MUC21

Summary

MUC21 (mucin 21, cell surface associated, HGNC:21661) is a protein-coding gene on chromosome 6p21.33, encoding Mucin-21 (Q5SSG8).

This gene encodes a large membrane-bound glycoprotein which is a member of the mucin family. Mucins are O-glycosylated proteins that play an essential role in forming protective mucous barriers on epithelial surfaces. These proteins also play a role in intracellular signaling. The encoded protein contains an N-terminal signal sequence, an extracellular mucin domain, a stem domain, a transmembrane domain, and a C-terminal cytoplasmic tail domain. The mucin domain contains O-glycosylation sites and is polymorphic with isoforms containing a variable number of nonidentical proline-, threonine-, and serine-rich tandem repeats of 15 amino acids each. The aberrent expression of this gene is associated with lung adenocarcinoma.

Source: NCBI Gene 394263 — RefSeq curated summary.

At a glance

• GWAS associations: 32
• Clinical variants (ClinVar): 58 total
• MANE Select transcript: NM_001010909

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21661
Approved symbol	MUC21
Name	mucin 21, cell surface associated
Location	6p21.33
Locus type	gene with protein product
Status	Approved
Aliases	bCX31G15.2
Ensembl gene	ENSG00000204544
Ensembl biotype	protein_coding
OMIM	616991
Entrez	394263

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000376296, ENST00000486149

RefSeq mRNA: 1 — MANE Select: NM_001010909 NM_001010909

CCDS: CCDS34388

Canonical transcript exons

ENST00000376296 — 3 exons

Exon	Start	End
ENSE00001866178	30983718	30984019
ENSE00001928294	30988000	30989903
ENSE00003542461	30986237	30987681

Expression profiles

Bgee: expression breadth ubiquitous, 103 present calls, max score 99.76.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.1148 / max 1776.1451, expressed in 40 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66847	3.0728	40
66849	0.0163	8
66851	0.0142	7
66850	0.0080	4
66848	0.0036	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.76	gold quality
esophagus mucosa	UBERON:0002469	98.60	gold quality
vagina	UBERON:0000996	87.47	gold quality
esophagus	UBERON:0001043	78.80	gold quality
tonsil	UBERON:0002372	70.31	gold quality
ectocervix	UBERON:0012249	70.31	gold quality
minor salivary gland	UBERON:0001830	66.91	gold quality
uterine cervix	UBERON:0000002	66.77	gold quality
saliva-secreting gland	UBERON:0001044	64.13	gold quality
right coronary artery	UBERON:0001625	61.80	gold quality
body of stomach	UBERON:0001161	60.34	gold quality
fundus of stomach	UBERON:0001160	59.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	59.07	gold quality
upper lobe of left lung	UBERON:0008952	58.62	gold quality
stomach	UBERON:0000945	57.44	gold quality
lower esophagus	UBERON:0013473	56.64	gold quality
lower esophagus muscularis layer	UBERON:0035833	56.57	gold quality
endocervix	UBERON:0000458	54.11	gold quality
lung	UBERON:0002048	54.05	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	53.85	gold quality
right uterine tube	UBERON:0001302	53.54	gold quality
left uterine tube	UBERON:0001303	53.44	gold quality
body of pancreas	UBERON:0001150	51.75	gold quality
islet of Langerhans	UBERON:0000006	51.35	gold quality
right lobe of liver	UBERON:0001114	51.33	gold quality
pancreas	UBERON:0001264	51.21	gold quality
urinary bladder	UBERON:0001255	51.09	gold quality
gastrocnemius	UBERON:0001388	50.92	gold quality
left adrenal gland	UBERON:0001234	50.50	gold quality
left adrenal gland cortex	UBERON:0035825	49.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	2.85

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting MUC21, 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-6867-5P	100.00	82.21	3464
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-488-3P	99.61	68.79	1731
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4318	99.38	66.94	1505
HSA-MIR-1273H-3P	99.29	67.55	980
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-6852-5P	99.17	66.69	2073
HSA-MIR-3152-3P	99.10	66.35	678
HSA-MIR-661	99.09	65.94	2062
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-5187-5P	98.54	67.94	952
HSA-MIR-4490	98.51	68.47	943
HSA-MIR-1248	98.47	67.54	1314
HSA-MIR-541-5P	98.24	67.77	1181
HSA-MIR-3166	98.24	66.63	1223
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-6730-5P	98.03	68.12	1299
HSA-MIR-6728-5P	97.79	66.33	891
HSA-MIR-4724-3P	97.57	67.31	785

Literature-anchored findings (GeneRIF, showing 8)

• Identification and expression of human epiglycanin/MUC21: a novel transmembrane mucin (PMID:17977904)
• Mucin 21/epiglycanin modulates cell adhesion (PMID:20388707)
• CC genotype of rs886403 in MUC21 is associated with recurrence in colorectal cancer. (PMID:27803053)
• MUC21 is significantly upregulated in human masticatory mucosa during wound healing (PMID:28005267)
• MUC21 could be used as an additional, novel, negative immunohistochemical marker to differentiate mesothelioma from lung adenocarcinoma. (PMID:30329165)
• MUC21 proteins with a specific glycosylation status may be involved in the progression of EGFR-mutated lung adenocarcinomas, particularly at the stage where tumors are transforming from pure lepidic to micropapillary through low papillary lepidic lesions. (PMID:30973916)
• MUC21 controls melanoma progression via regulating SLITRK5 and hedgehog signaling pathway. (PMID:35579188)
• A CRISPR activation screen identifies MUC-21 as critical for resistance to NK and T cell-mediated cytotoxicity. (PMID:37858248)

Cross-species orthologs

0 orthologs

Protein

Protein identifiers

Mucin-21 — Q5SSG8 (reviewed: Q5SSG8)

Alternative names: Epiglycanin

All UniProt accessions (2): A0A0C4DGM6, Q5SSG8

UniProt curated annotations — full annotation on UniProt →

Subcellular location. Cell membrane.

Tissue specificity. Expressed in lung, large intestine, thymus, and testis. Expressed in normal and malignant bronchial epithelial cells.

Post-translational modifications. O-glycosylated.

Miscellaneous. Could be considered as a marker for lung carcinomas.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5SSG8-1	1	yes
Q5SSG8-2	2
Q5SSG8-3	3

RefSeq proteins (1): NP_001010909* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008519	Tandem-repeating_mucin	Domain
IPR028199	Mucin_dom	Domain

Pfam: PF05647, PF14654

UniProt features (75 total): repeat 28, sequence conflict 20, sequence variant 14, region of interest 4, topological domain 2, splice variant 2, signal peptide 1, chain 1, transmembrane region 1, site 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5SSG8-F1	74.30	0.26

Functional residue map

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

Catalytic / active sites (1): 502–503 (cleavage)

Glycosylation sites (1): 25

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-5083625	Defective GALNT3 causes HFTC
R-HSA-5083632	Defective C1GALT1C1 causes TNPS
R-HSA-5083636	Defective GALNT12 causes CRCS1
R-HSA-5621480	Dectin-2 family
R-HSA-913709	O-linked glycosylation of mucins
R-HSA-977068	Termination of O-glycan biosynthesis
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-3781865	Diseases of glycosylation
R-HSA-3906995	Diseases associated with O-glycosylation of proteins
R-HSA-392499	Metabolism of proteins
R-HSA-5173105	O-linked glycosylation
R-HSA-5621481	C-type lectin receptors (CLRs)
R-HSA-5668914	Diseases of metabolism
R-HSA-597592	Post-translational protein modification

MSigDB gene sets: 38 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_NEGATIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GOCC_GOLGI_LUMEN, GOBP_NEGATIVE_REGULATION_OF_CELL_ADHESION, REACTOME_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, BOSCO_EPITHELIAL_DIFFERENTIATION_MODULE, REACTOME_DISEASES_OF_GLYCOSYLATION, REACTOME_DISEASES_ASSOCIATED_WITH_O_GLYCOSYLATION_OF_PROTEINS, REACTOME_DEFECTIVE_GALNT3_CAUSES_HFTC, REACTOME_DEFECTIVE_C1GALT1C1_CAUSES_TNPS, REACTOME_O_LINKED_GLYCOSYLATION, REACTOME_DECTIN_2_FAMILY, REACTOME_C_TYPE_LECTIN_RECEPTORS_CLRS, REACTOME_DISEASES_OF_METABOLISM

GO Biological Process (1): negative regulation of cell-cell adhesion (GO:0022408)

GO Molecular Function (0):

GO Cellular Component (3): Golgi lumen (GO:0005796), plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Diseases associated with O-glycosylation of proteins	3
C-type lectin receptors (CLRs)	1
O-linked glycosylation	1
O-linked glycosylation of mucins	1
Immune System	1
Diseases of metabolism	1
Diseases of glycosylation	1
Post-translational protein modification	1
Innate Immune System	1
Disease	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
negative regulation of cell adhesion	1
regulation of cell-cell adhesion	1
cell-cell adhesion	1
Golgi apparatus	1
intracellular organelle lumen	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MUC21	MUC13	Q9H3R2	837
MUC21	MUC20	Q8N307	801
MUC21	MUC15	Q8N387	792
MUC21	MUC4	Q99102	781
MUC21	MUC12	Q9UKN1	774
MUC21	MUC3A	Q02505	728
MUC21	MUC17	Q685J3	720
MUC21	MUC19	Q7Z5P9	720
MUC21	MUC7	Q8TAX7	720
MUC21	MUC6	Q6W4X9	682
MUC21	MUC5B	Q9HC84	671
MUC21	MUC16	Q8WXI7	664
MUC21	MUC5AC	P98088	625
MUC21	MUC1	P13931	622
MUC21	MUC2	Q02817	612

IntAct

0 interactions, top by confidence:

ESM2 similar proteins: A0A0H2URK1, A0A0H3HIJ5, A0A1D8PQ86, A1C3L3, A8AWU7, O86487, P05227, P08519, P08640, P0C727, P0C728, P0CG48, P0CG50, P0CG61, P0CG64, P0CG66, P0CG69, P0CG71, P0CH28, P12027, P13821, P15941, P19837, P24856, P32768, P39712, P46804, P62976, Q02192, Q27905, Q2FJ79, Q2G0L5, Q41406, Q49537, Q49538, Q4L9P0, Q54GV8, Q59SG9, Q5HIB4, Q5SSG8

Diamond homologs: E2RYF6, Q5SSG8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	18
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

227 predictions. Top by Δscore:

Variant	Effect	Δscore
6:30987994:TTTTA:T	acceptor_loss	0.9900
6:30987998:A:AG	acceptor_gain	0.9900
6:30987998:A:AT	acceptor_loss	0.9900
6:30987999:G:GG	acceptor_gain	0.9900
6:30987999:GA:G	acceptor_gain	0.9900
6:30983835:G:GT	donor_gain	0.9800
6:30984016:GCTG:G	donor_gain	0.9800
6:30987999:GAGA:G	acceptor_gain	0.9800
6:30983975:G:GT	donor_gain	0.9700
6:30986224:AT:A	acceptor_gain	0.9700
6:30986225:T:G	acceptor_gain	0.9700
6:30986235:A:AG	acceptor_gain	0.9700
6:30986236:G:GG	acceptor_gain	0.9700
6:30987999:GAGAA:G	acceptor_gain	0.9700
6:30983814:C:G	donor_gain	0.9600
6:30983976:A:T	donor_gain	0.9600
6:30986225:T:TA	acceptor_gain	0.9600
6:30986236:GC:G	acceptor_gain	0.9600
6:30986236:GCAAC:G	acceptor_gain	0.9400
6:30987677:GTGTG:G	donor_gain	0.9400
6:30987682:G:GG	donor_gain	0.9400
6:30987997:TAGAG:T	acceptor_gain	0.9400
6:30987998:AGAGA:A	acceptor_gain	0.9400
6:30987571:G:GG	donor_gain	0.9300
6:30987999:G:C	acceptor_gain	0.9300
6:30984021:TGAG:T	donor_loss	0.9200
6:30984022:GAGT:G	donor_loss	0.9200
6:30987996:TTAG:T	acceptor_gain	0.9200
6:30987997:TAG:T	acceptor_gain	0.9200
6:30987998:AGA:A	acceptor_gain	0.9200

AlphaMissense

3718 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:30987652:G:A	G493R	0.965
6:30987652:G:C	G493R	0.965
6:30987664:G:A	G497R	0.942
6:30987664:G:C	G497R	0.942
6:30987653:G:A	G493E	0.935
6:30987665:G:A	G497E	0.926
6:30987609:G:C	W478C	0.920
6:30987609:G:T	W478C	0.920
6:30987607:T:A	W478R	0.914
6:30987607:T:C	W478R	0.914
6:30987632:T:A	V486D	0.902
6:30987612:A:C	E479D	0.901
6:30987612:A:T	E479D	0.901
6:30987647:C:A	A491D	0.892
6:30987620:T:C	L482P	0.890
6:30987614:T:C	I480T	0.888
6:30987638:T:A	V488D	0.880
6:30987629:T:C	L485P	0.871
6:30987623:T:A	I483N	0.866
6:30987620:T:A	L482H	0.865
6:30987629:T:G	L485R	0.856
6:30987614:T:G	I480S	0.853
6:30987656:T:G	L494R	0.850
6:30987623:T:G	I483S	0.847
6:30987646:G:C	A491P	0.846
6:30987656:T:C	L494P	0.845
6:30987641:T:A	V489E	0.842
6:30987662:C:A	A496D	0.842
6:30987620:T:G	L482R	0.832
6:30987623:T:C	I483T	0.822

dbSNP variants (sampled 300 via entrez): RS1000175654 (6:30989774 T>C), RS1000583547 (6:30988759 C>T), RS1000765494 (6:30981975 C>T), RS1001478867 (6:30985188 C>T), RS1001610464 (6:30984115 A>G), RS1001805226 (6:30984907 G>A), RS1003342484 (6:30982256 A>G), RS1004166255 (6:30984937 T>C), RS1004505513 (6:30983364 A>C,G), RS1005787204 (6:30983674 C>T), RS1006127187 (6:30982201 G>C), RS1006178066 (6:30981835 G>C), RS1006381668 (6:30989146 T>A), RS1006741119 (6:30989492 T>C), RS1006948371 (6:30984169 A>G)

Disease associations

OMIM: gene MIM:616991 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

32 associations (top):

Study	Trait	p-value
GCST001137_9	White blood cell count	4.000000e-13
GCST001181_1	Drug-induced Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN)	3.000000e-07
GCST001200_5	Graves’ disease	4.000000e-51
GCST001779_4	Hematology traits	5.000000e-07
GCST001784_12	Pulmonary function (smoking interaction)	1.000000e-07
GCST001784_34	Pulmonary function (smoking interaction)	1.000000e-07
GCST001949_5	Preeclampsia	3.000000e-06
GCST002884_4	Cutaneous lupus erythematosus	2.000000e-11
GCST003123_16	Severe influenza A (H1N1) infection	2.000000e-14
GCST003156_41	Systemic lupus erythematosus	6.000000e-92
GCST004521_114	Autism spectrum disorder or schizophrenia	3.000000e-17
GCST004521_117	Autism spectrum disorder or schizophrenia	3.000000e-15
GCST004521_132	Autism spectrum disorder or schizophrenia	2.000000e-09
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_19	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_2	Autism spectrum disorder or schizophrenia	2.000000e-16
GCST004521_209	Autism spectrum disorder or schizophrenia	5.000000e-16
GCST004521_210	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_211	Autism spectrum disorder or schizophrenia	5.000000e-15
GCST004521_265	Autism spectrum disorder or schizophrenia	7.000000e-14
GCST004521_27	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_282	Autism spectrum disorder or schizophrenia	5.000000e-09
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_3	Autism spectrum disorder or schizophrenia	2.000000e-15
GCST004521_48	Autism spectrum disorder or schizophrenia	1.000000e-09
GCST004521_70	Autism spectrum disorder or schizophrenia	8.000000e-20
GCST007254_3	Broad depression or major depressive disorder (self-reported)	1.000000e-08
GCST010286_2	Oropharynx cancer	1.000000e-10
GCST010725_70	Malaria	5.000000e-06
GCST010725_9	Malaria	6.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004713	FEV/FVC ratio
EFO:1001488	influenza A (H1N1)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	3
Resveratrol	affects cotreatment, decreases expression	2
bisphenol A	affects cotreatment, increases methylation, decreases methylation	1
Fulvestrant	affects cotreatment, increases methylation	1
Acetaminophen	increases expression	1
Vehicle Emissions	decreases methylation	1
Copper	affects cotreatment, decreases expression	1
Phthalic Acids	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Tobacco Smoke Pollution	affects expression	1

Clinical trials (associated diseases)

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