TMEM43

Chr 3AD

transmembrane protein 43

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

NCBI Gene: 79188ENSG00000170876UniProt: Q9BTV4OMIM: 612048

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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismADLOEUF 1.283 OMIM phenotypes
Clinical Summary— TMEM43
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Gene-Disease Validity (ClinGen)
arrhythmogenic right ventricular dysplasia 5 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
4 unique Pathogenic / Likely Pathogenic· 604 VUS of 1175 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — TMEM43
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
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?
-0.42Z-score
OE missense 1.08 (0.97–1.19)
262 obs / 243.5 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?
LoF OE?0.88 (0.62–1.28)
0≤0.351.4
Missense OE?1.08 (0.97–1.19)
0≤0.61.4
Synonymous OE?1.07
0≤1.21.6
LoF obs/exp: 20 / 22.8Missense obs/exp: 262 / 243.5Syn Z: -0.57
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveTMEM43-related arrhythmogenic right ventricular cardiomyopathyOTHERAD

This gene — mechanism propensity

DN
0.4983th %ile
GOF
0.4184th %ile
LOF
0.3842th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DN1 literature citation
LOF1 literature citation

Literature Evidence

DNMechanistically, TMEM43 interacts with the Connexin26 and Connexin30 gap junction channels, disrupting the passive conductance current in GLSs in a dominant-negative fashion when the p.(Arg372Ter) variant is introduced.1
LOFThe purpose of the study was to gain insights into the molecular pathogenesis of ACM caused by TMEM43 haploinsufficiency.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

  1. 1.PMID 34050020 ↗
  2. 2.PMID 33070193 ↗

ClinVar Variant Classifications

1175 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic2
VUS604
Likely Benign406
Benign45
Conflicting109
2
Pathogenic
2
Likely Pathogenic
604
VUS
406
Likely Benign
45
Benign
109
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
1
0
2
Likely Pathogenic
2
0
0
0
2
VUS
78
466
52
8
604
Likely Benign
2
12
186
206
406
Benign
0
4
39
2
45
Conflicting
—109
Total824832782161,168

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

View in ClinVar →

23 pathogenic / likely-pathogenic (of 24) ClinVar copy-number / structural variants overlap TMEM43 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

TMEM43 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients