E	Q8NBZ0	656
DOC2A	ASPHD1	Q5U4P2	649
DOC2A	YPEL3	P61236	594
DOC2A	TAOK2	Q9UL54	590
DOC2A	TLCD3B	Q71RH2	587
DOC2A	FIMP1	Q96LL3	584
DOC2A	KIF22	Q14807	568
DOC2A	C16orf54	Q6UWD8	563
DOC2A	CDIPT	O14735	556
DOC2A	STXBP5	Q5T5C0	551
DOC2A	PPP4C	P33172	550
DOC2A	PRRT2	Q7Z6L0	547
DOC2A	UNC13B	O14795	547

IntAct

Human interaction partners of DOC2A in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

6 partners by confidence:

Partner	Interaction type	MIscore	Records
UBASH3B	physical association	0.800	4
DOC2B	association	0.530	2
GPR137B	association	0.530	1
VDAC1	physical association	0.400	1
RAP1GDS1	physical association	0.370	1
MVK	association	0.350	1

BioGRID (37 interactions; top human partners by supporting records): UBASH3B (Affinity Capture-MS; 5 records), UNC13B (Two-hybrid; 5 records), SCGN (Affinity Capture-MS; 4 records), DOC2B (Affinity Capture-MS; 3 records), GPR137B (Affinity Capture-MS; 3 records), KCTD21 (Affinity Capture-MS; 3 records), TTC21B (Affinity Capture-MS; 3 records), CEBPZ (Cross-Linking-MS (XL-MS)), EEA1 (Cross-Linking-MS (XL-MS)), FOXP1 (Protein-RNA), MVK (Affinity Capture-MS), PARP6 (Proximity Label-MS), RAP1GDS1 (Two-hybrid), SETMAR (Affinity Capture-MS), SLC22A23 (Affinity Capture-MS)

Disease & clinical

Genetic variants

Variant evidence for DOC2A: 73 ClinVar records (2 pathogenic / likely pathogenic); 9 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	64
Likely benign	3
Benign	4

Top pathogenic / likely-pathogenic (2)

Showing all 2 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
1176676	GRCh37/hg19 16p11.2(chr16:29675050-30200008)x1	Pathogenic	criteria provided, single submitter	1
1684661	NC_000016.10:g.29640592_30187862del	Pathogenic	criteria provided, single submitter	1

Per-variant reference — Sugi Variant

Explore DOC2A’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 31 predictions of 907):

Position(s)	Effect	Δscore	Sites
16:30006406	donor_gain	1.0000
16:30006411–30006412	donor_loss	1.0000	5
16:30006679	acceptor_loss	1.0000	2
16:30006684	acceptor_gain	1.0000
16:30006949–30006950	acceptor_loss	1.0000	4
16:30007029–30007030	donor_loss	1.0000	3
16:30008994–30008995	donor_loss	1.0000	5
16:30009106–30009107	acceptor_loss	1.0000	4
16:30009111	acceptor_gain	1.0000
16:30009200–30009201	donor_loss	1.0000	5

HPA cancer prognostics

RNA cancer specificity: Cancer enhanced (Kidney Renal Clear Cell Carcinoma, Kidney Renal Papillary Cell Carcinoma)

Disease associations

OMIM: gene MIM:604567 | disease phenotypes: MIM:611913

GenCC curated gene-disease

Mondo (1): proximal 16p11.2 microdeletion syndrome (MONDO:0012756)

Orphanet (1): Proximal 16p11.2 microdeletion syndrome (Orphanet:261197)

GWAS associations

9 associations:

Study	Trait	p-value
GCST010703_221	Brain morphology (MOSTest)	4e-13
GCST006803_39	Schizophrenia	6e-13
GCST004946_82	Schizophrenia	8e-13
GCST002539_42	Schizophrenia	5e-11
GCST004521_137	Autism spectrum disorder or schizophrenia	4e-10
GCST007611_19	Chronic obstructive pulmonary disease or high blood pressure (pleiotropy)	7e-9
GCST007293_130	Body fat distribution (arm fat ratio)	4e-8
GCST008163_71	Height	1e-6
GCST007293_84	Body fat distribution (arm fat ratio)	6e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004341	body fat distribution
EFO:0004346	neuroimaging measurement

MeSH disease descriptors

1 disease descriptors:

Descriptor	Name	Tree numbers
C579850	16p11.2 Deletion Syndrome *(supp.)*

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Resveratrol	affects cotreatment, decreases expression	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 abundance, increases expression	1
Atrazine	increases expression	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Methapyrilene	decreases methylation	1
Plant Extracts	decreases expression, affects cotreatment	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	affects expression	1
Cyclosporine	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Particulate Matter	decreases expression, increases expression	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

2 trials:

NCT	Phase	Status	Title
NCT04271332	Phase 2	UNKNOWN	Safety, Tolerability, and Efficacy of Arbaclofen in 16p11.2 Deletion
NCT01238250	Not specified	RECRUITING	Online Study of People Who Have Genetic Changes and Features of Autism: Simons Searchlight