ICA1

Summary

ICA1 (islet cell autoantigen 1, HGNC:5343) is a protein-coding gene on chromosome 7p21.3, encoding Islet cell autoantigen 1 (Q05084). May play a role in neurotransmitter secretion.

This gene encodes a protein with an arfaptin homology domain that is found both in the cytosol and as membrane-bound form on the Golgi complex and immature secretory granules. This protein is believed to be an autoantigen in insulin-dependent diabetes mellitus and primary Sjogren’s syndrome. Several transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 3382 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 123 total
• MANE Select transcript: NM_001136020

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5343
Approved symbol	ICA1
Name	islet cell autoantigen 1
Location	7p21.3
Locus type	gene with protein product
Status	Approved
Aliases	ICAp69, ICA69
Ensembl gene	ENSG00000003147
Ensembl biotype	protein_coding
OMIM	147625
Entrez	3382

Gene structure

Transcript identifiers

Ensembl transcripts: 65 — 57 protein_coding, 4 nonsense_mediated_decay, 2 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000265577, ENST00000317367, ENST00000339809, ENST00000396675, ENST00000401396, ENST00000402384, ENST00000406470, ENST00000407906, ENST00000422063, ENST00000430867, ENST00000446305, ENST00000447326, ENST00000455539, ENST00000457755, ENST00000470696, ENST00000476942, ENST00000486677, ENST00000490041, ENST00000650486, ENST00000902478, ENST00000902479, ENST00000902480, ENST00000902481, ENST00000902482, ENST00000902483, ENST00000902484, ENST00000902485, ENST00000902486, ENST00000902487, ENST00000902488, ENST00000902489, ENST00000902490, ENST00000902491, ENST00000902492, ENST00000902493, ENST00000902494, ENST00000902495, ENST00000902496, ENST00000923898, ENST00000923899, ENST00000923900, ENST00000923901, ENST00000923902, ENST00000923903, ENST00000923904, ENST00000923905, ENST00000923906, ENST00000944692, ENST00000944693, ENST00000944694, ENST00000944695, ENST00000944696, ENST00000944697, ENST00000944698, ENST00000944699, ENST00000944700, ENST00000944701, ENST00000944702, ENST00000944703, ENST00000944704, ENST00000944705, ENST00000944706, ENST00000944707, ENST00000944708, ENST00000944709

RefSeq mRNA: 23 — MANE Select: NM_001136020 NM_001136020, NM_001276478, NM_001350819, NM_001350820, NM_001350821, NM_001350823, NM_001350824, NM_001350825, NM_001350826, NM_001350827, NM_001350828, NM_001350829, NM_001350830, NM_001350831, NM_001350832, NM_001350833, NM_001350834, NM_001350835, NM_001350836, NM_001350837, NM_001350838, NM_004968, NM_022307

CCDS: CCDS34602, CCDS64595, CCDS87478

Canonical transcript exons

ENST00000402384 — 14 exons

Exon	Start	End
ENSE00001343723	8232590	8232755
ENSE00001430354	8228601	8228673
ENSE00001819953	8113184	8114044
ENSE00001870178	8262094	8262167
ENSE00003509774	8221275	8221398
ENSE00003528321	8138985	8139047
ENSE00003531574	8141765	8141817
ENSE00003573196	8218305	8218503
ENSE00003616940	8235910	8236005
ENSE00003619153	8143875	8143972
ENSE00003639357	8138840	8138881
ENSE00003685824	8127873	8128142
ENSE00003689959	8158527	8158652
ENSE00003790617	8157116	8157214

Expression profiles

Bgee: expression breadth ubiquitous, 260 present calls, max score 97.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.4384 / max 249.1513, expressed in 1209 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
82703	6.5705	1191
82712	1.0571	328
82713	0.3090	178
82704	0.2938	127
82702	0.0706	23
82714	0.0234	3
82711	0.0214	7
82706	0.0188	2
82701	0.0171	3
82708	0.0157	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
body of pancreas	UBERON:0001150	97.84	gold quality
apex of heart	UBERON:0002098	95.18	gold quality
pancreas	UBERON:0001264	95.00	gold quality
left testis	UBERON:0004533	94.62	gold quality
right testis	UBERON:0004534	94.59	gold quality
islet of Langerhans	UBERON:0000006	93.80	gold quality
type B pancreatic cell	CL:0000169	93.38	silver quality
cerebellar cortex	UBERON:0002129	93.34	gold quality
cerebellar hemisphere	UBERON:0002245	93.33	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.09	gold quality
right atrium auricular region	UBERON:0006631	93.05	gold quality
rectum	UBERON:0001052	92.84	gold quality
right frontal lobe	UBERON:0002810	92.78	gold quality
heart left ventricle	UBERON:0002084	92.53	gold quality
minor salivary gland	UBERON:0001830	92.48	gold quality
cardiac ventricle	UBERON:0002082	92.34	gold quality
male germ cell	CL:0000015	92.25	gold quality
sperm	CL:0000019	92.22	gold quality
testis	UBERON:0000473	92.18	gold quality
cerebellum	UBERON:0002037	91.97	gold quality
sural nerve	UBERON:0015488	91.95	gold quality
metanephros cortex	UBERON:0010533	91.83	gold quality
body of stomach	UBERON:0001161	91.82	gold quality
saliva-secreting gland	UBERON:0001044	91.78	gold quality
endometrium epithelium	UBERON:0004811	91.76	gold quality
buccal mucosa cell	CL:0002336	91.60	silver quality
stomach	UBERON:0000945	91.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	91.00	gold quality
colonic epithelium	UBERON:0000397	90.81	gold quality
cardiac atrium	UBERON:0002081	90.65	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 8.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	437.52
E-GEOD-139324	yes	321.76
E-CURD-119	yes	56.12
E-ANND-3	yes	13.85
E-MTAB-8410	yes	12.81
E-CURD-114	yes	12.80
E-HCAD-10	yes	4.10
E-MTAB-9801	yes	2.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE

miRNA regulators (miRDB)

29 targeting ICA1, 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-5692A	100.00	74.40	6850
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-3140-3P	99.88	68.47	2069
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-6512-3P	99.65	66.07	1468
HSA-MIR-6720-5P	99.65	66.22	1459
HSA-MIR-5197-5P	99.64	69.08	1494
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-587	99.64	70.86	2611
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-183-5P	99.31	72.27	1164
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-2276-3P	98.76	67.75	1384
HSA-MIR-3188	98.58	65.60	878
HSA-MIR-3144-3P	98.15	67.34	677
HSA-MIR-4772-3P	98.04	65.60	1203
HSA-MIR-4305	97.94	68.63	533
HSA-MIR-6806-5P	96.37	68.74	587
HSA-MIR-3943	95.87	64.57	523

Literature-anchored findings (GeneRIF, showing 7)

• The exon A promoter exhibits greater activity in islet cells, whereas the exon B promoter more efficiently activates transcription in neuronal cells. (PMID:12409289)
• ICA69 as a novel Rab2 effector and its role in regulating the early transport of insulin secretory granule proteins (PMID:18187231)
• polymorphisms within the NOD Ica1 core promoter may determine AIRE-mediated down-regulation of ICA69 expression in medullary thymic epithelial cells. (PMID:22447927)
• Novel association was found between intraocular pressure and a common variant at 7p21 near to GLCCI1 and ICA1. (PMID:23836780)
• C-terminal domain of ICA69 interacts with PICK1 and acts on trafficking of PICK1-PKCalpha complex and cerebellar plasticity. (PMID:24358315)
• Novel SRF-ICA1L Fusions in Cellular Myoid Neoplasms With Potential For Malignant Behavior (PMID:31478943)
• ICA1 affects APP processing through the PICK1-PKCalpha signaling pathway. (PMID:38884369)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ica1	ENSDARG00000042608
mus_musculus	Ica1	ENSMUSG00000062995
rattus_norvegicus	Ica1	ENSRNOG00000008628
drosophila_melanogaster	ICA69	FBGN0037050
caenorhabditis_elegans	ric-19	WBGENE00004368

Paralogs (1): ICA1L (ENSG00000163596)

Protein

Protein identifiers

Islet cell autoantigen 1 — Q05084 (reviewed: Q05084)

Alternative names: 69 kDa islet cell autoantigen, Islet cell autoantigen p69

All UniProt accessions (12): Q05084, A0A024RA29, A0A3B3IST8, B9ZVM7, C9IZC7, C9J3Y4, C9J8Y3, E7ENI6, E9PDL4, F8WET5, Q6LCR0, Q6LCT9

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in neurotransmitter secretion.

Subcellular location. Cytoplasm. Cytosol. Golgi apparatus membrane. Cytoplasmic vesicle. Secretory vesicle membrane. Secretory vesicle. Synaptic vesicle membrane.

Tissue specificity. Expressed abundantly in pancreas, heart and brain with low levels of expression in lung, kidney, liver and thyroid.

Isoforms (3)

UniProt ID	Names	Canonical?
Q05084-1	1	yes
Q05084-2	2
Q05084-3	3

RefSeq proteins (23): NP_001129492, NP_001263407, NP_001337748, NP_001337749, NP_001337750, NP_001337752, NP_001337753, NP_001337754, NP_001337755, NP_001337756, NP_001337757, NP_001337758, NP_001337759, NP_001337760, NP_001337761, NP_001337762, NP_001337763, NP_001337764, NP_001337765, NP_001337766, NP_001337767, NP_004959, NP_071682 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006723	Islet_autoAg_Ica1_C	Domain
IPR010504	AH_dom	Domain
IPR024114	Islet_autoAg_Ica1/Ica1-like	Family
IPR027267	AH/BAR_dom_sf	Homologous_superfamily

Pfam: PF04629, PF06456

UniProt features (9 total): compositionally biased region 2, splice variant 2, sequence conflict 2, chain 1, domain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q05084-F1	70.93	0.41

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 196 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, BROWNE_HCMV_INFECTION_6HR_DN, GRUETZMANN_PANCREATIC_CANCER_DN, GOCC_SECRETORY_GRANULE, GOBP_NEUROTRANSMITTER_TRANSPORT, CREBP1_Q2, AATGGAG_MIR136, TTGGGAG_MIR150, WATANABE_ULCERATIVE_COLITIS_WITH_CANCER_UP, MODULE_120, MODULE_205, KEGG_TYPE_I_DIABETES_MELLITUS, CAATGCA_MIR33, GOBP_SECRETION, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5

GO Biological Process (3): neurotransmitter transport (GO:0006836), regulation of secretion (GO:0051046), membrane bending (GO:0097753)

GO Molecular Function (3): protein domain specific binding (GO:0019904), membrane curvature sensor activity (GO:0140090), protein binding (GO:0005515)

GO Cellular Component (11): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), cytosol (GO:0005829), secretory granule membrane (GO:0030667), synaptic vesicle membrane (GO:0030672), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505), membrane (GO:0016020), transport vesicle membrane (GO:0030658), cytoplasmic vesicle (GO:0031410), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
bounding membrane of organelle	3
cytoplasm	3
cytoplasmic vesicle membrane	2
transport	1
secretion	1
regulation of transport	1
membrane organization	1
protein binding	1
lipid binding	1
molecular sensor activity	1
binding	1
Golgi apparatus	1
intracellular anatomical structure	1
secretory granule	1
synaptic vesicle	1
exocytic vesicle membrane	1
endomembrane system	1
intracellular membrane-bounded organelle	1
vacuole	1
plasma membrane	1
transport vesicle	1
intracellular vesicle	1
cell junction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

40 interactions, top by confidence:

A	B	Type	Score
NELFA	NELFE	psi-mi:“MI:0914”(association)	0.900
RAB2A	ICA1	psi-mi:“MI:0915”(physical association)	0.670
ICA1	RAB2B	psi-mi:“MI:0915”(physical association)	0.670
ICA1	RAB2A	psi-mi:“MI:0915”(physical association)	0.670
RAB2B	ICA1	psi-mi:“MI:0915”(physical association)	0.670
ICA1	MBD3	psi-mi:“MI:0915”(physical association)	0.560
CCDC28A	ICA1	psi-mi:“MI:0915”(physical association)	0.560
ING5	ICA1	psi-mi:“MI:0915”(physical association)	0.560
MBD3	ICA1	psi-mi:“MI:0915”(physical association)	0.560
ICA1	CCDC28A	psi-mi:“MI:0915”(physical association)	0.560
PICK1	ILVBL	psi-mi:“MI:0914”(association)	0.530
PICK1	ATP6AP2	psi-mi:“MI:0914”(association)	0.530
ICA1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
ICA1	TSC1	psi-mi:“MI:0915”(physical association)	0.370
ICA1	EXOC5	psi-mi:“MI:0915”(physical association)	0.370
CACNA1C	SYT5	psi-mi:“MI:0914”(association)	0.350
CACNA1C	IGLL5	psi-mi:“MI:0914”(association)	0.350
S100A2	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CLPB	GTPBP10	psi-mi:“MI:0914”(association)	0.350

BioGRID (32): RAB2A (Two-hybrid), CCDC28A (Two-hybrid), MBD3 (Two-hybrid), ING5 (Two-hybrid), RAB2B (Two-hybrid), ICA1 (Affinity Capture-MS), MORF4L1 (Co-fractionation), ICA1 (Affinity Capture-MS), STK16 (Affinity Capture-MS), CNTF (Affinity Capture-MS), KRT33B (Affinity Capture-MS), MKKS (Affinity Capture-MS), ICA1 (Affinity Capture-MS), ICA1 (Two-hybrid), ICA1 (Two-hybrid)

ESM2 similar proteins: A9ZLX4, B5DF41, D3Z6Q9, D3ZFJ3, F1LQX4, O00499, O08539, O08839, O15079, O75151, P49140, P59672, P78524, P97411, Q05084, Q13191, Q13905, Q14432, Q17R89, Q3B7M3, Q3TTA7, Q3TY65, Q3YEC7, Q5SSM3, Q5U2T3, Q5U3K5, Q5ZKL7, Q62739, Q62865, Q63054, Q68EM7, Q68FR2, Q6DFR2, Q6GQL0, Q6RUG5, Q80U23, Q86XL3, Q86XZ4, Q8K1N4, Q8K4S7

Diamond homologs: P91124, P97411, Q05084, Q3TY65, Q63054, Q6RUG5, Q8NDH6

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
AIRE	“down-regulates quantity by repression”	ICA1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	82
Likely benign	7
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

3535 predictions. Top by Δscore:

Variant	Effect	Δscore
7:8141763:A:AC	donor_gain	1.0000
7:8141764:C:CC	donor_gain	1.0000
7:8141764:CT:C	donor_gain	1.0000
7:8141819:T:C	acceptor_gain	1.0000
7:8143873:A:AC	donor_gain	1.0000
7:8143874:C:CT	donor_gain	1.0000
7:8143874:CTGG:C	donor_gain	1.0000
7:8143985:CCA:C	acceptor_gain	1.0000
7:8143986:C:T	acceptor_gain	1.0000
7:8143987:A:AC	acceptor_gain	1.0000
7:8143987:A:C	acceptor_gain	1.0000
7:8143995:A:AC	acceptor_gain	1.0000
7:8143995:A:C	acceptor_gain	1.0000
7:8157215:C:CC	acceptor_gain	1.0000
7:8158650:TACC:T	acceptor_loss	1.0000
7:8158651:ACC:A	acceptor_loss	1.0000
7:8158652:CCTAT:C	acceptor_loss	1.0000
7:8158653:C:CA	acceptor_loss	1.0000
7:8158654:T:G	acceptor_loss	1.0000
7:8218307:T:TA	donor_gain	1.0000
7:8221304:T:A	donor_gain	1.0000
7:8221325:T:A	donor_gain	1.0000
7:8221394:CAAGA:C	acceptor_gain	1.0000
7:8221399:C:CC	acceptor_gain	1.0000
7:8228599:A:AC	donor_gain	1.0000
7:8228600:C:CC	donor_gain	1.0000
7:8228600:CAA:C	donor_gain	1.0000
7:8228671:CAG:C	acceptor_gain	1.0000
7:8232584:GCTCA:G	donor_loss	1.0000
7:8232585:CTCA:C	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000006203 (7:8197185 T>A,C), RS1000007784 (7:8169906 G>C), RS1000017447 (7:8148332 T>G), RS1000020067 (7:8243397 GGTATTGATGGAAC>G), RS1000052579 (7:8113302 G>A,C), RS1000065257 (7:8246495 C>T), RS1000096513 (7:8214038 C>T), RS1000137155 (7:8155812 G>A), RS1000137482 (7:8178636 T>C), RS1000145215 (7:8206509 C>G), RS1000168738 (7:8178994 A>G), RS1000169437 (7:8164337 T>A,C), RS1000186123 (7:8226907 A>G), RS1000192129 (7:8200607 G>A), RS1000196637 (7:8248982 A>C)

Disease associations

OMIM: gene MIM:147625 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001762_145	Obesity-related traits	1.000000e-06
GCST002089_1	Intraocular pressure	1.000000e-08
GCST002118_17	Metabolite levels (Pyroglutamine)	1.000000e-06
GCST002386_3	Cognitive function	4.000000e-06
GCST003542_38	Night sleep phenotypes	6.000000e-06
GCST005752_178	Systemic lupus erythematosus	1.000000e-06

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004810	interleukin-6 measurement
EFO:0004695	intraocular pressure measurement
EFO:0005408	pyroglutamine measurement
EFO:0003925	cognition

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs62435418	Metabolism/PK	3	o-desmethyltramadol;tramadol

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs62435418	ICA1	3	1.50	1	o-desmethyltramadol;tramadol

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Valproic Acid	decreases expression, affects cotreatment, increases expression	3
Particulate Matter	decreases expression, increases abundance, increases expression, affects cotreatment	3
Arsenic	increases abundance, increases expression, affects methylation, affects cotreatment	2
afuresertib	increases expression	1
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
beta-lapachone	increases expression	1
methylparaben	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
vanadyl sulfate	decreases expression	1
beta-methylcholine	affects expression	1
pentanal	increases expression	1
CGP 52608	affects binding, increases reaction	1
2-palmitoylglycerol	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
dorsomorphin	affects cotreatment, increases expression	1
prothioconazole	increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Aldehydes	increases expression	1
Atrazine	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1

Clinical trials (associated diseases)

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