MACIR

Summary

MACIR (macrophage immunometabolism regulator, HGNC:25052) is a protein-coding gene on chromosome 5q21.1, encoding Macrophage immunometabolism regulator (Q96GV9). Regulates the macrophage function, by enhancing the resolution of inflammation and wound repair functions mediated by M2 macrophages.

This gene, MACIR (previously known as C5orf30), has been associated with rheumatoid arthritis, functioning as a negative regulator of tissue damage and modulating the activity of synovial fibroblasts and macrophages. The encoded protein is highly conserved in vertebrate genomes but has no significant similarity to any other human protein.

Source: NCBI Gene 90355 — RefSeq curated summary.

At a glance

• GWAS associations: 19
• Clinical variants (ClinVar): 6 total
• MANE Select transcript: NM_033211

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25052
Approved symbol	MACIR
Name	macrophage immunometabolism regulator
Location	5q21.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ25291
Ensembl gene	ENSG00000181751
Ensembl biotype	protein_coding
OMIM	616608
Entrez	90355

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 15 protein_coding

ENST00000319933, ENST00000510890, ENST00000515669, ENST00000867637, ENST00000867638, ENST00000867639, ENST00000867640, ENST00000867641, ENST00000911272, ENST00000911273, ENST00000911274, ENST00000911275, ENST00000911276, ENST00000953412, ENST00000953413

RefSeq mRNA: 9 — MANE Select: NM_033211 NM_001316968, NM_001316969, NM_001377283, NM_001377284, NM_001377285, NM_001377286, NM_001377287, NM_001377288, NM_033211

CCDS: CCDS4095

Canonical transcript exons

ENST00000319933 — 3 exons

Exon	Start	End
ENSE00001260401	103265908	103265997
ENSE00001260407	103258763	103258896
ENSE00001260417	103275897	103278660

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 95.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.9371 / max 331.6085, expressed in 1746 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
57843	8.0336	1598
57842	2.7778	1465
57844	1.4749	805
57845	1.2846	692
57846	0.2482	100
57841	0.1180	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
middle temporal gyrus	UBERON:0002771	95.56	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.38	gold quality
colonic mucosa	UBERON:0000317	92.64	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	92.51	gold quality
mucosa of transverse colon	UBERON:0004991	91.81	gold quality
trigeminal ganglion	UBERON:0001675	91.68	gold quality
subthalamic nucleus	UBERON:0001906	91.58	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.50	gold quality
mucosa of sigmoid colon	UBERON:0004993	91.47	gold quality
lateral nuclear group of thalamus	UBERON:0002736	91.31	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.25	gold quality
lateral globus pallidus	UBERON:0002476	90.89	gold quality
dorsal root ganglion	UBERON:0000044	90.37	gold quality
primary visual cortex	UBERON:0002436	89.92	gold quality
Brodmann (1909) area 9	UBERON:0013540	89.91	gold quality
substantia nigra pars compacta	UBERON:0001965	89.87	gold quality
dorsal plus ventral thalamus	UBERON:0001897	89.70	gold quality
occipital lobe	UBERON:0002021	89.48	gold quality
inferior olivary complex	UBERON:0002127	89.40	gold quality
inferior vagus X ganglion	UBERON:0005363	89.32	gold quality
superior frontal gyrus	UBERON:0002661	89.31	gold quality
globus pallidus	UBERON:0001875	89.20	gold quality
prefrontal cortex	UBERON:0000451	89.17	gold quality
rectum	UBERON:0001052	89.03	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	88.95	gold quality
ventricular zone	UBERON:0003053	88.76	gold quality
medial globus pallidus	UBERON:0002477	88.45	gold quality
orbitofrontal cortex	UBERON:0004167	88.28	gold quality
medulla oblongata	UBERON:0001896	88.26	gold quality
frontal cortex	UBERON:0001870	88.24	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.82

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

177 targeting MACIR, 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-4776-3P	100.00	68.73	1340
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-25-3P	99.98	74.60	1817
HSA-MIR-32-5P	99.98	75.21	1964
HSA-MIR-363-3P	99.98	74.72	1821
HSA-MIR-367-3P	99.98	74.83	1819
HSA-MIR-92A-3P	99.98	75.21	1960
HSA-MIR-92B-3P	99.98	75.25	1955
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 3)

• The variant rs26232, in the first intron of the C5orf30 locus, is associated with the severity of radiologic damage in rheumatoid arthritis and is independent of established prognostic biomarkers. (PMID:23817893)
• C5orf30 is a previously unidentified negative regulator of tissue damage in rheumatoid arthritis, and this protein may act by modulating the autoaggressive phenotype that is characteristic of synovial fibroblasts (PMID:26316022)
• C5orf30 skews macrophage immunometabolism, demonstrating a mechanism for C5orf30-mediated immune regulation (PMID:30659109)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	macir	ENSDARG00000093498
mus_musculus	Macir	ENSMUSG00000044768
rattus_norvegicus	Macir	ENSRNOG00000032398

Protein

Protein identifiers

Macrophage immunometabolism regulator — Q96GV9 (reviewed: Q96GV9)

All UniProt accessions (1): Q96GV9

UniProt curated annotations — full annotation on UniProt →

Function. Regulates the macrophage function, by enhancing the resolution of inflammation and wound repair functions mediated by M2 macrophages. The regulation of macrophage function is, due at least in part, to its ability to inhibit glycolysis. May also play a role in trafficking of proteins via its interaction with UNC119 and UNC119B cargo adapters: may help the release of UNC119 and UNC119B cargo or the recycling of UNC119 and UNC119B. May play a role in ciliary membrane localization via its interaction with UNC119B and protein transport into photoreceptor cells.

Subunit / interactions. Interacts with UNC119 and UNC119B; interaction preferentially takes place when UNC119 and UNC119B are unliganded with myristoylated proteins.

Subcellular location. Cytoplasm. Cell projection. Cilium.

Tissue specificity. High expression in normal macrophages, monocytes, and cultured rheumatoid arthritis synovial fibroblasts (RASFs), with lower expression in B- and T-cells, and little to no expression in other tissues and cell lines.

Post-translational modifications. Phosphorylated.

Induction. Up-regulated by hypoxia in cultured rheumatoid arthritis synovial fibroblasts. Down-regulated by TNF in cultured rheumatoid arthritis synovial fibroblasts. Down-regulated by the inflammatory mediators LPS and TNF in primary monocyte-derived macrophages via a c-Jun N-terminal kinase mediated mechanism.

Similarity. Belongs to the UNC119-binding protein family.

RefSeq proteins (9): NP_001303897, NP_001303898, NP_001364212, NP_001364213, NP_001364214, NP_001364215, NP_001364216, NP_001364217, NP_149988* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR029219	UNC119-bd	Family

Pfam: PF15435

UniProt features (6 total): modified residue 4, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96GV9-F1	58.00	0.00

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 (4): 1, 25, 140, 167

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 277 (showing top): GCACCTT_MIR18A_MIR18B, MODULE_52, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, GOBP_INFLAMMATORY_RESPONSE, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_REGULATION_OF_FIBROBLAST_MIGRATION, RODWELL_AGING_KIDNEY_NO_BLOOD_DN, GOBP_AMEBOIDAL_TYPE_CELL_MIGRATION, MODULE_66, MODULE_118, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, CATTTCA_MIR203, MODULE_379, FOSTER_TOLERANT_MACROPHAGE_UP

GO Biological Process (10): inflammatory response (GO:0006954), epithelial cell migration (GO:0010631), negative regulation of epithelial cell migration (GO:0010633), fibroblast migration (GO:0010761), negative regulation of fibroblast migration (GO:0010764), protein transport (GO:0015031), negative regulation of inflammatory response (GO:0050728), cilium assembly (GO:0060271), negative regulation of cytokine production involved in inflammatory response (GO:1900016), cell projection organization (GO:0030030)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (4): cytoplasm (GO:0005737), ciliary transition zone (GO:0035869), cilium (GO:0005929), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
ameboidal-type cell migration	2
negative regulation of cell migration	2
defense response	1
epithelium migration	1
epithelial cell migration	1
regulation of epithelial cell migration	1
negative regulation of multicellular organismal process	1
fibroblast migration	1
regulation of fibroblast migration	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
inflammatory response	1
negative regulation of defense response	1
negative regulation of response to external stimulus	1
regulation of inflammatory response	1
axoneme assembly	1
intraciliary transport involved in cilium assembly	1
cilium organization	1
protein localization to cilium	1
organelle assembly	1
trans-Golgi to periciliary membrane compartment transport	1
plasma membrane bounded cell projection assembly	1
ciliary transition zone assembly	1
negative regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
cellular component organization	1
binding	1
intracellular anatomical structure	1
cilium	1
intraciliary transport particle	1
membrane-bounded organelle	1
plasma membrane bounded cell projection	1

Protein interactions and networks

STRING

442 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MACIR	TRMT11	Q7Z4G4	612
MACIR	ANKRD55	Q3KP44	548
MACIR	GIN1	Q9NXP7	542
MACIR	MAN2A1	Q16706	468
MACIR	UNC119	Q13432	451
MACIR	TMEM135	Q86UB9	448
MACIR	DEUP1	Q05D60	447
MACIR	LRRC59	Q96AG4	438
MACIR	NUDT12	Q9BQG2	434
MACIR	SMIM21	Q3B7S5	431
MACIR	CCNH	P51946	420
MACIR	PLCL2	Q9UPR0	406
MACIR	AFF3	P51826	404
MACIR	PPIP5K2	O43314	402
MACIR	CLEC16A	Q2KHT3	401

IntAct

78 interactions, top by confidence:

A	B	Type	Score
MACIR	YWHAG	psi-mi:“MI:0915”(physical association)	0.800
YWHAB	PIK3C2A	psi-mi:“MI:0914”(association)	0.800
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
LRRC57	MACIR	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
MACIR	TRAF1	psi-mi:“MI:0915”(physical association)	0.560
PNMA1	MACIR	psi-mi:“MI:0915”(physical association)	0.560
TRAF1	MACIR	psi-mi:“MI:0915”(physical association)	0.560
MACIR	PNMA1	psi-mi:“MI:0915”(physical association)	0.560
EXOSC8	MACIR	psi-mi:“MI:0915”(physical association)	0.560
MACIR	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
KAT5	MACIR	psi-mi:“MI:0915”(physical association)	0.560
LMO3	MACIR	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (49): C5orf30 (Two-hybrid), C5orf30 (Two-hybrid), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Affinity Capture-MS), C5orf30 (Two-hybrid), C5orf30 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTI1, A2BIL8, A5PKK9, C5DY61, E2QSX5, E7F555, O35147, O43151, P11805, P19416, P24940, P27579, Q06616, Q17QE3, Q1LZE2, Q1RMQ5, Q1T763, Q28CW2, Q2HR82, Q2TBN9, Q3B8E9, Q3ZBS1, Q567C6, Q5RDK8, Q62417, Q68FW2, Q6AY26, Q6DFB0, Q6P6I6, Q6PKN7, Q80U49, Q86YL5, Q8C3W1, Q8QVM1, Q8VEB3, Q8VI59, Q96FT9, Q96GV9, Q96GY3, Q99618

Diamond homologs: A4IGV6, B3DHS1, Q3ZBS1, Q5RDK8, Q6DFB0, Q8VEB3, Q96GV9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 56 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	6	123.5×	6e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	108.9×	7e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	108.9×	7e-10
Activation of BH3-only proteins	6	80.5×	5e-09
RHO GTPases activate PKNs	6	51.4×	5e-08
Intrinsic Pathway for Apoptosis	6	47.5×	8e-08
SARS-CoV-1-host interactions	7	33.2×	5e-08
Apoptosis	6	27.2×	2e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	36.6×	1e-04
intracellular protein localization	6	12.6×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	5
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

502 predictions. Top by Δscore:

Variant	Effect	Δscore
5:103265901:T:G	acceptor_gain	1.0000
5:103265906:A:AG	acceptor_gain	1.0000
5:103265907:G:GG	acceptor_gain	1.0000
5:103275896:GGATT:G	acceptor_gain	1.0000
5:103258896:GGTAG:G	donor_loss	0.9900
5:103258897:G:GG	donor_gain	0.9900
5:103258897:G:T	donor_loss	0.9900
5:103258898:T:G	donor_loss	0.9900
5:103265900:A:AG	acceptor_gain	0.9900
5:103265900:AT:A	acceptor_gain	0.9900
5:103265907:GT:G	acceptor_gain	0.9900
5:103265907:GTAC:G	acceptor_gain	0.9900
5:103265997:GGTA:G	donor_loss	0.9900
5:103265998:G:GA	donor_loss	0.9900
5:103265999:TA:T	donor_loss	0.9900
5:103266000:AAG:A	donor_loss	0.9900
5:103270038:T:TA	acceptor_gain	0.9900
5:103275894:TA:T	acceptor_loss	0.9900
5:103275895:A:AC	acceptor_loss	0.9900
5:103275895:A:AG	acceptor_gain	0.9900
5:103275895:AG:A	acceptor_gain	0.9900
5:103275896:G:GG	acceptor_gain	0.9900
5:103275896:G:GT	acceptor_loss	0.9900
5:103275896:GG:G	acceptor_gain	0.9900
5:103265907:GTA:G	acceptor_gain	0.9800
5:103265993:GTCTG:G	donor_gain	0.9800
5:103265998:G:GG	donor_gain	0.9800
5:103275896:GGA:G	acceptor_gain	0.9800
5:103275896:GGAT:G	acceptor_gain	0.9800
5:103266002:G:C	donor_loss	0.9700

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000005826 (5:103257929 A>G), RS1000098595 (5:103258309 T>C,G), RS1000243541 (5:103263681 A>C), RS1000654048 (5:103277697 T>G), RS1000981437 (5:103265141 G>A), RS1001009609 (5:103259017 A>G), RS1001042158 (5:103258790 G>A), RS1001350377 (5:103265367 T>C), RS1001664766 (5:103256428 T>C), RS1002072954 (5:103268996 G>A), RS1002104192 (5:103268737 A>C,G), RS1002462746 (5:103276472 G>A), RS1002587921 (5:103272921 A>G), RS1002735403 (5:103265848 T>C), RS1003276305 (5:103261034 A>C,G)

Disease associations

OMIM: gene MIM:616608 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST002318_143	Rheumatoid arthritis	1.000000e-10
GCST002318_16	Rheumatoid arthritis	2.000000e-11
GCST003129_2	Primary biliary cholangitis	1.000000e-08
GCST005568_19	Rheumatoid arthritis (ACPA-positive)	3.000000e-06
GCST005569_41	Rheumatoid arthritis	9.000000e-08
GCST006048_1	Rheumatoid arthritis (ACPA-positive)	1.000000e-09
GCST006959_162	Rheumatoid arthritis	6.000000e-10
GCST006959_65	Rheumatoid arthritis	5.000000e-10
GCST007324_97	Adventurousness	7.000000e-09
GCST007325_126	General risk tolerance (MTAG)	4.000000e-11
GCST007325_142	General risk tolerance (MTAG)	2.000000e-12
GCST007559_21	Sleep duration (short sleep)	2.000000e-08
GCST007932_126	Medication use (thyroid preparations)	5.000000e-12
GCST009391_960	Metabolite levels	3.000000e-06
GCST010571_32	Autoimmune thyroid disease	5.000000e-11
GCST90002390_136	Mean corpuscular hemoglobin	1.000000e-21
GCST90002392_634	Mean corpuscular volume	9.000000e-25
GCST90002397_44	Mean spheric corpuscular volume	9.000000e-11
GCST90002403_408	Red blood cell count	9.000000e-10

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008579	risk-taking behaviour
EFO:0009933	Thyroid preparation use measurement
EFO:0010444	triacylglycerol 60:12 measurement
EFO:0004527	mean corpuscular hemoglobin
EFO:0004305	erythrocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
trichostatin A	increases expression, affects cotreatment	3
Tretinoin	decreases expression	3
Arsenic	affects methylation, affects cotreatment, increases abundance, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	decreases phosphorylation	1
bisphenol A	increases methylation	1
sodium arsenite	affects cotreatment, increases abundance, increases expression	1
manganese chloride	increases abundance, increases expression, affects cotreatment	1
cupric chloride	increases expression	1
coumarin	increases phosphorylation	1
tamibarotene	decreases expression	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
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	decreases expression	1
Demecolcine	decreases expression	1
Diethylhexyl Phthalate	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Formaldehyde	decreases expression	1
Lead	affects splicing	1
Manganese	increases abundance, increases expression, affects cotreatment	1

Clinical trials (associated diseases)

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