ERC2

Summary

ERC2 (ELKS/RAB6-interacting/CAST family member 2, HGNC:31922) is a protein-coding gene on chromosome 3p14.3, encoding ERC protein 2 (O15083). Thought to be involved in the organization of the cytomatrix at the nerve terminals active zone (CAZ) which regulates neurotransmitter release.

This gene encodes a protein that belongs to the Rab3-interacting molecule (RIM)-binding protein family. Members of this protein family form part of the cytomatrix at the active zone (CAZ) complex and function as regulators of neurotransmitter release. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 26059 — RefSeq curated summary.

At a glance

• GWAS associations: 40
• Clinical variants (ClinVar): 108 total
• MANE Select transcript: NM_015576

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:31922
Approved symbol	ERC2
Name	ELKS/RAB6-interacting/CAST family member 2
Location	3p14.3
Locus type	gene with protein product
Status	Approved
Aliases	CAST, CAST1, KIAA0378, SPBC110, Spc110, ELKSL
Ensembl gene	ENSG00000187672
Ensembl biotype	protein_coding
OMIM	617250
Entrez	26059

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 9 protein_coding_CDS_not_defined, 4 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000288221, ENST00000460849, ENST00000466358, ENST00000468118, ENST00000469720, ENST00000472917, ENST00000473469, ENST00000477381, ENST00000484530, ENST00000484857, ENST00000486496, ENST00000487287, ENST00000492584, ENST00000940588, ENST00000941628

RefSeq mRNA: 1 — MANE Select: NM_015576 NM_015576

CCDS: CCDS46851

Canonical transcript exons

ENST00000288221 — 18 exons

Exon	Start	End
ENSE00001032767	56080817	56080984
ENSE00001079906	55734771	55734918
ENSE00001079907	55888389	55888549
ENSE00001079909	56007181	56007321
ENSE00001079911	55992057	55992250
ENSE00001079913	56010449	56010589
ENSE00001079914	56018894	56019031
ENSE00001373167	56296019	56296435
ENSE00001373656	56139509	56139676
ENSE00001374854	56173446	56173520
ENSE00001380801	56434351	56435147
ENSE00001382378	56148977	56149132
ENSE00001383965	56468248	56468467
ENSE00001533867	55950425	55950560
ENSE00001947225	55508311	55511276
ENSE00002412308	55985977	55985988
ENSE00003502145	55699378	55699512
ENSE00003672006	55683794	55683859

Expression profiles

Bgee: expression breadth ubiquitous, 195 present calls, max score 96.65.

FANTOM5 (CAGE): breadth broad, TPM avg 3.7929 / max 229.6578, expressed in 598 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42612	2.0355	518
42613	1.1004	377
42614	0.2064	92
42607	0.1620	37
42615	0.1100	51
42606	0.0823	28
42594	0.0653	29
42608	0.0228	8
42603	0.0082	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	96.65	gold quality
Brodmann (1909) area 23	UBERON:0013554	96.17	gold quality
orbitofrontal cortex	UBERON:0004167	94.26	gold quality
endothelial cell	CL:0000115	94.18	gold quality
Brodmann (1909) area 46	UBERON:0006483	92.62	gold quality
superior frontal gyrus	UBERON:0002661	92.03	gold quality
substantia nigra pars compacta	UBERON:0001965	91.91	gold quality
entorhinal cortex	UBERON:0002728	91.53	gold quality
cortical plate	UBERON:0005343	91.36	gold quality
postcentral gyrus	UBERON:0002581	91.18	gold quality
parietal lobe	UBERON:0001872	90.34	gold quality
frontal pole	UBERON:0002795	89.54	gold quality
substantia nigra pars reticulata	UBERON:0001966	89.48	gold quality
primary visual cortex	UBERON:0002436	88.77	gold quality
Brodmann (1909) area 10	UBERON:0013541	88.65	gold quality
prefrontal cortex	UBERON:0000451	88.49	gold quality
CA1 field of hippocampus	UBERON:0003881	87.28	gold quality
occipital lobe	UBERON:0002021	87.12	gold quality
frontal lobe	UBERON:0016525	86.94	gold quality
frontal cortex	UBERON:0001870	86.93	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	86.40	gold quality
cerebral cortex	UBERON:0000956	86.35	gold quality
neocortex	UBERON:0001950	86.24	gold quality
temporal lobe	UBERON:0001871	85.44	gold quality
Brodmann (1909) area 9	UBERON:0013540	85.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.93	gold quality
pons	UBERON:0000988	83.55	gold quality
Ammon’s horn	UBERON:0001954	83.50	gold quality
cingulate cortex	UBERON:0003027	83.29	gold quality
anterior cingulate cortex	UBERON:0009835	83.14	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	3028.24
E-GEOD-180759	yes	2987.71
E-GEOD-81383	yes	200.07
E-HCAD-25	yes	80.92
E-ANND-3	yes	6.61
E-MTAB-8060	no	33.62

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

255 targeting ERC2, 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-1252-5P	100.00	69.80	2774
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-23B-5P	99.98	66.07	587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964

Literature-anchored findings (GeneRIF, showing 3)

• In vitro results indicate that ERC2/CAST, an active zone-specific isoform, interacts with all of the known isoforms of liprin-alpha and that liprin-alpha1 associates with both ERC2 and ERC1b (PMID:12923177)
• Serine-Arginine Protein Kinase SRPK2 Modulates the Assembly of the Active Zone Scaffolding Protein CAST1/ERC2. (PMID:31671734)
• IDH1 R132C and ERC2 L309I Mutations Contribute to the Development of Maffucci’s Syndrome. (PMID:34790172)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	erc2	ENSDARG00000105178
mus_musculus	Erc2	ENSMUSG00000040640
rattus_norvegicus	Erc2	ENSRNOG00000015148
caenorhabditis_elegans		WBGENE00018330

Paralogs (1): ERC1 (ENSG00000082805)

Protein

Protein identifiers

ERC protein 2 — O15083 (reviewed: O15083)

All UniProt accessions (2): O15083, H7C4G9

UniProt curated annotations — full annotation on UniProt →

Function. Thought to be involved in the organization of the cytomatrix at the nerve terminals active zone (CAZ) which regulates neurotransmitter release. Seems to act together with BSN. May recruit liprin-alpha proteins to the CAZ.

Subunit / interactions. Interacts with BSN, ERC1, PPFIA1, PPFIA2, PPFIA3 and PPFIA4. Interacts through its C-terminus with the PDZ domain of RIMS1. Part of a complex consisting of ERC2, RIMS1 and UNC13A.

Subcellular location. Cytoplasm. Synapse. Presynaptic active zone. Cytoskeleton.

RefSeq proteins (1): NP_056391* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019323	ELKS/CAST	Family

Pfam: PF10174

UniProt features (11 total): compositionally biased region 4, region of interest 2, modified residue 2, chain 1, sequence variant 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15083-F1	74.26	0.41

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 (2): 65, 666

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 240 (showing top): GOBP_REGULATION_OF_VESICLE_FUSION, GGTGTGT_MIR329, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_VESICLE_ORGANIZATION, GOBP_MEMBRANE_FUSION, GOBP_CELLULAR_COMPONENT_MAINTENANCE, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_EXOCYTOSIS, GOBP_CELL_JUNCTION_ORGANIZATION, GOBP_VESICLE_FUSION_TO_PLASMA_MEMBRANE, AAACCAC_MIR140

GO Biological Process (4): synaptic vesicle priming (GO:0016082), maintenance of presynaptic active zone structure (GO:0048790), regulation of presynaptic cytosolic calcium ion concentration (GO:0099509), regulation of calcium-dependent activation of synaptic vesicle fusion (GO:0150037)

GO Molecular Function (2): structural constituent of presynaptic active zone (GO:0098882), protein binding (GO:0005515)

GO Cellular Component (11): cytoskeleton (GO:0005856), growth cone (GO:0030426), presynaptic membrane (GO:0042734), presynaptic active zone (GO:0048786), presynaptic active zone cytoplasmic component (GO:0098831), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737), cell projection (GO:0042995), synapse (GO:0045202), presynapse (GO:0098793)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
presynapse	3
synapse	3
presynaptic active zone	2
synaptic vesicle exocytosis	1
protein-containing complex assembly	1
exocytic process	1
maintenance of synapse structure	1
presynaptic active zone organization	1
regulation of cytosolic calcium ion concentration	1
neuron cellular homeostasis	1
regulation of synaptic vesicle fusion to presynaptic active zone membrane	1
calcium-dependent activation of synaptic vesicle fusion	1
maintenance of presynaptic active zone structure	1
structural constituent of synapse	1
binding	1
intracellular membraneless organelle	1
site of polarized growth	1
distal axon	1
synaptic membrane	1
cell cortex region	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1492 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ERC2	PCNT	O95613	906
ERC2	CALML3	P27482	889
ERC2	CALML6	Q8TD86	889
ERC2	CALML4	Q96GE6	889
ERC2	CALML5	Q9NZT1	889
ERC2	RIMS1	Q86UR5	886
ERC2	CALM1	P02593	844
ERC2	TUBGCP3	Q96CW5	825
ERC2	TUBGCP2	Q9BSJ2	796
ERC2	MZT1	Q08AG7	721
ERC2	TUBG1	P23258	717
ERC2	RAB6A	P20340	658
ERC2	UNC13A	Q9UPW8	658
ERC2	BSN	Q9UPA5	639
ERC2	ERC1	Q8IUD2	625

IntAct

16 interactions, top by confidence:

A	B	Type	Score
ERC2	MYB	psi-mi:“MI:0915”(physical association)	0.520
ERC2	YWHAE	psi-mi:“MI:0915”(physical association)	0.400
Cd2ap		psi-mi:“MI:0914”(association)	0.350
Erc1	CIT	psi-mi:“MI:0914”(association)	0.350
OCRL	ERC2	psi-mi:“MI:0914”(association)	0.350
OCRL	MYO1C	psi-mi:“MI:0914”(association)	0.350
SDCCAG8	MYO1C	psi-mi:“MI:0914”(association)	0.350
DGUOK	DNM1L	psi-mi:“MI:0914”(association)	0.350
IQCB1	PCP4L1	psi-mi:“MI:0914”(association)	0.350
SHANK3	IGKV3D-15	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
KRT38	KRBA1	psi-mi:“MI:0914”(association)	0.350
ERC2	MYB	psi-mi:“MI:0915”(physical association)	0.000
NRIP1	ERC2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (59): ERC2 (Affinity Capture-MS), ERC2 (Affinity Capture-MS), ERC2 (Affinity Capture-MS), ERC2 (Affinity Capture-MS), ERC2 (Co-localization), ERC2 (Affinity Capture-MS), ERC2 (Affinity Capture-MS), BSN (Affinity Capture-Western), RIMS1 (Affinity Capture-Western), UNC13A (Affinity Capture-Western), ERC2 (Affinity Capture-Western), PCLO (Affinity Capture-Western), ERC2 (Two-hybrid), ERC2 (Two-hybrid), ERC2 (Two-hybrid)

ESM2 similar proteins: A0A8M2BID5, A0A8M9PQ61, A1Z8P9, A6QR54, B4KE73, E9Q7G0, F1R4Y7, O15083, O55156, O60437, O61308, Q11102, Q13439, Q15643, Q3SWS9, Q5DTN8, Q5M9N0, Q5PQ23, Q5RI56, Q5U4E6, Q5VZ66, Q5ZKK5, Q66H89, Q6DFL0, Q6PH08, Q6ZU80, Q7ZW57, Q811U3, Q8BI22, Q8BVL9, Q8CDI6, Q8CDI7, Q8CGB3, Q8HYY4, Q8IUD2, Q8K3M6, Q8WXW3, Q91VW5, Q96AA8, Q96N16

Diamond homologs: O15083, Q6PH08, Q811U3, Q8IUD2, Q8K3M6, Q99MI1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	99
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

5304 predictions. Top by Δscore:

Variant	Effect	Δscore
3:55699513:C:CC	acceptor_gain	1.0000
3:55699515:G:C	acceptor_gain	1.0000
3:55734914:CCTGT:C	acceptor_loss	1.0000
3:55734915:CTGT:C	acceptor_gain	1.0000
3:55734916:TGTCT:T	acceptor_loss	1.0000
3:55734917:GTCTG:G	acceptor_loss	1.0000
3:55734918:TCTGG:T	acceptor_loss	1.0000
3:55734919:C:CC	acceptor_gain	1.0000
3:55734919:CTGGT:C	acceptor_loss	1.0000
3:55734920:T:A	acceptor_loss	1.0000
3:55734922:G:C	acceptor_gain	1.0000
3:55734922:G:GC	acceptor_gain	1.0000
3:55888383:A:AC	donor_gain	1.0000
3:55888383:ACT:A	donor_loss	1.0000
3:55888384:C:CC	donor_gain	1.0000
3:55888384:CTCA:C	donor_gain	1.0000
3:55888386:CACTT:C	donor_loss	1.0000
3:55888387:A:AC	donor_gain	1.0000
3:55888387:ACTT:A	donor_gain	1.0000
3:55888388:C:CG	donor_gain	1.0000
3:55888388:CT:C	donor_gain	1.0000
3:55888388:CTT:C	donor_gain	1.0000
3:55888388:CTTC:C	donor_gain	1.0000
3:55888388:CTTCA:C	donor_gain	1.0000
3:55888546:CTAT:C	acceptor_gain	1.0000
3:55888547:TAT:T	acceptor_gain	1.0000
3:55888548:ATC:A	acceptor_loss	1.0000
3:55888549:TC:T	acceptor_loss	1.0000
3:55888550:C:CC	acceptor_gain	1.0000
3:55950420:CTTA:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003631 (3:55717630 TCAAC>T), RS1000005325 (3:56302005 T>C), RS1000007197 (3:55787967 T>C), RS1000009357 (3:55785873 A>G), RS1000010263 (3:56042395 G>A,C,T), RS1000010955 (3:55866732 G>A), RS1000012398 (3:56399977 A>C), RS1000014481 (3:56440265 C>A,T), RS1000017525 (3:56339320 G>A), RS1000019848 (3:56099480 G>A), RS1000021420 (3:56426806 G>A), RS1000025761 (3:55952101 C>T), RS1000025812 (3:56087529 T>C), RS1000027136 (3:56178196 A>G), RS1000029887 (3:56301617 T>C)

Disease associations

OMIM: gene MIM:617250 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

40 associations (top):

Study	Trait	p-value
GCST000101_1	Hip geometry	6.000000e-07
GCST000862_4	Bipolar disorder and schizophrenia	6.000000e-06
GCST001320_12	Acute lymphoblastic leukemia (childhood)	5.000000e-06
GCST002127_21	Periodontitis (Mean PAL)	4.000000e-06
GCST003174_12	Sense of smell	1.000000e-06
GCST003264_765	Post bronchodilator FEV1/FVC ratio	3.000000e-07
GCST003453_8	Chronotype	3.000000e-08
GCST003454_6	Morning vs. evening chronotype	1.000000e-06
GCST003518_1	Daytime sleep phenotypes	2.000000e-06
GCST003542_62	Night sleep phenotypes	5.000000e-06
GCST003838_14	Morning vs. evening chronotype	2.000000e-06
GCST004711_48	Alcohol dependence	9.000000e-06
GCST006288_249	Heel bone mineral density	5.000000e-09
GCST006288_250	Heel bone mineral density	6.000000e-08
GCST006288_306	Heel bone mineral density	1.000000e-06
GCST006288_307	Heel bone mineral density	6.000000e-08
GCST006288_514	Heel bone mineral density	4.000000e-14
GCST006288_515	Heel bone mineral density	5.000000e-16
GCST006979_67	Heel bone mineral density	2.000000e-09
GCST006979_68	Heel bone mineral density	9.000000e-12
GCST006979_69	Heel bone mineral density	4.000000e-44
GCST006979_70	Heel bone mineral density	2.000000e-29
GCST007277_5	Tourette syndrome	3.000000e-06
GCST008279_1	Trochanter size	1.000000e-07
GCST008280_7	Intertrochanteric region size	3.000000e-11
GCST008281_8	Hip bone size	8.000000e-14
GCST008660_4	Lung function in never smokers (high FEV1 vs average FEV1)	7.000000e-08
GCST010002_425	Refractive error	2.000000e-10
GCST010698_4	Subcortical volume (min-P)	5.000000e-08
GCST010699_60	Brain morphology (min-P)	9.000000e-30

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0004685	hip geometry
EFO:0004713	FEV/FVC ratio
EFO:0007828	daytime rest measurement
EFO:0007827	nighttime rest measurement
EFO:0007835	alcohol dependence measurement
EFO:0009270	heel bone mineral density
EFO:0010075	intertrochanteric region size
EFO:0004314	forced expiratory volume
EFO:0004346	neuroimaging measurement
EFO:0004327	electrocardiography
EFO:0006935	thalamus volume
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

37 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects cotreatment, decreases expression	4
Arsenic	decreases methylation, increases methylation, affects methylation	3
Benzo(a)pyrene	affects expression, affects methylation, increases methylation	3
bisphenol A	affects methylation, decreases methylation	2
Valproic Acid	affects expression, decreases methylation	2
Aflatoxin B1	decreases expression, increases methylation	2
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression, increases expression	1
terbufos	increases methylation	1
arsenite	increases methylation	1
sodium arsenite	increases expression	1
benzo(e)pyrene	increases methylation	1
ferrous chloride	increases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
pentabromodiphenyl ether	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	decreases phosphorylation	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Cadmium	increases expression, decreases reaction	1
Fonofos	increases methylation	1
Estradiol	affects cotreatment, increases expression	1
Furaldehyde	decreases expression, affects cotreatment, affects localization	1
Lipopolysaccharides	increases expression, affects response to substance, affects cotreatment	1
Methapyrilene	increases methylation	1

Clinical trials (associated diseases)

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