GCA

Summary

GCA (grancalcin, HGNC:15990) is a protein-coding gene on chromosome 2q24.2, encoding Grancalcin (P28676). Calcium-binding protein that may play a role in the adhesion of neutrophils to fibronectin.

This gene encodes a calcium-binding protein that is abundant in neutrophils and macrophages. In the absence of divalent cation, this protein localizes to the cytosolic fraction; with magnesium alone, it partitions with the granule fraction; and in the presence of magnesium and calcium, it associates with both the granule and membrane fractions. Alternative splicing and use of alternative promoters results in multiple transcript variants.

Source: NCBI Gene 25801 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 35 total
• MANE Select transcript: NM_012198

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15990
Approved symbol	GCA
Name	grancalcin
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	GCL
Ensembl gene	ENSG00000115271
Ensembl biotype	protein_coding
OMIM	607030
Entrez	25801

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 12 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000233612, ENST00000414723, ENST00000429691, ENST00000437150, ENST00000446271, ENST00000453113, ENST00000473240, ENST00000479199, ENST00000481161, ENST00000487445, ENST00000884872, ENST00000884873, ENST00000884874, ENST00000935559, ENST00000935560, ENST00000958260

RefSeq mRNA: 7 — MANE Select: NM_012198 NM_001330265, NM_001330266, NM_001330267, NM_001330268, NM_001330270, NM_001330271, NM_012198

CCDS: CCDS2218, CCDS82527

Canonical transcript exons

ENST00000437150 — 8 exons

Exon	Start	End
ENSE00000779567	162359044	162359157
ENSE00000840795	162359494	162359552
ENSE00001725682	162360217	162363123
ENSE00001755889	162344132	162344275
ENSE00003476633	162356438	162356481
ENSE00003540959	162352338	162352407
ENSE00003568096	162347578	162347742
ENSE00003786144	162356758	162356905

Expression profiles

Bgee: expression breadth ubiquitous, 280 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.5336 / max 8724.0522, expressed in 1596 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23388	54.8634	1547
23390	2.2854	613
23391	2.0204	876
23382	1.9640	374
23389	1.4320	506
23383	1.0354	160
23384	0.7578	116
23392	0.0995	45
23385	0.0756	10

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.16	gold quality
mononuclear cell	CL:0000842	98.98	gold quality
leukocyte	CL:0000738	98.92	gold quality
blood	UBERON:0000178	98.68	gold quality
bone marrow	UBERON:0002371	98.55	gold quality
bone marrow cell	CL:0002092	98.03	gold quality
trabecular bone tissue	UBERON:0002483	97.03	gold quality
granulocyte	CL:0000094	96.85	gold quality
spleen	UBERON:0002106	96.58	gold quality
germinal epithelium of ovary	UBERON:0001304	96.52	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.82	gold quality
right lung	UBERON:0002167	95.76	gold quality
periodontal ligament	UBERON:0008266	95.54	gold quality
ventricular zone	UBERON:0003053	95.33	gold quality
corpus callosum	UBERON:0002336	95.24	gold quality
vermiform appendix	UBERON:0001154	95.04	gold quality
spinal cord	UBERON:0002240	94.58	gold quality
oocyte	CL:0000023	94.20	gold quality
gall bladder	UBERON:0002110	93.77	gold quality
ganglionic eminence	UBERON:0004023	93.74	gold quality
rectum	UBERON:0001052	93.35	gold quality
upper lobe of left lung	UBERON:0008952	93.30	gold quality
upper lobe of lung	UBERON:0008948	92.95	gold quality
body of pancreas	UBERON:0001150	92.67	gold quality
palpebral conjunctiva	UBERON:0001812	92.50	gold quality
islet of Langerhans	UBERON:0000006	92.19	gold quality
lymph node	UBERON:0000029	92.11	gold quality
pancreas	UBERON:0001264	91.92	gold quality
lower lobe of lung	UBERON:0008949	91.77	gold quality
medial globus pallidus	UBERON:0002477	91.71	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-149689	yes	1390.92
E-HCAD-10	yes	26.90
E-CURD-112	yes	22.17
E-ANND-3	yes	14.02
E-MTAB-9801	yes	9.22

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFKB1

miRNA regulators (miRDB)

122 targeting GCA, 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-3163	100.00	77.23	8605
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3646	100.00	73.56	5283
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-12136	99.98	72.81	5713
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-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-6835-3P	99.93	70.49	2904

Literature-anchored findings (GeneRIF, showing 6)

• GCA interacts with SRI in vivo and in vitro. (PMID:12804766)
• The reported type 1 diabetes association is from a linkage disequilibrium region including three candidate genes, FAP, IFIH1 and GCA. (PMID:18071670)
• IFIH1 interferon induced helicase, GCA grancalcin or the potassium channel KCNH7 - are potential candidates implicated in the pathogenesis of multiple sclerosis. (PMID:18285833)
• IFIH1-GCA-KCNH7 locus is not associated with genetic susceptibility to multiple sclerosis in French patients (PMID:19156166)
• Results indicate that heterodimerization of GCA and TLR9 is important for TLR9-mediated downstream signaling and might serve to fine tune processes against viral infection. (PMID:26648480)
• GCA activates TRAF6 ubiquitin ligase activity to induce Lys63 ubiquitination of ULK1, a crucial regulator of autophagy, resulting in its stabilization and activation. It was also highlighted the role of GCA-TRAF6-ULK1 autophagy regulatory axis in imatinib resistance. (PMID:30929559)

Cross-species orthologs

12 orthologs

Organism	Symbol	Gene ID
danio_rerio	gca	ENSDARG00000020187
mus_musculus	Gca	ENSMUSG00000026893
rattus_norvegicus	Gca	ENSRNOG00000007359
caenorhabditis_elegans		WBGENE00000542
caenorhabditis_elegans	clp-3	WBGENE00000544
caenorhabditis_elegans		WBGENE00000546
caenorhabditis_elegans		WBGENE00000547
caenorhabditis_elegans		WBGENE00006606
caenorhabditis_elegans	clp-8	WBGENE00009695
caenorhabditis_elegans	clpr-3	WBGENE00010417
caenorhabditis_elegans	clpr-1	WBGENE00012233
caenorhabditis_elegans	clpr-3	WBGENE00013184

Paralogs (20): CAPN1 (ENSG00000014216), SRI (ENSG00000075142), CAPN6 (ENSG00000077274), CAPN3 (ENSG00000092529), CAPN15 (ENSG00000103326), ADGB (ENSG00000118492), CAPNS1 (ENSG00000126247), CAPN7 (ENSG00000131375), CAPN9 (ENSG00000135773), CAPN11 (ENSG00000137225), CAPN10 (ENSG00000142330), CAPN5 (ENSG00000149260), PEF1 (ENSG00000162517), CAPN2 (ENSG00000162909), CAPN13 (ENSG00000162949), CAPN12 (ENSG00000182472), CAPN8 (ENSG00000203697), CAPN14 (ENSG00000214711), PDCD6 (ENSG00000249915), CAPNS2 (ENSG00000256812)

Protein

Protein identifiers

Grancalcin — P28676 (reviewed: P28676)

All UniProt accessions (6): P28676, C9JIZ3, C9JV47, C9JWQ8, H7BXD5, H7C2Z6

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-binding protein that may play a role in the adhesion of neutrophils to fibronectin. May play a role in the formation of focal adhesions.

Subunit / interactions. Homodimer. Interacts with SRI and LCP1.

Subcellular location. Cytoplasm. Cytoplasmic granule membrane.

Tissue specificity. Detected in neutrophils and macrophages (at protein level). Highly expressed in bone marrow.

Miscellaneous. This protein has been shown to bind calcium with high affinity.

RefSeq proteins (7): NP_001317194, NP_001317195, NP_001317196, NP_001317197, NP_001317199, NP_001317200, NP_036330* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002048	EF_hand_dom	Domain
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site

Pfam: PF13202, PF13833

UniProt features (31 total): helix 9, binding site 8, strand 6, domain 4, chain 1, sequence variant 1, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1K94	X-RAY DIFFRACTION	1.7
1F4Q	X-RAY DIFFRACTION	1.9
1K95	X-RAY DIFFRACTION	1.9
1F4O	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P28676-F1	82.55	0.74

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 (8): 136; 138; 143; 65; 69; 71; 132; 134

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6798695	Neutrophil degranulation

MSigDB gene sets: 272 (showing top): WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, CHUNG_BLISTER_CYTOTOXICITY_DN, MODULE_418, CGGAARNGGCNG_UNKNOWN, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_UP, GOBP_MEMBRANE_FUSION, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_E_UP, CTATGCA_MIR153, MORF_RAD51L3, FOSTER_TOLERANT_MACROPHAGE_UP, chr2q24, MORF_IL4

GO Biological Process (1): membrane fusion (GO:0061025)

GO Molecular Function (5): calcium ion binding (GO:0005509), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): extracellular region (GO:0005576), cytoplasm (GO:0005737), cytosol (GO:0005829), plasma membrane (GO:0005886), azurophil granule lumen (GO:0035578), extracellular exosome (GO:0070062), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Innate Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
protein dimerization activity	2
membrane organization	1
metal ion binding	1
identical protein binding	1
binding	1
cation binding	1
intracellular anatomical structure	1
cytoplasm	1
membrane	1
cell periphery	1
vacuolar lumen	1
secretory granule lumen	1
azurophil granule	1
extracellular vesicle	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

688 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GCA	KCNH7	Q9NS40	887
GCA	LCP1	P13796	765
GCA	IFIH1	Q9BYX4	629
GCA	GUF1	Q8N442	576
GCA	FSCN1	Q16658	417
GCA	SDF4	Q9BRK5	387
GCA	PLSCR3	Q9NRY6	373
GCA	RYR2	Q92736	371
GCA	TXNDC8	Q6A555	370
GCA	ZFYVE19	Q96K21	365
GCA	ANXA7	P20073	365
GCA	PEF1	Q9UBV8	353
GCA	RBM22	Q9NW64	337
GCA	PDCD6	O75340	332
GCA	MAP6	Q96JE9	324

IntAct

92 interactions, top by confidence:

A	B	Type	Score
MAGEA8	GCA	psi-mi:“MI:0915”(physical association)	0.830
GCA	MAGEA8	psi-mi:“MI:0915”(physical association)	0.830
GCA	ATXN1	psi-mi:“MI:0915”(physical association)	0.670
GCA	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
GCA	CALCOCO2	psi-mi:“MI:0915”(physical association)	0.560
GCA	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
PSMB4	GCA	psi-mi:“MI:0915”(physical association)	0.560
	GCA	psi-mi:“MI:0915”(physical association)	0.560
GCA	ABHD11	psi-mi:“MI:0915”(physical association)	0.560
GCA	C10orf55	psi-mi:“MI:0915”(physical association)	0.560
GCA	BPIFA1	psi-mi:“MI:0915”(physical association)	0.560
GCA	GSTO2	psi-mi:“MI:0915”(physical association)	0.560
GCA	CSTPP1	psi-mi:“MI:0915”(physical association)	0.560
GCA	HTT	psi-mi:“MI:0915”(physical association)	0.560
TMEM255A	WWP2	psi-mi:“MI:0914”(association)	0.530
ICMT	STXBP3	psi-mi:“MI:0914”(association)	0.530
PARVA	CCNB1	psi-mi:“MI:0914”(association)	0.530
SRI	GCA	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (59): GCA (Two-hybrid), GCA (Two-hybrid), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS), GCA (Affinity Capture-MS)

ESM2 similar proteins: A4IF97, F1SSF9, G3V7W1, O14950, O75340, P02608, P02609, P04466, P06815, P07461, P08733, P10916, P12815, P18666, P19105, P24732, P28676, P40423, P41691, P43367, P51667, P97457, Q01449, Q09510, Q0P571, Q0VFG3, Q27179, Q2QY10, Q3SEK0, Q3SZE5, Q3THE2, Q5E9E2, Q5PQ53, Q5RC34, Q5XJX1, Q63ZJ3, Q64122, Q641Z8, Q6DC93, Q7F0J0

Diamond homologs: A6NHC0, A8MX76, G3V7W1, O08529, O08688, O14815, O15484, O23184, O35350, O35646, O35920, O75808, O88456, O88501, P00789, P04574, P04632, P05044, P06813, P06814, P06815, P07384, P13135, P16259, P17655, P20807, P27398, P27730, P28676, P30626, P34308, P35750, P43367, P43368, P51186, P97571, Q07009, Q11002, Q22036, Q27970

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	18
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1076 predictions. Top by Δscore:

Variant	Effect	Δscore
2:162344271:GAGGG:G	donor_gain	1.0000
2:162344273:GGG:G	donor_gain	1.0000
2:162344273:GGGGT:G	donor_loss	1.0000
2:162344274:GG:G	donor_gain	1.0000
2:162344274:GGG:G	donor_gain	1.0000
2:162344275:GG:G	donor_gain	1.0000
2:162344275:GGT:G	donor_loss	1.0000
2:162344276:G:GG	donor_gain	1.0000
2:162344276:G:T	donor_loss	1.0000
2:162344277:T:G	donor_loss	1.0000
2:162347576:A:AG	acceptor_gain	1.0000
2:162347576:AGTTT:A	acceptor_gain	1.0000
2:162347577:G:GT	acceptor_gain	1.0000
2:162347577:GT:G	acceptor_gain	1.0000
2:162347577:GTTT:G	acceptor_gain	1.0000
2:162347577:GTTTG:G	acceptor_gain	1.0000
2:162347739:ACAGG:A	donor_loss	1.0000
2:162347741:AGG:A	donor_loss	1.0000
2:162347742:GGTGA:G	donor_loss	1.0000
2:162347743:GT:G	donor_loss	1.0000
2:162347744:T:G	donor_loss	1.0000
2:162352446:G:GT	donor_gain	1.0000
2:162359550:GAT:G	donor_gain	1.0000
2:162359553:G:GG	donor_gain	1.0000
2:162344271:G:GT	donor_gain	0.9900
2:162344278:G:GG	donor_loss	0.9900
2:162347575:T:G	acceptor_gain	0.9900
2:162347577:GTT:G	acceptor_gain	0.9900
2:162347743:G:GG	donor_gain	0.9900
2:162352408:G:GG	donor_gain	0.9900

AlphaMissense

1435 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:162356440:T:C	F89L	0.976
2:162356442:C:A	F89L	0.976
2:162356442:C:G	F89L	0.976
2:162356833:T:C	F128L	0.974
2:162356835:C:A	F128L	0.974
2:162356835:C:G	F128L	0.974
2:162360217:T:C	F210L	0.966
2:162360219:T:A	F210L	0.966
2:162360219:T:G	F210L	0.966
2:162352363:T:C	L73P	0.965
2:162356457:C:G	C94W	0.964
2:162359125:T:A	V179D	0.964
2:162359130:T:C	C181R	0.964
2:162347722:T:C	F58L	0.963
2:162347724:C:A	F58L	0.963
2:162347724:C:G	F58L	0.963
2:162359143:T:C	L185P	0.963
2:162356821:T:A	W124R	0.962
2:162356821:T:C	W124R	0.962
2:162359499:T:C	F192L	0.959
2:162359501:T:A	F192L	0.959
2:162359501:T:G	F192L	0.959
2:162356791:T:C	F114L	0.958
2:162356793:C:A	F114L	0.958
2:162356793:C:G	F114L	0.958
2:162352375:T:C	L77S	0.957
2:162356456:G:A	C94Y	0.949
2:162359148:G:C	A187P	0.948
2:162359127:G:C	A180P	0.946
2:162360218:T:C	F210S	0.946

dbSNP variants (sampled 300 via entrez): RS1000022905 (2:162361477 A>G,T), RS1000032022 (2:162317015 G>A,C), RS1000160870 (2:162341787 A>G,T), RS1000287098 (2:162333785 T>C,G), RS1000302152 (2:162333684 T>C), RS1000375995 (2:162347240 G>A), RS1000443943 (2:162341184 G>A), RS1000456407 (2:162361265 G>A,C), RS1000466625 (2:162340835 T>C), RS1000537191 (2:162366747 T>A), RS1000634642 (2:162333461 T>C), RS1000651716 (2:162367011 C>G), RS1000743769 (2:162348094 T>A,G), RS1000744895 (2:162327435 A>G), RS1000781873 (2:162373536 C>T)

Disease associations

OMIM: gene MIM:607030 | 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
GCST006585_661	Blood protein levels	7.000000e-06

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases methylation, increases expression	4
Air Pollutants	decreases expression, increases abundance	3
Nickel	decreases expression, increases expression	3
Tretinoin	increases expression	3
methylmercuric chloride	decreases expression	2
sodium arsenite	increases expression, increases abundance	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
potassium chromate(VI)	decreases expression, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	increases reaction, affects binding	1
entinostat	increases expression	1
ICG 001	increases expression	1
abrine	decreases expression	1
MT19c compound	increases expression	1
monoethyl phthalate	increases methylation	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Vorinostat	increases expression	1
Air Pollutants, Occupational	decreases expression	1
Arsenic	increases abundance, increases expression	1

Clinical trials (associated diseases)

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