TMEM43

Chr 3AD

transmembrane protein 43

Also known as: ARVC5, ARVD5, AUNA3, EDMD7, EDMD7; AUNA2, LUMA

NCBI Gene: 79188ENSG00000170876UniProt: Q9BTV4

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. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

Arrhythmogenic right ventricular dysplasia 5MIM #604400
AD
Auditory neuropathy, autosomal dominant 3MIM #619832
AD
Emery-Dreifuss muscular dystrophy 7, ADMIM #614302
AD
1196
ClinVar variants
3
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— TMEM43
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
3 Pathogenic / Likely Pathogenic· 104 VUS of 1196 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.28LOEUF
pLI 0.000
Z-score 0.54
OE 0.88 (0.62–1.28)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.42Z-score
OE missense 1.08 (0.97–1.19)
262 obs / 243.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.88 (0.62–1.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.08 (0.97–1.19)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.07
0≤1.21.6
LoF obs/exp: 20 / 22.8Missense obs/exp: 262 / 243.5Syn Z: -0.57

ClinVar Variant Classifications

1196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic1
VUS104
Likely Benign87
Conflicting3
2
Pathogenic
1
Likely Pathogenic
104
VUS
87
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
2
0
2
Likely Pathogenic
1
0
0
0
1
VUS
11
79
13
1
104
Likely Benign
1
0
48
38
87
Benign
0
0
0
0
0
Conflicting
—3
Total13796339197

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

TMEM43 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

TMEM43-related arrhythmogenic right ventricular cardiomyopathy

definitive
ADUndeterminedAltered Gene Product Structure
Cardiac
G2P ↗
missense variant

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Arrhythmogenic right ventricular dysplasia 5

MIM #604400

Molecular basis of disorder known

Autosomal dominant

Auditory neuropathy, autosomal dominant 3

MIM #619832

Molecular basis of disorder known

Autosomal dominant

Emery-Dreifuss muscular dystrophy 7, AD

MIM #614302

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dilated cardiomyopathy in the era of precision medicine: latest concepts and developments.
Orphanou N et al.·Heart Fail Rev
2022Review
Overexpression of Wild-Type TMEM43 Improves Cardiac Function in Arrhythmogenic Right Ventricular Cardiomyopathy Type 5.
Lalaguna L et al.·Circ Res
2025
Cardiac MRI and Clinical Outcomes in TMEM43 Arrhythmogenic Cardiomyopathy.
Matos J et al.·Radiol Cardiothorac Imaging
2023
Clinical characteristics and determinants of the phenotype in TMEM43 arrhythmogenic right ventricular cardiomyopathy type 5.
Dominguez F et al.·Heart Rhythm
2020
Aberrant accumulation of TMEM43 accompanied by perturbed transmural gene expression in arrhythmogenic cardiomyopathy.
Shinomiya H et al.·FASEB J
2021
Altered Expression of TMEM43 Causes Abnormal Cardiac Structure and Function in Zebrafish.
Zink M et al.·Int J Mol Sci
2022Functional
Mutations with pathogenic potential in proteins located in or at the composite junctions of the intercalated disk connecting mammalian cardiomyocytes: a reference thesaurus for arrhythmogenic cardiomyopathies and for Naxos and Carvajal diseases.
Rickelt S et al.·Cell Tissue Res
2012Review
GSK3 inhibition ameliorates the abnormal contractility of Newfoundland ACM patient iPSC-cardiomyocytes.
Noort RJ et al.·Am J Physiol Cell Physiol
2025
Electrophysiological Phenotype-Genotype Study of Sustained Monomorphic Ventricular Tachycardia in Inherited, High Arrhythmic Risk, Left Ventricular Cardiomyopathy.
Cabrera-Borrego E et al.·Circ Arrhythm Electrophysiol
2024
Arrhythmic genotypes in dilated cardiomyopathy and risk of advanced heart failure.
Mora-Ayestarán N et al.·Eur Heart J
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Arrhythmogenic Cardiomyopathies

Tissue and Metabolic Characterization of Arrhythmogenic Cardiomyopathies by Hybrid PET-MRI Imaging, Impact of the Observed Profiles on the Phenotype and on the Evolution of Cardiomyopathy

RECRUITING
NCT05450783Nantes University HospitalStarted 2022-09-01
Biocollection

External Resources

Links to major genomics databases and tools