TMEM65

Chr 8

transmembrane protein 65

NCBI Gene: 157378ENSG00000164983UniProt: Q6PI78

TMEM65 encodes a protein essential for maintaining cardiac intercalated disc structure and function, stabilizing gap junction and sodium channel localization, and regulating mitochondrial respiration. Mutations cause autosomal recessive arrhythmogenic cardiomyopathy with conduction defects and sudden cardiac death in infancy and childhood. The protein's critical role in cardiac conduction system development and function makes this a severe early-onset cardiac condition requiring immediate cardiology management.

Summary from RefSeq, UniProt
Research Assistant →
0
Active trials
13
Pubs (1 yr)
51
P/LP submissions
0%
P/LP missense
0.83
LOEUF
DN
Mechanism· predicted
Clinical Summary— TMEM65
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Gene-Disease Validity (ClinGen)
mitochondrial disease · ARLimited

Limited evidence — not for standalone diagnostic reporting

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.32) despite low pLI — interpret in context.
📋
ClinVar Variants
51 unique Pathogenic / Likely Pathogenic· 27 VUS of 94 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.83LOEUF
pLI 0.111
Z-score 1.91
OE 0.32 (0.15–0.83)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.38Z-score
OE missense 0.60 (0.49–0.75)
58 obs / 96.2 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.32 (0.15–0.83)
0≤0.351.4
Missense OE0.60 (0.49–0.75)
0≤0.61.4
Synonymous OE0.97
0≤1.21.6
LoF obs/exp: 3 / 9.3Missense obs/exp: 58 / 96.2Syn Z: 0.13
DN
0.76top 25%
GOF
0.5366th %ile
LOF
0.3261th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

94 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
VUS27
Likely Benign6
51
Pathogenic
27
VUS
6
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
51
0
51
Likely Pathogenic
0
0
0
0
0
VUS
0
21
6
0
27
Likely Benign
0
3
1
2
6
Benign
0
0
0
0
0
Total02458284

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM65 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

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