TMEM43

Summary

TMEM43 (transmembrane protein 43, HGNC:28472) is a protein-coding gene on chromosome 3p25.1, encoding Transmembrane protein 43 (Q9BTV4). May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane.

This gene belongs to the TMEM43 family. Defects in this gene are the cause of familial arrhythmogenic right ventricular dysplasia type 5 (ARVD5), also known as arrhythmogenic right ventricular cardiomyopathy type 5 (ARVC5). Arrhythmogenic right ventricular dysplasia is an inherited disorder, often involving both ventricles, and is characterized by ventricular tachycardia, heart failure, sudden cardiac death, and fibrofatty replacement of cardiomyocytes. This gene contains a response element for PPAR gamma (an adipogenic transcription factor), which may explain the fibrofatty replacement of the myocardium, a characteristic pathological finding in ARVC.

Source: NCBI Gene 79188 — RefSeq curated summary.

At a glance

• Gene–disease (curated): arrhythmogenic right ventricular dysplasia 5 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 1,174 total — 1 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_024334

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28472
Approved symbol	TMEM43
Name	transmembrane protein 43
Location	3p25.1
Locus type	gene with protein product
Status	Approved
Aliases	MGC3222, DKFZp586G1919, LUMA
Ensembl gene	ENSG00000170876
Ensembl biotype	protein_coding
OMIM	612048
Entrez	79188

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000306077, ENST00000432444, ENST00000713947, ENST00000855535, ENST00000855536, ENST00000926410, ENST00000926411, ENST00000949126, ENST00000949127, ENST00000949128

RefSeq mRNA: 8 — MANE Select: NM_024334 NM_001407274, NM_001407275, NM_001407276, NM_001407277, NM_001407278, NM_001407279, NM_001407280, NM_024334

CCDS: CCDS2618

Canonical transcript exons

ENST00000306077 — 12 exons

Exon	Start	End
ENSE00001160486	14135807	14135908
ENSE00001160494	14135158	14135232
ENSE00001160503	14134770	14134891
ENSE00001160509	14133739	14133809
ENSE00001160517	14132866	14132935
ENSE00001603190	14141593	14143680
ENSE00001806353	14125052	14125205
ENSE00003533556	14129412	14129561
ENSE00003537434	14131580	14131674
ENSE00003548358	14139180	14139297
ENSE00003611738	14132546	14132595
ENSE00003628207	14130822	14130956

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 98.06.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.3895 / max 365.9881, expressed in 1821 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35436	12.4242	1704
35433	11.5343	1796
35434	10.7877	1790
35435	10.6433	1777

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
descending thoracic aorta	UBERON:0002345	98.06	gold quality
thoracic aorta	UBERON:0001515	97.82	gold quality
ascending aorta	UBERON:0001496	97.78	gold quality
right coronary artery	UBERON:0001625	97.69	gold quality
aorta	UBERON:0000947	97.63	gold quality
popliteal artery	UBERON:0002250	97.52	gold quality
tibial artery	UBERON:0007610	97.52	gold quality
skin of abdomen	UBERON:0001416	97.33	gold quality
skin of hip	UBERON:0001554	97.24	gold quality
skin of leg	UBERON:0001511	97.21	gold quality
tendon of biceps brachii	UBERON:0008188	97.20	gold quality
left coronary artery	UBERON:0001626	97.09	gold quality
body of uterus	UBERON:0009853	97.02	gold quality
coronary artery	UBERON:0001621	97.00	gold quality
zone of skin	UBERON:0000014	96.84	gold quality
mucosa of stomach	UBERON:0001199	96.82	gold quality
left uterine tube	UBERON:0001303	96.74	gold quality
endocervix	UBERON:0000458	96.64	gold quality
calcaneal tendon	UBERON:0003701	96.58	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.54	gold quality
lower esophagus	UBERON:0013473	96.53	gold quality
saphenous vein	UBERON:0007318	96.44	gold quality
ectocervix	UBERON:0012249	96.41	gold quality
right ovary	UBERON:0002118	96.40	gold quality
left ovary	UBERON:0002119	96.35	gold quality
smooth muscle tissue	UBERON:0001135	96.27	gold quality
tendon	UBERON:0000043	96.26	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.25	gold quality
nipple	UBERON:0002030	96.21	gold quality
right lung	UBERON:0002167	96.21	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-6678	no	3.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

106 targeting TMEM43, 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-4455	100.00	65.48	1587
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-636	99.80	69.58	1500

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 21)

• LUMA (TMEM43) is a highly conserved protein located to inner nuclear membrane (INM) and interacting with A- and B-type lamins. It is particularly important for anchoring of emerin at the INM and may thus contribute to the pathogenesis of laminopathies. (PMID:18230648)
• In families with arrhythmogenic right ventricular cardiomyopathy, there was found a missense mutation in a highly conserved transmembrane domain of TMEM43 and was predicted to be deleterious. (PMID:18313022)
• Studies indicate that in 2007, the Newfoundland local research team discovered the causative mutation in a novel gene TMEM43 within the disease-associated founder haplotype. (PMID:20010364)
• The TMEM43 gene underlies a distinctive form of arrhythmogenic right ventricular cardiomyopathy (ARVC) which may share a final common pathway with desmosome-associated ARVC. (PMID:21214875)
• The results of study suggested that mutant LUMAs may be associated with EDMD-related myopathy. (PMID:21391237)
• Ser358Leu mutant TMEM43 exhibits normal cellular localization and does not disrupt integrity and localization of other nuclear envelope and desmosomal proteins. (PMID:22458570)
• ARVC due to p.S358L in TMEM43 is a variant form of ARVC with extreme variability of expression. It is sex influenced: males are more frequently hospitalized and have heart failure and SCD at a younger age than females. (PMID:22725725)
• full gene sequencing of TMEM43 in 143 ARVC probands (families) from the UK revealed three potential pathogenic variants (p.R312W, p.R28W, p.E142K). The p.R312W missense variant is a recurrent mutation due to a founder effect and is likely pathogenic. (PMID:23161701)
• TMEM43 mutations occur outside of the founder population of the island of Newfoundland where it was originally described. (PMID:23812740)
• Results suggest a link between missense mutation in this protein and the risk of familial ARVC (PMID:24598986)
• These observations suggest that expression of the p.S358L mutant of TMEM43 found in ARVC type 5 may affect localization of proteins involved in conduction, alter gap junction function and reduce conduction velocity in cardiac tissue. (PMID:25343256)
• Implantable cardioverter defibrillator therapy is indicated for primary prevention in postpubertal males and in females >/= 30 years with the p.S358L TMEM43 mutation. (PMID:26966288)
• A very rare mutation in TMEM 43 for the development of Arrhythmogenic cardiomyopathy has a definite connection with desmosomal proteins (plakoglobin) and justifies in a highly arrhythmogenic form of the disease. (PMID:27389450)
• TMEM43 deficiency significantly affects colony formation, survival of anoikis-induced cell death, migration and invasion of cancer cells in vitro, as well as tumor progression in vivo. (PMID:27991920)
• Arrhythmogenic right ventricular cardiomyopathy patients with TMEM43 gene mutations were more likely to have biventricular arrhythmogenic substrate and more inducible ventricular tachycardias. (PMID:28960618)
• Five TMEM43 mutations have been described resulting in clinical phenotype that presents significantly earlier in males, shows biventricular involvement and is characterised by a high incidence of premature Sudden Cardiac Death and severe Heart Failure in survivors. (PMID:30792239)
• Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5. (PMID:32062046)
• Exercise and arrhythmic risk in TMEM43 p.S358L arrhythmogenic right ventricular cardiomyopathy. (PMID:32120009)
• A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder. (PMID:34050020)
• Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy. (PMID:34674311)
• Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish. (PMID:36076925)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000115428
mus_musculus	Tmem43	ENSMUSG00000030095
rattus_norvegicus	Tmem43	ENSRNOG00000007519
drosophila_melanogaster	Tmem43	FBGN0035825

Protein

Protein identifiers

Transmembrane protein 43 — Q9BTV4 (reviewed: Q9BTV4)

Alternative names: Protein LUMA

All UniProt accessions (3): Q9BTV4, A0A024R2F9, F8WDL3

UniProt curated annotations — full annotation on UniProt →

Function. May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. Required for retaining emerin at the inner nuclear membrane. Plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26. In addition, functions as a critical signaling component in mediating NF-kappa-B activation by acting downstream of EGFR and upstream of CARD10. Contributes to passive conductance current in cochlear glia-like supporting cells, mediated by gap junctions and necessary for hearing and speech discrimination.

Subunit / interactions. Can form oligomers through the transmembrane domains. Interacts with EMD; the interaction retains EMD at the inner nuclear membrane. Interacts with LMNA and LMNB2. Interacts with SUN2. Interacts with RNF26; this interaction is important to modulate innate immune signaling through the cGAS-STING pathway. Interacts with CARD10. Interacts with gap junctions proteins GJB2/Cx26 and GJB4/Cx30.

Subcellular location. Endoplasmic reticulum membrane. Nucleus inner membrane. Cell membrane.

Tissue specificity. Highest expression in placenta. Also found at lower levels in heart, ovary, spleen, small intestine, thymus, prostate and testis.

Disease relevance. Arrhythmogenic right ventricular dysplasia, familial, 5 (ARVD5) [MIM:604400] A congenital heart disease characterized by infiltration of adipose and fibrous tissue into the right ventricle and loss of myocardial cells, resulting in ventricular and supraventricular arrhythmias. The disease is caused by variants affecting the gene represented in this entry. Emery-Dreifuss muscular dystrophy 7, autosomal dominant (EDMD7) [MIM:614302] A form of Emery-Dreifuss muscular dystrophy, a degenerative myopathy characterized by weakness and atrophy of muscle without involvement of the nervous system, early contractures of the elbows, Achilles tendons and spine, and cardiomyopathy associated with cardiac conduction defects. The disease is caused by variants affecting the gene represented in this entry. Auditory neuropathy, autosomal dominant 3 (AUNA3) [MIM:619832] A form of sensorineural hearing loss with absent or severely abnormal auditory brainstem response, in the presence of normal cochlear outer hair cell function and normal otoacoustic emissions. Auditory neuropathies result from a lesion in the area including the inner hair cells, connections between the inner hair cells and the cochlear branch of the auditory nerve, the auditory nerve itself and auditory pathways of the brainstem. Affected individuals typically respond to sound but have difficulties in speech discrimination. AUNA3 is a late-onset, progressive form. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the TMEM43 family.

RefSeq proteins (8): NP_001394203, NP_001394204, NP_001394205, NP_001394206, NP_001394207, NP_001394208, NP_001394209, NP_077310* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR012430	TMEM43_fam	Family

Pfam: PF07787

UniProt features (22 total): sequence variant 8, topological domain 5, transmembrane region 4, sequence conflict 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BTV4-F1	89.92	0.71

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 (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 301 (showing top): GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MEMORY, GOBP_COGNITION, GOBP_BEHAVIOR, GOBP_SODIUM_ION_TRANSMEMBRANE_TRANSPORT, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, TGACCTY_ERR1_Q2, GOBP_MONOATOMIC_CATION_TRANSPORT, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_NUCLEUS_ORGANIZATION, GOBP_CELL_COMMUNICATION_BY_ELECTRICAL_COUPLING, LANDIS_ERBB2_BREAST_PRENEOPLASTIC_DN, LANDIS_ERBB2_BREAST_TUMORS_65_DN, TGANTCA_AP1_C, PPAR_DR1_Q2

GO Biological Process (9): lipid metabolic process (GO:0006629), potassium ion transport (GO:0006813), sodium ion transport (GO:0006814), memory (GO:0007613), positive regulation of cell communication by electrical coupling (GO:0010650), metal ion transport (GO:0030001), innate immune response (GO:0045087), nuclear membrane organization (GO:0071763), immune system process (GO:0002376)

GO Molecular Function (5): voltage-gated sodium channel activity (GO:0005248), voltage-gated potassium channel activity (GO:0005249), voltage-gated monoatomic cation channel activity (GO:0022843), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): nuclear inner membrane (GO:0005637), endoplasmic reticulum lumen (GO:0005788), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), nucleus (GO:0005634), nuclear envelope (GO:0005635), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
endomembrane system	3
intracellular membrane-bounded organelle	3
metal ion transport	2
cytoplasm	2
cellular anatomical structure	2
primary metabolic process	1
learning or memory	1
cell communication by electrical coupling	1
positive regulation of cell communication	1
regulation of cell communication by electrical coupling	1
monoatomic cation transport	1
immune response	1
defense response to symbiont	1
nuclear envelope organization	1
membrane organization	1
biological_process	1
sodium channel activity	1
potassium channel activity	1
voltage-gated monoatomic cation channel activity	1
voltage-gated monoatomic ion channel activity	1
monoatomic cation channel activity	1
protein binding	1
binding	1
organelle inner membrane	1
nuclear membrane	1
endoplasmic reticulum	1
intracellular organelle lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
membrane	1
cell periphery	1
nucleus	1
organelle envelope	1
vacuole	1
plasma membrane	1

Protein interactions and networks

STRING

1118 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TMEM43	PKP2	Q99959	934
TMEM43	DSC2	Q02487	933
TMEM43	DSG2	Q14126	924
TMEM43	JUP	P14923	913
TMEM43	DSC3	Q14574	907
TMEM43	TGFB3	P10600	855
TMEM43	EMD	P50402	851
TMEM43	RYR2	Q92736	843
TMEM43	SUN2	Q9UH99	828
TMEM43	LMNA	P02545	801
TMEM43	FLNC	Q14315	718
TMEM43	ENDOD1	O94919	706
TMEM43	DSP	P15924	698
TMEM43	CTNNA3	Q9UI47	659
TMEM43	TMEM33	P57088	645

IntAct

217 interactions, top by confidence:

A	B	Type	Score
RAB11A	EVI5	psi-mi:“MI:0914”(association)	0.800
CUL4B	COPS2	psi-mi:“MI:0914”(association)	0.790
EXOC8	EXOC5	psi-mi:“MI:0914”(association)	0.730
TMEM43	GRAMD2B	psi-mi:“MI:0915”(physical association)	0.720
GRAMD2B	TMEM43	psi-mi:“MI:0915”(physical association)	0.720
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
COG7	ILVBL	psi-mi:“MI:0914”(association)	0.640
BZW2	ENDOD1	psi-mi:“MI:0914”(association)	0.640
BZW2	MUL1	psi-mi:“MI:0914”(association)	0.640
TMEM43	SIAH1	psi-mi:“MI:0915”(physical association)	0.560
FKBP8	TMEM43	psi-mi:“MI:0915”(physical association)	0.560
TMEM43	SYNDIG1	psi-mi:“MI:0915”(physical association)	0.560
TMEM43	USP25	psi-mi:“MI:0915”(physical association)	0.560
FAM209A	TMEM43	psi-mi:“MI:0915”(physical association)	0.560
SCGB1A1	TMEM43	psi-mi:“MI:0915”(physical association)	0.560
ARL13B	TMEM43	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (529): TMEM43 (Two-hybrid), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), CUL4B (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Affinity Capture-MS), TMEM43 (Proximity Label-MS)

ESM2 similar proteins: A2YMP7, A4FUZ5, A6QP01, A8WG88, F4I8Q7, O14657, P58499, P62341, P62342, Q08DK0, Q0IJ33, Q1H5H1, Q28EH9, Q502K9, Q53P98, Q5R9S8, Q5TYV0, Q5XF36, Q5XF80, Q5XIP9, Q5ZI25, Q5ZJN8, Q68G38, Q6GP98, Q6IR55, Q6PBD1, Q6PD82, Q6PHY8, Q6WRS2, Q6X4M2, Q7F613, Q7JW12, Q7ZV50, Q802F2, Q803X0, Q8K304, Q8VBZ3, Q8WQG1, Q94I55, Q9BN19

Diamond homologs: Q5R9S8, Q5XIP9, Q9BTV4, Q9DBS1, Q9VSB9

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 189 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
PD-L1(CD274) glycosylation and translocation to plasma membrane	5	22.8×	2e-04
Regulation of CDH1 posttranslational processing and trafficking to plasma membrane	6	17.7×	2e-04
Maturation of DENV proteins	8	14.8×	1e-05
Transport of vitamins, nucleosides, and related molecules	6	14.3×	3e-04
Maturation of spike protein	6	14.0×	3e-04
Defective CFTR causes cystic fibrosis	6	11.6×	8e-04
SLC transporter disorders	6	10.7×	1e-03
Disorders of transmembrane transporters	7	8.6×	1e-03

GO biological processes:

GO term	Partners	Fold	FDR
obsolete protein N-linked glycosylation via asparagine	5	20.6×	1e-03
ERAD pathway	9	9.9×	3e-04
protein N-linked glycosylation	6	9.6×	8e-03
transmembrane transport	7	7.2×	8e-03
positive regulation of canonical NF-kappaB signal transduction	10	4.4×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

1174 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	2
Uncertain significance	604
Likely benign	370
Benign	44

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
734	NM_024334.3(TMEM43):c.1073C>T (p.Ser358Leu)	Pathogenic
1701917	NM_024334.3(TMEM43):c.393-2A>G	Likely pathogenic
3027429	NM_024334.3(TMEM43):c.201dup (p.Leu68fs)	Likely pathogenic

SpliceAI

1868 predictions. Top by Δscore:

Variant	Effect	Δscore
3:14125202:GAAT:G	donor_gain	1.0000
3:14125204:AT:A	donor_gain	1.0000
3:14125204:ATGT:A	donor_loss	1.0000
3:14125205:TGTG:T	donor_loss	1.0000
3:14125206:G:GG	donor_gain	1.0000
3:14129410:A:AG	acceptor_gain	1.0000
3:14129411:G:GG	acceptor_gain	1.0000
3:14129411:GT:G	acceptor_gain	1.0000
3:14130817:CCCAG:C	acceptor_loss	1.0000
3:14130818:CCAG:C	acceptor_loss	1.0000
3:14130819:CAG:C	acceptor_loss	1.0000
3:14130820:AGGGC:A	acceptor_loss	1.0000
3:14130821:G:A	acceptor_loss	1.0000
3:14130955:AGG:A	donor_loss	1.0000
3:14130957:G:C	donor_loss	1.0000
3:14130957:G:GG	donor_gain	1.0000
3:14131556:T:A	acceptor_gain	1.0000
3:14131565:T:TA	acceptor_gain	1.0000
3:14131571:T:TA	acceptor_gain	1.0000
3:14131575:T:TA	acceptor_gain	1.0000
3:14132543:CAGG:C	acceptor_loss	1.0000
3:14132544:A:AG	acceptor_gain	1.0000
3:14132544:A:AT	acceptor_loss	1.0000
3:14132544:AG:A	acceptor_gain	1.0000
3:14132544:AGG:A	acceptor_gain	1.0000
3:14132545:G:GT	acceptor_gain	1.0000
3:14132545:GG:G	acceptor_gain	1.0000
3:14132545:GGG:G	acceptor_gain	1.0000
3:14132545:GGGA:G	acceptor_gain	1.0000
3:14132596:G:GG	donor_gain	1.0000

AlphaMissense

2601 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:14132874:T:A	W151R	1.000
3:14132874:T:C	W151R	1.000
3:14132876:G:C	W151C	1.000
3:14132876:G:T	W151C	1.000
3:14131626:T:C	L115P	0.999
3:14131652:T:A	W124R	0.999
3:14131652:T:C	W124R	0.999
3:14131654:G:C	W124C	0.999
3:14131654:G:T	W124C	0.999
3:14132904:T:C	F161L	0.999
3:14132905:T:G	F161C	0.999
3:14132906:C:A	F161L	0.999
3:14132906:C:G	F161L	0.999
3:14132930:C:A	N169K	0.999
3:14132930:C:G	N169K	0.999
3:14135171:G:C	R240P	0.999
3:14131632:G:T	R117M	0.998
3:14131633:G:C	R117S	0.998
3:14131633:G:T	R117S	0.998
3:14131646:T:G	Y122D	0.998
3:14131650:A:C	Q123P	0.998
3:14131651:A:C	Q123H	0.998
3:14131651:A:T	Q123H	0.998
3:14132875:G:C	W151S	0.998
3:14132905:T:C	F161S	0.998
3:14133780:T:A	V185D	0.998
3:14135174:T:A	V241D	0.998
3:14135180:T:C	F243S	0.998
3:14132922:C:G	H167D	0.997
3:14132928:A:G	N169D	0.997

dbSNP variants (sampled 300 via entrez): RS1000047694 (3:14131472 C>A,G), RS1000359755 (3:14140855 C>A), RS1000484109 (3:14126459 T>A), RS1000701784 (3:14131814 C>A,T), RS1000732027 (3:14127454 T>G), RS1000801639 (3:14137076 C>T), RS1000841306 (3:14137879 A>T), RS1000842802 (3:14142328 C>T), RS1000934196 (3:14138119 A>C), RS1001051157 (3:14132161 C>T), RS1001100012 (3:14126171 T>G), RS1001117751 (3:14124113 T>A), RS1001315430 (3:14142475 C>T), RS1001419903 (3:14135138 T>C), RS1001480864 (3:14128036 C>G,T)

Disease associations

OMIM: gene MIM:612048 | disease phenotypes: MIM:604400, MIM:614302, MIM:619832, MIM:192600, MIM:107970, MIM:159001, MIM:181350

GenCC curated gene-disease

Disease	Classification	Inheritance
arrhythmogenic right ventricular dysplasia 5	Definitive	Autosomal dominant
autosomal dominant Emery-Dreifuss muscular dystrophy	Supportive	Autosomal dominant
auditory neuropathy, autosomal dominant 3	Limited	Autosomal dominant
Emery-Dreifuss muscular dystrophy 7, autosomal dominant	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
arrhythmogenic right ventricular dysplasia 5	Definitive	AD

Mondo (13): arrhythmogenic right ventricular dysplasia 5 (MONDO:0011459), cardiomyopathy (MONDO:0004994), Emery-Dreifuss muscular dystrophy 7, autosomal dominant (MONDO:0013677), auditory neuropathy, autosomal dominant 3 (MONDO:0859235), arrhythmogenic right ventricular cardiomyopathy (MONDO:0016587), sudden cardiac arrest (MONDO:0100511), long QT syndrome (MONDO:0002442), familial hypertrophic cardiomyopathy (MONDO:0024573), dilated cardiomyopathy (MONDO:0005021), hypertrophic cardiomyopathy (MONDO:0005045), familial isolated arrhythmogenic right ventricular dysplasia (MONDO:0016342), Emery-Dreifuss muscular dystrophy 2, autosomal dominant (MONDO:0021569), autosomal dominant Emery-Dreifuss muscular dystrophy (MONDO:0020336)

Orphanet (9): Rare cardiomyopathy (Orphanet:167848), Emery-Dreifuss muscular dystrophy (Orphanet:261), Inherited arrhythmogenic cardiomyopathy (Orphanet:247), Rare familial disorder with hypertrophic cardiomyopathy (Orphanet:99739), Dilated cardiomyopathy (Orphanet:217604), Rare hypertrophic cardiomyopathy (Orphanet:217569), Inherited isolated arrhythmogenic cardiomyopathy (Orphanet:217656), Autosomal dominant limb-girdle muscular dystrophy type 1B (Orphanet:264), NON RARE IN EUROPE: Familial isolated hypertrophic cardiomyopathy (Orphanet:155)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000365	Hearing impairment
HP:0000467	Neck muscle weakness
HP:0000508	Ptosis
HP:0000767	Pectus excavatum
HP:0000912	Sprengel anomaly
HP:0001249	Intellectual disability
HP:0001252	Hypotonia
HP:0001288	Gait disturbance
HP:0001315	Reduced tendon reflexes
HP:0001387	Joint stiffness
HP:0001513	Obesity
HP:0001605	Vocal cord paralysis
HP:0001635	Congestive heart failure
HP:0001639	Hypertrophic cardiomyopathy
HP:0001644	Dilated cardiomyopathy
HP:0001645	Sudden cardiac death
HP:0001662	Bradycardia
HP:0001678	Atrioventricular block
HP:0001771	Achilles tendon contracture
HP:0001962	Palpitations
HP:0001963	Abnormal speech discrimination
HP:0002155	Hypertriglyceridemia
HP:0002486	Myotonia
HP:0002515	Waddling gait
HP:0002650	Scoliosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002808	Kyphosis
HP:0002987	Elbow flexion contracture
HP:0003141	Increased LDL cholesterol concentration

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_51	Heel bone mineral density	4.000000e-09
GCST012210_7	Longevity	4.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density

MeSH disease descriptors (8)

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
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547
C565776	Arrhythmogenic Right Ventricular Dysplasia, Familial, 5 (supp.)
C535898	Limb-girdle muscular dystrophy, type 1B (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067344 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

3 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs2228001	Toxicity	3	cisplatin	Neutropenia;Urinary Bladder Neoplasms
rs2228001	Toxicity	3	cisplatin	Drug Toxicity;Urinary Bladder Neoplasms
rs2228001	Toxicity	3	doxorubicin	Infectious disease;Osteosarcoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2228001	TMEM43, XPC	3	2.75	4	cisplatin;doxorubicin

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.21	Kd	6.152	nM	CHEMBL3752910
8.21	ED50	6.152	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149615: Binding affinity to human TMEM43 incubated for 45 mins by Kinobead based pull down assay	kd	0.0062	uM

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol F	increases expression	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
bisphenol AF	increases expression	1
Benzo(a)pyrene	decreases methylation	1
Cisplatin	affects cotreatment, decreases expression	1
Copper	affects binding, increases expression	1
Demecolcine	increases expression	1
Disulfiram	affects binding, increases expression	1
Diuron	decreases expression	1
Estradiol	affects expression	1
Hydrogen Peroxide	affects expression	1
Piroxicam	affects cotreatment, decreases expression	1
Smoke	decreases expression	1
Thiram	decreases expression	1
Vincristine	increases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Lactic Acid	decreases expression	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
CHEMBL5652657	Binding	Binding affinity to human TMEM43 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

6 cell lines: 5 induced pluripotent stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B7CI	UMi040-A	Induced pluripotent stem cell	Male
CVCL_D0QG	HDZi003-A	Induced pluripotent stem cell	Male
CVCL_D2XT	YCMi010-A	Induced pluripotent stem cell	Male
CVCL_D6IR	HDZi003-A-1	Induced pluripotent stem cell	Male
CVCL_E0RG	Ubigene HeLa TMEM43 KO	Cancer cell line	Female
CVCL_ZW15	HDZi001-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
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
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
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06846086	PHASE3	RECRUITING	Cardioprotective Effects of Melatonin in Patients With Cardiomyopathy
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00185250	PHASE2	COMPLETED	Betaferon/ Betaseron (Interferon Beta-1b) in Patients With Chronic Viral Cardiomyopathy
NCT00490347	PHASE2	COMPLETED	VentrAssistTM LVAD as a Bridge to Cardiac Transplantation - Feasibility Trial
NCT00694161	PHASE2	COMPLETED	The Effects Of Fx-1006A On Transthyretin Stabilization And Clinical Outcome Measures In Patients With V122I Or Wild-Type TTR Amyloid Cardiomyopathy