DSC3

Summary

DSC3 (desmocollin 3, HGNC:3037) is a protein-coding gene on chromosome 18q12.1, encoding Desmocollin-3 (Q14574). A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion.

The protein encoded by this gene is a calcium-dependent glycoprotein that is a member of the desmocollin subfamily of the cadherin superfamily. These desmosomal family members, along with the desmogleins, are found primarily in epithelial cells where they constitute the adhesive proteins of the desmosome cell-cell junction and are required for cell adhesion and desmosome formation. The desmosomal family members are arranged in two clusters on chromosome 18, occupying less than 650 kb combined. Mutations in this gene are a cause of hypotrichosis and recurrent skin vesicles disorder. The protein can act as an autoantigen in pemphigus diseases, and it is also considered to be a biomarker for some cancers. Alternative splicing of this gene results in multiple transcript variants.

Source: NCBI Gene 1825 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial isolated arrhythmogenic right ventricular dysplasia (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 2,428 total — 64 pathogenic, 43 likely-pathogenic
• Phenotypes (HPO): 16
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001941

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3037
Approved symbol	DSC3
Name	desmocollin 3
Location	18q12.1
Locus type	gene with protein product
Status	Approved
Aliases	CDHF3, DSC, DSC1, DSC2
Ensembl gene	ENSG00000134762
Ensembl biotype	protein_coding
OMIM	600271
Entrez	1825

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000360428, ENST00000434452, ENST00000584980

RefSeq mRNA: 2 — MANE Select: NM_001941 NM_001941, NM_024423

CCDS: CCDS32810

Canonical transcript exons

ENST00000360428 — 16 exons

Exon	Start	End
ENSE00000915986	30996791	30997048
ENSE00000915987	31001618	31001739
ENSE00000915988	31004142	31004366
ENSE00000915989	31006907	31007131
ENSE00000915990	31008016	31008158
ENSE00000915991	31008269	31008525
ENSE00001103909	31032192	31032276
ENSE00001103930	31024349	31024493
ENSE00001103937	31018666	31018800
ENSE00001103941	31022336	31022502
ENSE00001103946	31018071	31018256
ENSE00001103954	31029509	31029628
ENSE00001317535	31025760	31025915
ENSE00001506176	31030973	31031172
ENSE00001678807	30989365	30994372
ENSE00002687302	31042592	31042742

Expression profiles

Bgee: expression breadth ubiquitous, 177 present calls, max score 99.51.

FANTOM5 (CAGE): breadth broad, TPM avg 8.6642 / max 1641.0922, expressed in 458 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171541	5.7451	347
171542	1.0595	264
171546	0.6628	225
171543	0.5434	206
171540	0.4014	123
171544	0.1551	65
171545	0.0969	42

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	99.51	gold quality
gingival epithelium	UBERON:0001949	99.40	gold quality
gingiva	UBERON:0001828	99.37	gold quality
skin of hip	UBERON:0001554	99.36	gold quality
mammalian vulva	UBERON:0000997	99.07	gold quality
penis	UBERON:0000989	98.78	gold quality
hair follicle	UBERON:0002073	98.70	gold quality
tongue squamous epithelium	UBERON:0006919	98.40	gold quality
nipple	UBERON:0002030	98.27	gold quality
upper arm skin	UBERON:0004263	98.24	gold quality
skin of abdomen	UBERON:0001416	98.02	gold quality
cervix squamous epithelium	UBERON:0006922	98.02	gold quality
zone of skin	UBERON:0000014	97.83	gold quality
squamous epithelium	UBERON:0006914	97.65	gold quality
skin of leg	UBERON:0001511	97.32	gold quality
cervix epithelium	UBERON:0004801	97.05	gold quality
esophagus squamous epithelium	UBERON:0006920	96.73	gold quality
oral cavity	UBERON:0000167	96.67	gold quality
pharyngeal mucosa	UBERON:0000355	96.43	gold quality
epithelium of esophagus	UBERON:0001976	95.63	gold quality
esophagus mucosa	UBERON:0002469	95.63	gold quality
lower esophagus mucosa	UBERON:0035834	93.62	gold quality
germinal epithelium of ovary	UBERON:0001304	91.90	gold quality
palpebral conjunctiva	UBERON:0001812	91.66	gold quality
body of tongue	UBERON:0011876	90.94	gold quality
amniotic fluid	UBERON:0000173	88.67	gold quality
tongue	UBERON:0001723	87.28	gold quality
tonsil	UBERON:0002372	86.87	gold quality
vagina	UBERON:0000996	86.82	gold quality
epithelium of nasopharynx	UBERON:0001951	86.05	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	134.81
E-MTAB-10596	no	859.69
E-GEOD-86618	no	259.49
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

194 targeting DSC3, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-373-5P	99.98	75.36	4753

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• Gene-profiling experiments of breast cancer cells infected with wt p53 revealed both MASPIN and desmocollin 3 (DSC3) to be p53-target genes, even though both genes are silenced in association with aberrant cytosine methylation of their promoters (PMID:12789271)
• Lss of DSC3 expression is a common event in primary breast tumor specimens, and DSC3 gene silencing in breast tumors is frequently linked to aberrant cytosine methylation and concomitant changes in chromatin structure. (PMID:16168112)
• Increased Dsc3 protein is associated with colorectal cancer (PMID:17088906)
• results suggest an abnormal expression of Dsc3, Dsg3, & beta-catenin induced in the progression of oral carcinomas & that Dsc3 expression level might be related to the regulation of beta-catenin in lymph node metastasis and cell proliferation in OSCCs. (PMID:17846785)
• Desmocollin-3 was expressed in almost half of the undifferentiated large-cell cancers (PMID:19287461)
• Both the binding of desmocollin 3 (Dsc3) to plakoglobin and Dsc3 phosphorylation are involved in Dsc3 binding to desmoglein 3 (Dsg3) during Ca2+ -induced desmosome assembly. (PMID:19348003)
• loss of heterophilic Dsc3/Dsg1 binding may contribute to pemphigus skin blistering (PMID:19717567)
• a human desmocollin-3 (DSC3) nonsense mutation underlies hereditary hypotrichosis and recurrent skin vesicles (PMID:19765682)
• Autoimmunity to DSC3 in Pemphigus vulgaris. (PMID:20952584)
• These findings demonstrate that IgG autoantibodies against an additional component of the desmosomes, Dsc3, induce loss of keratinocyte adhesion and thus may contribute to blister formation in pemphigus. (PMID:21281804)
• Methylation status of DSC3 DNA is a prognostic marker for colorectal cancer. P53 appears to have an important role in regulating DSC3 expression. (PMID:21364582)
• High expression of desmocollin 1 (DSC1) was observed in 41.6%, DSC2 in 58.0%, DSC3 in 61.4%, E-cadherin in 71.4%, CDX2 in 58.0%, PITX1 in 55.0%, CDK4 in 0.2%, TLE1 in 1.3%, Factor H in 42.5%, and MDM2 in 0.2% of colorectal carcinomas. (PMID:22438068)
• The p53 target gene desmocollin 3 acts as a novel tumor suppressor through inhibiting EGFR/ERK pathway in human lung cancer. (PMID:22941060)
• The data show an important role of physiologically occurring transcript d2-d4 in normal brain function. Interference with this role by DSC3 is a likely pathological mechanism in X-chromosomal dystonia parkinsonism syndrome (PMID:23184149)
• Low expression of DSC 1, 2, and 3 was observed in 55, 54, and 79 % of liver metastases. (PMID:23975055)
• data suggests that DNA methylation contributes to down-regulation of DSC3 in prostate cancer, and loss of DSC3 predicts poor clinical outcome. (PMID:24664224)
• Suggest that Dsc3 can mediate FSH-induced ovarian cancer cell proliferation by activating the EGFR/Akt signaling pathway. (PMID:26261554)
• Napsin-A, and Desmocollin-3 were sensitive and specific markers for the diagnosis of AC and SCC, respectively. Both markers allowed classification of 54/60 cases into either AC or SCC. (PMID:26710975)
• The Findings of this study imply early alteration of the substantia nigra in XDP mutation carriers prone to develop parkinsonism. (PMID:28094105)
• Data show that fetal pMSCs (mesenchymal stromal cells) expressing the highest levels of desmoglein 2, desmocollin 3 and plakophilin 2, followed by maternal pMSCs, while bmMSCs expressed the lowest levels. (PMID:28154962)
• DSC3 suppresses colorectal cancer cell growth through inhibition of AKT pathway and regulation of E-cadherin (PMID:30857973)
• Autoantibodies to DSC3 in Pemphigus Exclusively Recognize Calcium-Dependent Epitope in Extracellular Domain 2. (PMID:33766509)
• Two cases of Hallopeau-type pemphigus vegetans with anti-desmoglein 1 and anti-desmocollin 3 antibodies without mucosal involvement. (PMID:36305887)
• Upregulation of Anti-Desmocollin 3 Antibodies in Pemphigus Diseases: A Case-control Study. (PMID:38651843)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	dsc2l	ENSDARG00000039677
mus_musculus	Dsc3	ENSMUSG00000059898
rattus_norvegicus	Dsc3	ENSRNOG00000017159

Paralogs (6): DSG2 (ENSG00000046604), DSC2 (ENSG00000134755), DSG3 (ENSG00000134757), DSG1 (ENSG00000134760), DSC1 (ENSG00000134765), DSG4 (ENSG00000175065)

Protein

Protein identifiers

Desmocollin-3 — Q14574 (reviewed: Q14574)

Alternative names: Cadherin family member 3, Desmocollin-4, HT-CP

All UniProt accessions (2): Q14574, J3QRL9

UniProt curated annotations — full annotation on UniProt →

Function. A component of desmosome cell-cell junctions which are required for positive regulation of cellular adhesion. Required for cell-cell adhesion in the epidermis, as a result required for the maintenance of the dermal cohesion and the dermal barrier function. Required for cell-cell adhesion of epithelial cell layers surrounding the telogen hair club, as a result plays an important role in telogen hair shaft anchorage. Essential for successful completion of embryo compaction and embryo development.

Subunit / interactions. May form homodimers. Interacts with DSG1; there is evidence to suggest that the interaction promotes cell-cell adhesion of keratinocytes.

Subcellular location. Cell membrane. Cell junction. Desmosome. Cytoplasm.

Tissue specificity. Expressed throughout the basal and spinous layer of the epidermis with weak expression in the granular layer (at protein level). Also expressed in the buccal mucosa, esophagus and cervix (at protein level).

Disease relevance. Hypotrichosis and recurrent skin vesicles (HRSV) [MIM:613102] A disorder characterized by hypotrichosis and the appearance of recurrent skin vesicle formation. Affected individuals show sparse and fragile hair on scalp, as well as absent eyebrows and eyelashes. Vesicles filled with thin, watery fluid are observed on the scalp and skin of most of the body. Mucosal vesicles are absent. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Calcium may be bound by the cadherin-like repeats. Three calcium ions are usually bound at the interface of each cadherin domain and rigidify the connections, imparting a strong curvature to the full-length ectodomain.

Induction. Induced in the hours following cyclic mechanical strain in keratinocytes.

Miscellaneous. There is some evidence to suggest that pemphigus vulgaris antibodies may disrupt cell-cell adhesion via interfering with the interaction between DSC3 and DSG1.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14574-1	3A	yes
Q14574-2	3B

RefSeq proteins (2): NP_001932, NP_077741 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000233	Cadherin_Y-type_LIR	Domain
IPR002126	Cadherin-like_dom	Domain
IPR009122	Desmosomal_cadherin	Family
IPR014868	Cadherin_pro_dom	Domain
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site
IPR027397	Catenin-bd_sf	Homologous_superfamily
IPR050971	Cadherin-domain_protein	Family

Pfam: PF00028, PF01049, PF08758

UniProt features (23 total): sequence variant 6, domain 5, glycosylation site 4, splice variant 2, topological domain 2, signal peptide 1, propeptide 1, chain 1, transmembrane region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14574-F1	75.53	0.41

Functional residue map

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

Glycosylation sites (4): 166, 392, 546, 629

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6805567	Keratinization
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 540 (showing top): GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_DN, GOBP_NEGATIVE_REGULATION_OF_EPITHELIAL_CELL_PROLIFERATION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, REACTOME_INNATE_IMMUNE_SYSTEM, BENPORATH_ES_WITH_H3K27ME3, GOBP_EPIDERMIS_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, JAEGER_METASTASIS_DN, GOCC_SECRETORY_GRANULE, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, YANG_BREAST_CANCER_ESR1_LASER_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE

GO Biological Process (5): in utero embryonic development (GO:0001701), cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156), protein stabilization (GO:0050821), cell-cell adhesion (GO:0098609)

GO Molecular Function (3): calcium ion binding (GO:0005509), gamma-catenin binding (GO:0045295), metal ion binding (GO:0046872)

GO Cellular Component (9): cornified envelope (GO:0001533), extracellular region (GO:0005576), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), cell junction (GO:0030054), desmosome (GO:0030057), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Developmental Biology	1
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
chordate embryonic development	1
cellular process	1
cell-cell adhesion	1
regulation of protein stability	1
cell adhesion	1
metal ion binding	1
protein binding	1
cation binding	1
plasma membrane	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
anchoring junction	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

1256 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DSC3	PKP2	Q99959	950
DSC3	JUP	P14923	920
DSC3	DSG2	Q14126	914
DSC3	TMEM43	Q9BTV4	907
DSC3	DSP	P15924	881
DSC3	DSG1	Q02413	837
DSC3	PKP3	Q9Y446	786
DSC3	DSG3	P32926	741
DSC3	RYR2	Q92736	731
DSC3	SOCS6	O14544	723
DSC3	PKP1	Q13835	706
DSC3	LPAR6	P43657	685
DSC3	KLHL1	Q9NR64	667
DSC3	CDSN	Q15517	648
DSC3	TGFB3	P10600	615

IntAct

72 interactions, top by confidence:

A	B	Type	Score
FANCG	FANCA	psi-mi:“MI:0914”(association)	0.960
PRKAG2	PRKAB2	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
RYK	PCDH7	psi-mi:“MI:0914”(association)	0.530
TMEM30B	KLRG2	psi-mi:“MI:0914”(association)	0.530
FCGRT	GOLIM4	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
DSC3	DSG1	psi-mi:“MI:0407”(direct interaction)	0.440
DSG2	DSC3	psi-mi:“MI:0407”(direct interaction)	0.440
MET	NDUFA4	psi-mi:“MI:0914”(association)	0.420
MET	NDUFA4	psi-mi:“MI:2364”(proximity)	0.420
MAPK6		psi-mi:“MI:0914”(association)	0.350
K14	MAP2K7	psi-mi:“MI:0914”(association)	0.350
LAMP1	HAX1	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
incE	STX7	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
M		psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
	TMEM223	psi-mi:“MI:0914”(association)	0.350
YES1	HSPB1	psi-mi:“MI:0914”(association)	0.350
PRKAG1	TGM1	psi-mi:“MI:0914”(association)	0.350
FASTK	TGM1	psi-mi:“MI:0914”(association)	0.350
CDKL3		psi-mi:“MI:0914”(association)	0.350
TEX14	DNAJB6	psi-mi:“MI:0914”(association)	0.350
NCAPD3	NDUFS8	psi-mi:“MI:0914”(association)	0.350

BioGRID (146): DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Two-hybrid), DSC3 (Proximity Label-MS), DSC3 (Proximity Label-MS), DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Affinity Capture-MS), DSC3 (Proximity Label-MS), DSC3 (Proximity Label-MS), DSC3 (Affinity Capture-MS), DSC3 (Two-hybrid)

ESM2 similar proteins: A0A8M2BIB6, F1QSQ0, F8W3X3, H2EQR6, O35902, O54800, O55111, O93319, P32926, P33545, P55280, P55285, P55286, P55287, P55288, P55289, P55292, P55849, P55850, P70407, P70408, P79995, P97291, P97326, Q01107, Q02413, Q02487, Q08554, Q08DJ5, Q13634, Q14126, Q14574, Q28060, Q3SWX5, Q5DWV1, Q5RJH3, Q61495, Q68SP4, Q6W3B0, Q7TMD7

Diamond homologs: A0A8M2BIB6, B0KW95, B2KI42, B4USZ0, F1PAA9, H2EQR6, O18926, O35902, O55075, O55111, O88277, P08641, P09803, P10287, P10288, P12830, P15116, P19022, P19534, P19535, P20310, P22223, P24503, P30944, P32926, P33145, P33146, P33147, P33148, P33150, P33152, P33545, P39038, P55283, P55290, P55291, P55292, P55849, P55850, P79883

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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.

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	6	11.8×	2e-03
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	9	8.0×	4e-04
positive regulation of MAPK cascade	7	6.4×	6e-03
positive regulation of cell migration	8	5.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

2428 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	64
Likely pathogenic	43
Uncertain significance	1340
Likely benign	587
Benign	104

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065567	NM_001941.5(DSC3):c.2180T>G (p.Leu727Ter)	Pathogenic
1068704	NM_024422.6(DSC2):c.729del (p.Phe243fs)	Pathogenic
1074769	NM_024422.6(DSC2):c.110_114del (p.Leu37fs)	Pathogenic
1075964	NM_024422.6(DSC2):c.1571del (p.Thr524fs)	Pathogenic
1319918	NM_024422.6(DSC2):c.685del (p.Pro228_Leu229insTer)	Pathogenic
1322771	NM_024422.6(DSC2):c.1858C>T (p.Gln620Ter)	Pathogenic
1359544	NM_024422.6(DSC2):c.1720_1733del (p.Asn573_Ser574insTer)	Pathogenic
1381031	NM_024422.6(DSC2):c.2136dup (p.Thr713fs)	Pathogenic
1405349	NM_024422.6(DSC2):c.1053_1059del (p.His351fs)	Pathogenic
1429683	NM_024422.6(DSC2):c.1023dup (p.Ile342fs)	Pathogenic
1455627	NM_024422.6(DSC2):c.1840_1841dup (p.Ser614fs)	Pathogenic
151144	GRCh38/hg38 18q12.1(chr18:29365057-31236305)x1	Pathogenic
16848	NM_024422.6(DSC2):c.1430del (p.Thr477fs)	Pathogenic
1693178	NM_024422.6(DSC2):c.1577C>A (p.Ser526Ter)	Pathogenic
1693187	NM_024422.6(DSC2):c.501_502dup (p.Thr168fs)	Pathogenic
1694869	NM_024422.6(DSC2):c.1239del (p.Asn413fs)	Pathogenic
1741492	NM_024422.6(DSC2):c.456_458delinsCG (p.Pro153fs)	Pathogenic
1749235	NM_024422.6(DSC2):c.571_572dup (p.Asp191fs)	Pathogenic
1750194	NM_024422.6(DSC2):c.587_597del (p.Tyr196fs)	Pathogenic
1779905	NM_024422.6(DSC2):c.1777G>T (p.Glu593Ter)	Pathogenic
1967841	NM_024422.6(DSC2):c.929delinsTT (p.Gln310fs)	Pathogenic
2024891	NM_024422.6(DSC2):c.991C>T (p.Gln331Ter)	Pathogenic
2132520	NM_024422.6(DSC2):c.1260del (p.Lys421fs)	Pathogenic
235909	NM_024422.6(DSC2):c.1660C>T (p.Gln554Ter)	Pathogenic
2413319	NM_024422.6(DSC2):c.1187T>G (p.Leu396Ter)	Pathogenic
2426820	NC_000018.9:g.(?28681846)(28681934_?)del	Pathogenic
2426821	NC_000018.9:g.(?28673522)(28673606_?)del	Pathogenic
2705962	NM_024422.6(DSC2):c.1187dup (p.Leu396fs)	Pathogenic
2824457	NM_024422.6(DSC2):c.2203C>T (p.Gln735Ter)	Pathogenic
2835126	NM_024422.6(DSC2):c.2136del (p.Phe712fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

5871 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:31029572:C:A	W137C	0.998
18:31029572:C:G	W137C	0.998
18:31008410:A:T	V460D	0.997
18:31024413:A:C	N237K	0.997
18:31024413:A:T	N237K	0.997
18:31029574:A:G	W137R	0.997
18:31029574:A:T	W137R	0.997
18:31008416:A:T	V458D	0.996
18:31018123:A:G	F404S	0.996
18:31025782:C:G	R203P	0.996
18:31022466:T:G	D271A	0.995
18:31024411:T:G	D238A	0.995
18:31024421:C:G	D235H	0.995
18:31025812:C:A	G193V	0.995
18:31025833:A:G	F186S	0.995
18:31022394:A:G	F295S	0.994
18:31022434:A:C	Y282D	0.994
18:31022466:T:A	D271V	0.994
18:31029546:T:A	E146V	0.994
18:31018084:A:T	L417H	0.993
18:31018764:C:G	D327H	0.993
18:31022478:G:T	A267D	0.993
18:31024402:G:T	P241H	0.993
18:31024411:T:A	D238V	0.993
18:31024414:T:A	N237I	0.993
18:31024419:A:C	D235E	0.993
18:31024419:A:T	D235E	0.993
18:31025812:C:T	G193E	0.993
18:31025872:A:T	I173K	0.993
18:31018084:A:G	L417P	0.992

dbSNP variants (sampled 300 via entrez): RS1000097511 (18:31011023 T>A,C), RS1000192557 (18:31022563 G>A,C), RS1000283160 (18:31020233 A>G), RS1000337528 (18:30990982 A>G,T), RS1000359441 (18:30989876 G>A,C), RS1000373634 (18:31036498 A>C,G), RS1000373688 (18:31028108 A>G,T), RS1000389040 (18:31043064 C>A,G,T), RS1000433012 (18:30997275 T>G), RS1000491306 (18:31036186 G>C), RS1000532904 (18:31011310 A>C), RS1000559510 (18:31021672 A>T), RS1000573475 (18:31015813 G>A), RS1000624540 (18:31041934 C>G,T), RS1000628044 (18:31022866 T>A)

Disease associations

OMIM: gene MIM:600271 | disease phenotypes: MIM:610476, MIM:107970, MIM:613102, MIM:115200, MIM:192600, MIM:613426, MIM:609040, MIM:610193, MIM:612877, MIM:105210

GenCC curated gene-disease

Disease	Classification	Inheritance
arrhythmogenic right ventricular dysplasia 11	Definitive	Semidominant
hereditary hypotrichosis with recurrent skin vesicles	Strong	Autosomal recessive
colorectal adenoma	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial isolated arrhythmogenic right ventricular dysplasia	Definitive	AD

Mondo (20): arrhythmogenic right ventricular dysplasia 11 (MONDO:0012506), cardiomyopathy (MONDO:0004994), familial isolated arrhythmogenic right ventricular dysplasia (MONDO:0016342), hereditary hypotrichosis with recurrent skin vesicles (MONDO:0013136), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), dilated cardiomyopathy (MONDO:0005021), arrhythmogenic right ventricular dysplasia 1 (MONDO:0007152), cardiac rhythm disease (MONDO:0007263), long QT syndrome (MONDO:0002442), hypertrophic cardiomyopathy (MONDO:0005045), dilated cardiomyopathy 1A (MONDO:0007269), familial hypertrophic cardiomyopathy (MONDO:0024573), familial dilated cardiomyopathy (MONDO:0016333), dilated cardiomyopathy 1S (MONDO:0013262), arrhythmogenic right ventricular dysplasia 9 (MONDO:0012180)

Orphanet (15): Rare cardiomyopathy (Orphanet:167848), Inherited isolated arrhythmogenic cardiomyopathy (Orphanet:217656), Hereditary hypotrichosis with recurrent skin vesicles (Orphanet:217407), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Dilated cardiomyopathy (Orphanet:217604), Uhl anomaly (Orphanet:3403), Rare hypertrophic cardiomyopathy (Orphanet:217569), Familial dilated cardiomyopathy with conduction defect due to LMNA mutation (Orphanet:300751), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Familial dilated cardiomyopathy (Orphanet:217607), Familial isolated dilated cardiomyopathy (Orphanet:154), Left ventricular noncompaction (Orphanet:54260), ATTRV30M amyloidosis (Orphanet:85447), ATTRV122I amyloidosis (Orphanet:85451), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

16 total (18 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000164	Abnormality of the dentition
HP:0000653	Sparse eyelashes
HP:0001820	Leukonychia
HP:0002209	Sparse scalp hair
HP:0002215	Sparse axillary hair
HP:0002231	Sparse body hair
HP:0003115	Abnormal EKG
HP:0003593	Infantile onset
HP:0007502	Follicular hyperkeratosis
HP:0008066	Abnormal blistering of the skin
HP:0008070	Sparse hair
HP:0025092	Epidermal acanthosis
HP:0030318	Angular cheilitis
HP:0045075	Sparse eyebrow
HP:0200037	Skin vesicle
HP:0001644	Dilated cardiomyopathy
HP:0001639	Hypertrophic cardiomyopathy

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000189_49	Protein quantitative trait loci	3.000000e-06
GCST001762_663	Obesity-related traits	3.000000e-06
GCST001860_14	Multiple sclerosis	1.000000e-06
GCST002104_25	Bronchopulmonary dysplasia	7.000000e-06
GCST005936_6	Supraventricular ectopy	3.000000e-09
GCST006585_2482	Blood protein levels	1.000000e-07
GCST008114_22	Type 2 diabetes	1.000000e-06
GCST009391_1316	Metabolite levels	4.000000e-06
GCST009698_69	Metabolite levels	9.000000e-09
GCST010278_8	Hand grip strength (Mahalanobis distance)	3.000000e-06
GCST012118_3	Response to immune checkpoint inhibitors in melanoma (immune-related adverse events)	9.000000e-06

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0005190	urinary nitrogen measurement
EFO:0009277	supraventricular ectopy
EFO:0010519	pantothenic acid measurement
EFO:0006941	grip strength measurement
EFO:0011053	immune system toxicity
EFO:0600023	response to immune checkpoint inhibitor

MeSH disease descriptors (14)

Descriptor	Name	Tree numbers
D019571	Arrhythmogenic Right Ventricular Dysplasia	C14.240.400.145; C14.280.238.028; C14.280.400.145; C16.131.240.400.145
D009202	Cardiomyopathies	C14.280.238
D002311	Cardiomyopathy, Dilated	C14.280.195.160; C14.280.238.070; C16.320.488.750
D002312	Cardiomyopathy, Hypertrophic	C14.280.238.100; C14.280.484.048.750.070.160
D024741	Cardiomyopathy, Hypertrophic, Familial	C14.280.238.100.500; C14.280.484.048.750.070.160.500; C16.320.160
D006323	Heart Arrest	C14.280.383
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C565707	Arrhythmogenic Right Ventricular Dysplasia, Familial, 10 (supp.)
C566471	Arrhythmogenic Right Ventricular Dysplasia, Familial, 11 (supp.)
C563808	Arrhythmogenic Right Ventricular Dysplasia, Familial, 9 (supp.)
C567877	Cardiomyopathy, Dilated, 1BB (supp.)
C563538	Cardiomyopathy, Dilated, 1s (supp.)
C567751	Hypotrichosis And Recurrent Skin Vesicles (supp.)
C536231	familial dilated cardiomyopathy (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	6
Valproic Acid	affects cotreatment, increases expression	5
Tobacco Smoke Pollution	decreases expression	3
bisphenol A	decreases expression, increases methylation	2
sodium arsenite	decreases expression, increases expression	2
mercuric bromide	increases expression, affects cotreatment	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
methylmercuric chloride	increases expression	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, affects localization	1
terbufos	increases methylation	1
trichostatin A	increases expression	1
butyraldehyde	decreases expression	1
benzo(e)pyrene	increases methylation	1
potassium chromate(VI)	increases expression	1
N-acetyl-4-benzoquinoneimine	affects response to substance	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
dibenzo(a,l)pyrene	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
jinfukang	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Decitabine	affects expression	1
Aerosols	decreases expression	1
Arsenic	affects methylation	1
Calcitriol	increases expression	1
Camptothecin	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01767870	PHASE4	UNKNOWN	Efficacy Combined Fecal Immunochemical Test-Sigmoidoscopy for the Detection of Advanced Colorectal Neoplasia
NCT07167342	PHASE4	RECRUITING	The Effect of Oral Clostridium Butyricum on the Recurrence After Colonoscopic Resection of Colorectal Adenoma
NCT00348530	PHASE4	UNKNOWN	Carvedilol Versus Verapamil in Chronic Heart Failure Secondary to Non-Ischemic Cardiomyopathy
NCT00371891	PHASE4	COMPLETED	Ontario Multidetector Computed Tomographic (MDCT) Coronary Angiography Study (OMCAS)
NCT00401856	PHASE4	COMPLETED	CMR to Assess Fibrosis in Cardiomyopathy Using Eplerenone
NCT00559338	PHASE4	COMPLETED	Impact of Nesiritide Infusion for Decompensated Heart Failure in the Emergency Department
NCT00606775	PHASE4	UNKNOWN	The Preventive Efficacy of Carvedilol on Cardiac Dysfunction in Duchenne Muscular Dystrophy
NCT00658203	PHASE4	COMPLETED	Clinical Evaluation on Advanced Resynchronization
NCT00701220	PHASE4	COMPLETED	Statin Therapy for Ischemic and Nonischemic Cardiomyopathy
NCT00800761	PHASE4	COMPLETED	Intensive Combined Chelation Therapy for Iron-Induced Cardiac Disease in Patients With Thalassemia Major
NCT00806390	PHASE4	TERMINATED	Prevention of Anthracycline or Trastuzumab Induced Cardiomyopathy by Metoprolol
NCT01006473	PHASE4	COMPLETED	Exercise Training in Chagas Cardiomyopathy
NCT01261065	PHASE4	COMPLETED	Mechanisms of Improvement With Beta-Blocker Treatment in Heart Failure
NCT01345188	PHASE4	COMPLETED	Ranolazine in Ischemic Cardiomyopathy
NCT01868841	PHASE4	COMPLETED	123-I mIBG (AdreView) Heart-to-Mediastinal (H/M) Ratio and SPECT Imaging on a Small Field of View-High Efficiency Cardiac SPECT System
NCT02640846	PHASE4	UNKNOWN	Effects of Levosimendan, Milrinone and Norepinephrine on Left and Right Ventricular Function in Septic Shock
NCT03228823	PHASE4	UNKNOWN	Prospective Assessment of Premature Ventricular Contractions Suppression in Cardiomyopathy(PAPS)
NCT04323852	PHASE4	COMPLETED	Can Vitamin D Reduce Heart Muscle Damage After Bypass Surgery?
NCT05034432	PHASE4	RECRUITING	The PIVATAL Study -Study of Ventricular Arrhythmia (VTA) Ablation in Left Ventricular Assist Device (LVAD) Patients
NCT05718128	PHASE4	RECRUITING	Clinical Study of Endocardial Myocardial Biopsy
NCT06964464	PHASE4	RECRUITING	Comparative Effectiveness of Carvedilol Versus Metoprolol Succinate in Heart Failure Patients With an Implantable Cardioverter Defibrillator
NCT00141193	PHASE3	COMPLETED	Prevention of Colorectal Sporadic Adenomatous Polyps (PRESAP)
NCT00282386	PHASE3	COMPLETED	A Study to Evaluate the Effect of MK0966 (Rofecoxib) on the Recurrence of Colorectal Adenomas (0966-122)
NCT01437826	PHASE3	TERMINATED	Antioxidant Supplement and Reduction of Metachronous Adenomas of the Large Bowel: a Double Blind Randomized Trial
NCT07505056	PHASE3	NOT_YET_RECRUITING	Jianpi Lishi Jiedu Granules for Prevention of Postoperative Recurrence in Colorectal Advanced Adenomas
NCT00170183	PHASE3	COMPLETED	Brain Natriuretic Peptide (BNP) to Preserve Renal Function in Hospitalized Patients With Heart Failure
NCT00270387	PHASE3	COMPLETED	A Study of Short-Term Outcomes and Economic Impact For Patients With Worsening Congestive Heart Failure When Natrecor (Nesiritide) is Added to Standard-Care Therapy, Compared to Administration of Placebo With Standard-Care Therapy
NCT00321295	PHASE3	COMPLETED	Biventricular Pacing In Patients With Left Ventricular Dysfunction After Cardiovascular Surgery
NCT00483197	PHASE3	UNKNOWN	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Pivotal Trial
NCT00490321	PHASE3	UNKNOWN	VentrAssistTM LVAD for the Treatment of Advanced Heart Failure - Destination Therapy
NCT00626028	PHASE3	COMPLETED	Comparison of Inhaled Nitric Oxide and Oxygen in Participants Reactivity During Acute Pulmonary Vasodilator Testing
NCT01013714	PHASE3	UNKNOWN	Cardiac Sympathetic Denervation for Prevention of Ventricular Tachyarrhythmias
NCT01217827	PHASE3	COMPLETED	Implantable Cardioverter-Defibrillator Use in the VA System
NCT01648634	PHASE3	COMPLETED	Nebivolol for the Prevention of Left Ventricular Systolic Dysfunction in Patients With Duchenne Muscular Dystrophy
NCT02924285	PHASE3	COMPLETED	Catheter Ablation Versus Amiodarone for Therapy of Premature Ventricular Contractions in Patients With Structural Heart Disease
NCT03860935	PHASE3	COMPLETED	Efficacy and Safety of AG10 in Subjects With Transthyretin Amyloid Cardiomyopathy
NCT04166331	PHASE3	COMPLETED	Adjunctive DobutAmine in sePtic Cardiomyopathy With Tissue Hypoperfusion
NCT05175066	PHASE3	COMPLETED	Bisoprolol Administration to Prevent Anthracycline-induced Cardiotoxicity
NCT05237323	PHASE3	COMPLETED	Micophenolate Mofetil Versus Azathioprine in Myocarditis
NCT06158698	PHASE3	RECRUITING	CMP-MYTHiC Trial and Registry - CardioMyoPathy With MYocarditis THerapy With Colchicine