IFNA21

Summary

IFNA21 (interferon alpha 21, HGNC:5424) is a protein-coding gene on chromosome 9p21.3, encoding Interferon alpha-21 (P01568). Produced by macrophages, IFN-alpha have antiviral activities.

This gene is a member of the alpha interferon gene cluster on the short arm of chromosome 9. Interferons are cytokines produced in response to viral infection that mediate the immune response and interfere with viral replication. The encoded protein is a type I interferon and may play a specific role in the antiviral response to rubella virus.

Source: NCBI Gene 3452 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 42 total
• Druggable target: yes
• MANE Select transcript: NM_002175

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5424
Approved symbol	IFNA21
Name	interferon alpha 21
Location	9p21.3
Locus type	gene with protein product
Status	Approved
Aliases	IFN-alphaI
Ensembl gene	ENSG00000137080
Ensembl biotype	protein_coding
OMIM	147584
Entrez	3452

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000380225

RefSeq mRNA: 1 — MANE Select: NM_002175 NM_002175

CCDS: CCDS6497

Canonical transcript exons

ENST00000380225 — 1 exons

Exon	Start	End
ENSE00001484149	21165637	21166660

Expression profiles

Bgee: expression breadth broad, 26 present calls, max score 67.88.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
sperm	CL:0000019	67.88	gold quality
choroid plexus epithelium	UBERON:0003911	66.28	gold quality
endothelial cell	CL:0000115	64.02	gold quality
parotid gland	UBERON:0001831	60.22	gold quality
epithelium of nasopharynx	UBERON:0001951	55.31	gold quality
mucosa of paranasal sinus	UBERON:0005030	54.88	gold quality
nasal cavity epithelium	UBERON:0005384	54.73	gold quality
buccal mucosa cell	CL:0002336	54.50	gold quality
gingival epithelium	UBERON:0001949	54.43	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	53.72	gold quality
cartilage tissue	UBERON:0002418	52.08	gold quality
blood vessel layer	UBERON:0004797	50.48	gold quality
gingiva	UBERON:0001828	50.24	gold quality
substantia nigra pars reticulata	UBERON:0001966	49.39	gold quality
quadriceps femoris	UBERON:0001377	49.15	gold quality
vastus lateralis	UBERON:0001379	48.93	gold quality
Brodmann (1909) area 46	UBERON:0006483	48.20	gold quality
inferior olivary complex	UBERON:0002127	47.45	gold quality
periodontal ligament	UBERON:0008266	47.14	gold quality
cerebellar hemisphere	UBERON:0002245	47.05	gold quality
right hemisphere of cerebellum	UBERON:0014890	47.01	gold quality
mammalian vulva	UBERON:0000997	47.00	gold quality
cerebellar cortex	UBERON:0002129	47.00	silver quality
renal glomerulus	UBERON:0000074	46.86	gold quality
metanephric glomerulus	UBERON:0004736	46.77	gold quality
nephron tubule	UBERON:0001231	46.71	gold quality
cerebellum	UBERON:0002037	46.45	silver quality
inferior vagus X ganglion	UBERON:0005363	45.44	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	45.35	gold quality
biceps brachii	UBERON:0001507	45.10	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF5

miRNA regulators (miRDB)

26 targeting IFNA21, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-7978	99.86	66.90	856
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-3911	99.38	66.95	1087
HSA-MIR-6507-5P	99.36	70.46	2524
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-876-3P	98.76	68.23	945
HSA-MIR-633	98.35	69.45	1167
HSA-MIR-924	97.78	66.21	681
HSA-MIR-3156-5P	96.93	67.36	800
HSA-MIR-6894-3P	96.73	65.64	798
HSA-MIR-627-5P	95.51	66.80	509
HSA-MIR-1269A	92.75	64.61	542
HSA-MIR-1269B	92.75	64.73	538

Literature-anchored findings (GeneRIF, showing 3)

• Structural AA changes in the C-helix interacting with IFNAlphaR1 may change the signaling dynamics leading to elevated APOBEC3 & lower IDO by an engineered mutant derived from the amino-terminal region of IFNalpha21b and the COOH-terminus from IFNalpha2c. (PMID:21757613)
• IFNA21 may be involved in inflammatory processes in an age-dependent manner and in progression of coronary artery disease. Several 9p21 SNPs may modulate inflammatory processes mediated by IFNA21 and may, therefore, contribute to pathophysiology of coronary artery disease. (PMID:32248921)
• Alpha interferon suppresses the cyclin D3 and cdc25A genes, leading to a reversible G0-like arrest. (PMID:8668211)

Cross-species orthologs

34 orthologs

Organism	Symbol	Gene ID
danio_rerio	ifnphi2	ENSDARG00000069012
danio_rerio	ifnphi3	ENSDARG00000070676
mus_musculus	Ifna13	ENSMUSG00000063376
mus_musculus	Ifna4	ENSMUSG00000070904
mus_musculus	Ifna12	ENSMUSG00000073811
mus_musculus	Ifna2	ENSMUSG00000078354
mus_musculus	Ifna16	ENSMUSG00000078355
mus_musculus	Ifna9	ENSMUSG00000095270
mus_musculus	Ifna1	ENSMUSG00000095498
mus_musculus	Ifna14	ENSMUSG00000095896
mus_musculus	Ifna15	ENSMUSG00000096011
mus_musculus	Ifna5	ENSMUSG00000096682
mus_musculus	Ifnab	ENSMUSG00000100079
mus_musculus	Ifna11	ENSMUSG00000100549
mus_musculus	Ifna7	ENSMUSG00000100713
mus_musculus	Ifna6	ENSMUSG00000101252
rattus_norvegicus		ENSRNOG00000071845
rattus_norvegicus	Ifna12l	ENSRNOG00000072681
rattus_norvegicus	Ifna16l1	ENSRNOG00000074841
rattus_norvegicus		ENSRNOG00000075722
rattus_norvegicus		ENSRNOG00000076372
rattus_norvegicus	Ifna4	ENSRNOG00000077072
rattus_norvegicus	Ifna2	ENSRNOG00000078310
rattus_norvegicus	Ifna5	ENSRNOG00000079725
rattus_norvegicus	Ifna1l1	ENSRNOG00000079800
rattus_norvegicus		ENSRNOG00000079804
rattus_norvegicus		ENSRNOG00000081823
rattus_norvegicus		ENSRNOG00000082441
rattus_norvegicus		ENSRNOG00000082845
rattus_norvegicus		ENSRNOG00000083047
rattus_norvegicus	Ifna1	ENSRNOG00000084770
rattus_norvegicus		ENSRNOG00000085373
rattus_norvegicus		ENSRNOG00000085882
rattus_norvegicus		ENSRNOG00000086565

Paralogs (16): IFNA6 (ENSG00000120235), IFNA8 (ENSG00000120242), IFNA5 (ENSG00000147873), IFNA16 (ENSG00000147885), IFNK (ENSG00000147896), IFNB1 (ENSG00000171855), IFNW1 (ENSG00000177047), IFNE (ENSG00000184995), IFNA10 (ENSG00000186803), IFNA2 (ENSG00000188379), IFNA1 (ENSG00000197919), IFNA7 (ENSG00000214042), IFNA14 (ENSG00000228083), IFNA13 (ENSG00000233816), IFNA17 (ENSG00000234829), IFNA4 (ENSG00000236637)

Protein

Protein identifiers

Interferon alpha-21 — P01568 (reviewed: P01568)

Alternative names: Interferon alpha-F

All UniProt accessions (2): A0A7R8GUQ6, P01568

UniProt curated annotations — full annotation on UniProt →

Function. Produced by macrophages, IFN-alpha have antiviral activities. Interferon stimulates the production of two enzymes: a protein kinase and an oligoadenylate synthetase.

Subcellular location. Secreted.

Similarity. Belongs to the type-I (or alpha/beta) interferon family.

RefSeq proteins (1): NP_002166* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000471	Interferon_alpha/beta/delta	Family
IPR009079	4_helix_cytokine-like_core	Homologous_superfamily

Pfam: PF00143

UniProt features (7 total): disulfide bond 2, sequence variant 2, signal peptide 1, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01568-F1	85.36	0.54

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 24–122, 52–162

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-912694	Regulation of IFNA/IFNB signaling
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983231	Factors involved in megakaryocyte development and platelet production
R-HSA-9833109	Evasion by RSV of host interferon responses

MSigDB gene sets: 126 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_CELLULAR_RESPONSE_TO_VIRUS, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_RESPONSE_TO_PEPTIDE, GOBP_B_CELL_ACTIVATION, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_RESPONSE_TO_TYPE_I_INTERFERON, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, KEGG_AUTOIMMUNE_THYROID_DISEASE, MODULE_99, GOBP_NATURAL_KILLER_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE

GO Biological Process (11): adaptive immune response (GO:0002250), T cell activation involved in immune response (GO:0002286), B cell activation involved in immune response (GO:0002312), natural killer cell activation involved in immune response (GO:0002323), humoral immune response (GO:0006959), response to exogenous dsRNA (GO:0043330), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), cellular response to virus (GO:0098586), defense response (GO:0006952), signal transduction (GO:0007165)

GO Molecular Function (4): cytokine activity (GO:0005125), cytokine receptor binding (GO:0005126), type I interferon receptor binding (GO:0005132), protein binding (GO:0005515)

GO Cellular Component (2): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
Interferon Signaling	1
Interferon alpha/beta signaling	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
SARS-CoV-2-host interactions	1
Hemostasis	1
RSV-host interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	4
lymphocyte activation involved in immune response	3
response to virus	2
T cell activation	1
B cell activation	1
natural killer cell activation	1
innate immune response	1
response to dsRNA	1
defense response	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
receptor ligand activity	1
signaling receptor binding	1
cytokine receptor binding	1
protein-containing complex binding	1
binding	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1350 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IFNA21	IL2	P01585	855
IFNA21	IFNG	P01579	762
IFNA21	IFNAR1	P17181	721
IFNA21	CR2	P20023	668
IFNA21	IFNL3	Q8IZI9	667
IFNA21	IL6	P05231	661
IFNA21	ISG15	P05161	642
IFNA21	TLR3	O15455	629
IFNA21	ABL1	P00519	624
IFNA21	GPT	P24298	624
IFNA21	CD4	P01730	620
IFNA21	MX1	P20591	611
IFNA21	TNF	P01375	608
IFNA21	MX2	P20592	585
IFNA21	CD8A	P01732	582

IntAct

16 interactions, top by confidence:

A	B	Type	Score
FAM228A	IFNA21	psi-mi:“MI:0915”(physical association)	0.590
ATP11B	IFNA21	psi-mi:“MI:0915”(physical association)	0.590
IFNA21	IFIT3	psi-mi:“MI:0914”(association)	0.530
REEP5	SCAMP1	psi-mi:“MI:0914”(association)	0.530
IFNA13	IFNA21	psi-mi:“MI:0914”(association)	0.530
SLC30A2	ESYT2	psi-mi:“MI:0914”(association)	0.530
MBP	CTDSPL	psi-mi:“MI:0914”(association)	0.350
IFNA21	CPD	psi-mi:“MI:0914”(association)	0.350
IFNA21	OASL	psi-mi:“MI:0914”(association)	0.350
IFNA8	IFNA21	psi-mi:“MI:0914”(association)	0.350

BioGRID (49): IFNA4 (Affinity Capture-MS), IFNA21 (Affinity Capture-MS), IFNA6 (Affinity Capture-MS), IFNA13 (Affinity Capture-MS), ISG15 (Affinity Capture-MS), UBR3 (Affinity Capture-MS), IFI44 (Affinity Capture-MS), IFI44L (Affinity Capture-MS), IFIT1 (Affinity Capture-MS), IFNA14 (Affinity Capture-MS), PCYOX1L (Affinity Capture-MS), IFIT3 (Affinity Capture-MS), EMC3 (Affinity Capture-MS), CD109 (Affinity Capture-MS), IFNA21 (Affinity Capture-MS)

ESM2 similar proteins: O46633, P01562, P01563, P01566, P01567, P01568, P01569, P01570, P01571, P01572, P05000, P05002, P05003, P05004, P05005, P05006, P05007, P05008, P05009, P05010, P05013, P05014, P05015, P07348, P07349, P07352, P09235, P15696, P28169, P28171, P28172, P32881, P49876, P49877, P49878, P49879, P56828, P56829, P56830, P56831

Diamond homologs: A7UHZ5, O46633, O77812, O97945, P01562, P01563, P01566, P01567, P01568, P01569, P01570, P01571, P01572, P01573, P01574, P01575, P01576, P01577, P01578, P05000, P05001, P05002, P05003, P05004, P05005, P05006, P05007, P05008, P05009, P05010, P05011, P05012, P05013, P05014, P05015, P06799, P07348, P07349, P07350, P07351

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

257 predictions. Top by Δscore:

Variant	Effect	Δscore
9:21165907:T:A	donor_gain	0.7200
9:21166329:T:TA	donor_gain	0.7000
9:21166511:A:AC	donor_gain	0.6500
9:21165904:CA:C	donor_gain	0.6300
9:21166236:T:TA	donor_gain	0.6100
9:21165874:G:A	donor_gain	0.6000
9:21165903:A:AC	donor_gain	0.5900
9:21165904:C:CC	donor_gain	0.5900
9:21166166:T:TA	donor_gain	0.5900
9:21166232:A:T	donor_gain	0.5800
9:21165870:TAG:T	donor_gain	0.5700
9:21165903:ACACT:A	donor_gain	0.5600
9:21165904:CACTC:C	donor_gain	0.5600
9:21166242:A:AC	donor_gain	0.5600
9:21165871:AGTG:A	donor_gain	0.5500
9:21165904:CACT:C	donor_gain	0.5500
9:21166224:TCC:T	donor_gain	0.5400
9:21166254:T:TA	donor_gain	0.5400
9:21166368:T:TG	acceptor_gain	0.5400
9:21166025:T:A	donor_gain	0.5300
9:21166051:T:A	donor_gain	0.5300
9:21166478:T:TA	donor_gain	0.5300
9:21165840:G:C	donor_gain	0.5200
9:21165655:T:TC	acceptor_gain	0.5100
9:21165858:T:C	donor_gain	0.5100
9:21165898:T:TA	donor_gain	0.5100
9:21165936:A:C	donor_gain	0.5100
9:21165940:ATG:A	donor_gain	0.5100
9:21165940:A:AC	donor_gain	0.5000
9:21166229:C:A	donor_gain	0.5000

AlphaMissense

1247 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:21166172:G:C	F147L	0.944
9:21166172:G:T	F147L	0.944
9:21166174:A:G	F147L	0.944
9:21166436:A:C	F59L	0.937
9:21166436:A:T	F59L	0.937
9:21166438:A:G	F59L	0.937
9:21166121:C:A	W164C	0.908
9:21166121:C:G	W164C	0.908
9:21166340:G:C	F91L	0.855
9:21166340:G:T	F91L	0.855
9:21166342:A:G	F91L	0.855
9:21166313:C:A	W100C	0.839
9:21166313:C:G	W100C	0.839
9:21166152:A:G	L154P	0.819
9:21166109:T:A	R168S	0.817
9:21166109:T:G	R168S	0.817
9:21166266:A:G	L116P	0.809
9:21166113:A:T	V167D	0.797
9:21166123:A:G	W164R	0.796
9:21166123:A:T	W164R	0.796
9:21166437:A:C	F59C	0.790
9:21166344:A:G	L90P	0.779
9:21166176:T:G	Y146S	0.776
9:21166177:A:G	Y146H	0.774
9:21166278:A:G	L112P	0.772
9:21166458:C:G	C52S	0.767
9:21166459:A:G	C52R	0.767
9:21166459:A:T	C52S	0.767
9:21166457:G:C	C52W	0.764
9:21166128:C:G	C162S	0.762

dbSNP variants (sampled 300 via entrez): RS1000062385 (9:21165875 C>T), RS1003913995 (9:21165553 A>G), RS1008198420 (9:21165496 G>A,T), RS1008422992 (9:21168389 C>G), RS1010109680 (9:21166785 ACT>A), RS1010753027 (9:21165890 A>G), RS10119942 (9:21166650 G>A,T), RS1012244826 (9:21167939 A>G,T), RS1012615391 (9:21167164 A>C,G), RS1012691952 (9:21168080 T>A,C), RS1012996560 (9:21167008 T>A), RS1015547977 (9:21165363 A>G,T), RS1015766747 (9:21165497 G>A,C,T), RS1015819138 (9:21165334 T>C), RS1016217464 (9:21167022 C>G,T)

Disease associations

OMIM: gene MIM:147584 | 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
GCST005001_19	Shingles	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008401	susceptibility to shingles measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3856161 (PROTEIN FAMILY)

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
hydroxyhydroquinone	increases expression	1
Glyphosate	increases expression	1
Amphotericin B	increases expression	1
Cadmium	decreases expression, increases abundance	1
Lead	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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