CIAO2A

Summary

CIAO2A (cytosolic iron-sulfur assembly component 2A, HGNC:26235) is a protein-coding gene on chromosome 15q22.31, encoding Cytosolic iron-sulfur assembly component 2A (Q9H5X1). Component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins. It is a selective cancer dependency (DepMap: 21.2% of cell lines).

Predicted to enable metal ion binding activity. Involved in protein maturation. Located in cytosol and nucleoplasm. Part of cytosolic [4Fe-4S] assembly targeting complex.

Source: NCBI Gene 84191 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 33 total
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 21.2% of screened cell lines
• MANE Select transcript: NM_032231

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26235
Approved symbol	CIAO2A
Name	cytosolic iron-sulfur assembly component 2A
Location	15q22.31
Locus type	gene with protein product
Status	Approved
Aliases	FLJ22875, CIA2A
Ensembl gene	ENSG00000166797
Ensembl biotype	protein_coding
OMIM	618382
Entrez	84191

Gene structure

Transcript identifiers

Ensembl transcripts: 12 — 11 protein_coding, 1 nonsense_mediated_decay

ENST00000300030, ENST00000380290, ENST00000557835, ENST00000558779, ENST00000559705, ENST00000559950, ENST00000851936, ENST00000851937, ENST00000851938, ENST00000927117, ENST00000927118, ENST00000927119

RefSeq mRNA: 3 — MANE Select: NM_032231 NM_001014812, NM_001289108, NM_032231

CCDS: CCDS10189, CCDS45278

Canonical transcript exons

ENST00000300030 — 5 exons

Exon	Start	End
ENSE00001724296	64072565	64073028
ENSE00001865659	64093645	64093838
ENSE00003615251	64075492	64075537
ENSE00003638599	64088687	64088851
ENSE00003666390	64081102	64081151

Expression profiles

Bgee: expression breadth ubiquitous, 255 present calls, max score 99.11.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 86.1553 / max 610.0781, expressed in 1827 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150448	64.1973	1826
150449	15.9368	1784
150450	6.0211	1577

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ileal mucosa	UBERON:0000331	99.11	gold quality
right lobe of liver	UBERON:0001114	98.62	gold quality
jejunal mucosa	UBERON:0000399	98.56	gold quality
left ventricle myocardium	UBERON:0006566	98.50	gold quality
duodenum	UBERON:0002114	98.12	gold quality
jejunum	UBERON:0002115	98.07	gold quality
monocyte	CL:0000576	98.05	gold quality
kidney epithelium	UBERON:0004819	98.05	gold quality
leukocyte	CL:0000738	97.97	gold quality
mucosa of transverse colon	UBERON:0004991	97.95	gold quality
right adrenal gland	UBERON:0001233	97.66	gold quality
metanephros	UBERON:0000081	97.62	gold quality
mucosa of sigmoid colon	UBERON:0004993	97.61	gold quality
right adrenal gland cortex	UBERON:0035827	97.61	gold quality
colonic mucosa	UBERON:0000317	97.60	gold quality
palpebral conjunctiva	UBERON:0001812	97.53	gold quality
liver	UBERON:0002107	97.52	gold quality
pancreatic ductal cell	CL:0002079	97.48	gold quality
left adrenal gland	UBERON:0001234	97.43	gold quality
epithelium of nasopharynx	UBERON:0001951	97.42	gold quality
quadriceps femoris	UBERON:0001377	97.38	gold quality
lymph node	UBERON:0000029	97.37	gold quality
adrenal tissue	UBERON:0018303	97.37	gold quality
vastus lateralis	UBERON:0001379	97.34	gold quality
left adrenal gland cortex	UBERON:0035825	97.31	gold quality
myocardium	UBERON:0002349	97.27	gold quality
adrenal cortex	UBERON:0001235	97.22	gold quality
rectum	UBERON:0001052	97.07	gold quality
deltoid	UBERON:0001476	97.06	gold quality
cortex of kidney	UBERON:0001225	97.05	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-GEOD-81383	no	283.68
E-MTAB-5061	no	3.22
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting CIAO2A, 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-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-3120-5P	100.00	65.56	965
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-7162-3P	99.89	68.16	1682
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-1200	99.71	70.42	1838
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4797-5P	99.39	68.01	1354
HSA-MIR-2115-3P	99.31	69.68	2026
HSA-MIR-6719-3P	99.29	67.78	1387
HSA-MIR-580-5P	99.28	70.94	1776
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4324	99.04	70.14	1569
HSA-MIR-4711-5P	98.89	68.00	965
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-501-5P	98.77	68.88	1328

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 21.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 5)

• putative metal-binding site of bacterial DUF59 proteins is not conserved in Fam96a, but Fam96a interacts tightly in vitro with Ciao1, the cytosolic iron-assembly protein (PMID:22683786)
• CIA2B-CIA1-MMS19 and CIA2A-CIA1 assist different branches of Fe/S protein assembly and intimately link this process to cellular iron regulation via IRP1 Fe/S cluster maturation and IRP2 stabilization. (PMID:23891004)
• FAM96A expression was much reduced in tumorigenic ICC-SCs. (PMID:25716227)
• our data suggest that hTERTR-FAM96A may serve as an efficient anti-tumor agent for the treatment of hepatocellular carcinoma. (PMID:28443470)
• FAM96A suppresses epithelial-mesenchymal transition and tumor metastasis by inhibiting TGFbeta1 signals. (PMID:35513087)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ciao2a	ENSDARG00000104940
mus_musculus	Ciao2a	ENSMUSG00000032381
rattus_norvegicus	Ciao2a	ENSRNOG00000017119
drosophila_melanogaster	galla-1	FBGN0034543

Paralogs (1): CIAO2B (ENSG00000166595)

Protein

Protein identifiers

Cytosolic iron-sulfur assembly component 2A — Q9H5X1 (reviewed: Q9H5X1)

Alternative names: MIP18 family protein FAM96A

All UniProt accessions (4): Q9H5X1, A0AAQ5BII0, H0YKV4, H0YLH6

UniProt curated annotations — full annotation on UniProt →

Function. Component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into extramitochondrial Fe/S proteins. As a CIA complex component and in collaboration with CIAO1 specifically matures ACO1 and stabilizes IREB2, connecting cytosolic iron-sulfur protein maturation with cellular iron regulation. May play a role in chromosome segregation through establishment of sister chromatid cohesion. May induce apoptosis in collaboration with APAF1.

Subunit / interactions. Monomer and homodimer. Component of the CIA complex. Interacts with CIAO1. Interacts with IREB2. Interacts with APAF1.

Subcellular location. Cytoplasm.

Tissue specificity. Substantially enriched in macrophages.

Similarity. Belongs to the MIP18 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H5X1-1	1	yes
Q9H5X1-2	2

RefSeq proteins (3): NP_001014812, NP_001276037, NP_115607* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002744	MIP18-like	Domain
IPR034904	FSCA_dom_sf	Homologous_superfamily
IPR039796	MIP18	Family

Pfam: PF01883

UniProt features (23 total): binding site 8, helix 6, strand 6, chain 1, turn 1, splice variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3UX2	X-RAY DIFFRACTION	1.8
3UX3	X-RAY DIFFRACTION	1.8
2M5H	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H5X1-F1	86.90	0.69

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): 89; 89; 123; 123; 150; 150; 153; 153

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 163 (showing top): MODULE_151, CHIANG_LIVER_CANCER_SUBCLASS_UNANNOTATED_DN, TGACCTY_ERR1_Q2, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PROTEIN_MATURATION, GATA6_01, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_13, DODD_NASOPHARYNGEAL_CARCINOMA_UP, RYTTCCTG_ETS2_B, MODULE_568, MODULE_491, MODULE_114, AACATTC_MIR4093P, GOBP_CELL_CYCLE_PROCESS

GO Biological Process (2): chromosome segregation (GO:0007059), protein maturation (GO:0051604)

GO Molecular Function (2): metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (4): nucleoplasm (GO:0005654), cytosol (GO:0005829), cytosolic [4Fe-4S] assembly targeting complex (GO:0097361), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cell cycle process	1
gene expression	1
protein metabolic process	1
cation binding	1
binding	1
nuclear lumen	1
cytoplasm	1
intracellular protein-containing complex	1
iron-sulfur cluster assembly complex	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

742 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CIAO2A	CIAO1	O76071	960
CIAO2A	MMS19	Q96T76	904
CIAO2A	NUBP1	P53384	773
CIAO2A	CIAO3	Q9H6Q4	702
CIAO2A	IREB2	P48200	663
CIAO2A	CIAPIN1	Q6FI81	616
CIAO2A	ABCB7	O75027	520
CIAO2A	NDOR1	Q9UHB4	519
CIAO2A	APAF1	O14727	505
CIAO2A	FBXL5	Q9UKA1	501
CIAO2A	CIAO2B	Q9Y3D0	476
CIAO2A	QNG1	Q5T6V5	474
CIAO2A	ACO1	P21399	452
CIAO2A	ERCC2	P18074	443
CIAO2A	NFS1	Q9Y697	428

IntAct

101 interactions, top by confidence:

A	B	Type	Score
CIAO1	CIAO2A	psi-mi:“MI:0915”(physical association)	0.950
CIAO2A	CIAO1	psi-mi:“MI:0915”(physical association)	0.950
CIAO1	CIAO2A	psi-mi:“MI:0407”(direct interaction)	0.950
CIAO2A	CIAO1	psi-mi:“MI:0914”(association)	0.950
CIAO2A	SETD4	psi-mi:“MI:0915”(physical association)	0.560
PLPP6	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
CIAO2A	RHBDD2	psi-mi:“MI:0915”(physical association)	0.560
TMED8	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
GSC2	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
CIAO2A	KCNIP1	psi-mi:“MI:0915”(physical association)	0.560
CREB3L1	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
DGAT2L6	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
CIAO2A	CMTM6	psi-mi:“MI:0915”(physical association)	0.560
VAMP3	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
RHBDD2	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
CIAO2A	TNFRSF10D	psi-mi:“MI:0915”(physical association)	0.560
EBAG9	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
PRAF2	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560
CIAO2A	FKBP7	psi-mi:“MI:0915”(physical association)	0.560
LIME1	CIAO2A	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (193): FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Co-fractionation), FAM96A (Two-hybrid), FAM96A (Affinity Capture-Western), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid), FAM96A (Two-hybrid)

ESM2 similar proteins: A0A096MJN4, A8MR89, B3MRT7, B3NYF7, B4H303, B4IMF6, B4JWR9, B4M375, B4NE93, B4PZ52, B4R3T1, B5DKJ8, O01479, O13718, O43236, O62252, P08761, P15807, P16393, P23337, P28661, P32783, P32860, P38829, P40487, P46580, P53893, Q3T0U7, Q54QK1, Q5R6R7, Q6BYP7, Q6CKE9, Q6CLC9, Q6CPN1, Q6FMP0, Q6FTG1, Q75AZ9, Q8RXN5, Q8SY96, Q92599

Diamond homologs: A8MR89, O62252, P38829, Q3T0U7, Q54QK1, Q9C9G6, Q9D187, Q9DCL2, Q9GPR0, Q9H5X1, Q9SR25, Q9UTL0, Q9V968, Q9VTC4, Q9Y3D0

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CIAO2A	“form complex”	“CIAO1-CIAO2A-CIAO3 cytosolic iron-sulfur protein assembly complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	25
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

631 predictions. Top by Δscore:

Variant	Effect	Δscore
15:64073025:TTGA:T	acceptor_gain	1.0000
15:64073026:TGA:T	acceptor_gain	1.0000
15:64073029:C:CC	acceptor_gain	1.0000
15:64075490:A:AC	donor_gain	1.0000
15:64075491:C:CT	donor_gain	1.0000
15:64075491:CTGT:C	donor_gain	1.0000
15:64075534:CCAA:C	acceptor_gain	1.0000
15:64075535:CAA:C	acceptor_gain	1.0000
15:64075535:CAAC:C	acceptor_gain	1.0000
15:64075538:C:CC	acceptor_gain	1.0000
15:64075545:G:C	acceptor_gain	1.0000
15:64075545:G:GC	acceptor_gain	1.0000
15:64088680:AACTT:A	donor_loss	1.0000
15:64088681:ACTTA:A	donor_loss	1.0000
15:64088682:CTTA:C	donor_loss	1.0000
15:64088683:TTAC:T	donor_loss	1.0000
15:64088684:TAC:T	donor_loss	1.0000
15:64088685:A:AC	donor_gain	1.0000
15:64088685:A:T	donor_loss	1.0000
15:64088686:C:CT	donor_gain	1.0000
15:64088847:CAAAT:C	acceptor_gain	1.0000
15:64088852:C:CC	acceptor_gain	1.0000
15:64093640:ATTAC:A	donor_loss	1.0000
15:64093642:TAC:T	donor_loss	1.0000
15:64093643:A:C	donor_loss	1.0000
15:64093644:C:CA	donor_loss	1.0000
15:64093668:T:TA	donor_gain	1.0000
15:64073024:ATTGA:A	acceptor_gain	0.9900
15:64073027:GA:G	acceptor_gain	0.9900
15:64073027:GACT:G	acceptor_loss	0.9900

AlphaMissense

1027 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:64072992:G:T	A141D	1.000
15:64072996:C:G	A140P	1.000
15:64073001:C:G	R138P	1.000
15:64073006:T:A	K136N	1.000
15:64073006:T:G	K136N	1.000
15:64073009:G:C	D135E	1.000
15:64073009:G:T	D135E	1.000
15:64073010:T:A	D135V	1.000
15:64073010:T:C	D135G	1.000
15:64073010:T:G	D135A	1.000
15:64073011:C:G	D135H	1.000
15:64081151:C:T	G97E	1.000
15:64088706:G:C	C90W	1.000
15:64088707:C:T	C90Y	1.000
15:64088708:A:G	C90R	1.000
15:64088830:T:C	D49G	1.000
15:64072971:A:G	L148S	0.999
15:64072989:G:T	A142E	0.999
15:64072990:C:G	A142P	0.999
15:64072993:C:G	A141P	0.999
15:64073004:T:A	E137V	0.999
15:64073004:T:G	E137A	0.999
15:64073005:C:T	E137K	0.999
15:64073007:T:A	K136I	0.999
15:64073011:C:A	D135Y	0.999
15:64073016:A:T	I133K	0.999
15:64073018:C:A	Q132H	0.999
15:64073018:C:G	Q132H	0.999
15:64073021:C:A	K131N	0.999
15:64073021:C:G	K131N	0.999

dbSNP variants (sampled 300 via entrez): RS1000007428 (15:64091126 G>A), RS1000038584 (15:64090860 A>G), RS1000061445 (15:64083642 A>G,T), RS1000113486 (15:64083461 T>C), RS1000113517 (15:64090603 G>C), RS1000275999 (15:64084821 G>A), RS1000285037 (15:64095093 G>A), RS1000528012 (15:64089685 C>T), RS1000582741 (15:64073642 T>C), RS1000627963 (15:64085000 G>A), RS1000660141 (15:64072884 A>C), RS1000844034 (15:64095818 C>T), RS1000989010 (15:64078829 A>G), RS1001060250 (15:64084986 G>A), RS1001134581 (15:64090907 C>G,T)

Disease associations

OMIM: gene MIM:618382 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295943 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

29 total (human), top 29 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	3
Cadmium	decreases expression	2
Cyclosporine	decreases expression	2
perfluorodecanesulfonic acid	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
arsenite	affects binding, increases reaction	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
perfluorooctane sulfonic acid	increases expression	1
K 7174	decreases expression	1
perfluorobutanesulfonic acid	increases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Antimycin A	decreases expression	1
Arsenic	affects cotreatment, increases abundance, increases expression	1
Cisplatin	increases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Doxorubicin	increases expression	1
Ivermectin	decreases expression	1
Manganese	increases abundance, increases expression, affects cotreatment	1
Rotenone	decreases expression	1
Urethane	decreases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	decreases expression	1
Okadaic Acid	decreases expression	1
Copper Sulfate	decreases expression	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118609	Binding	Binding affinity to FAM96A in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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