TMEM65

Chr 8

transmembrane protein 65

NCBI Gene: 157378 ENSG00000164983 UniProt: Q6PI78 OMIM: 616609

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.

OMIM ResearchSummary from RefSeq, UniProt

Enables calcium:sodium antiporter activity. Involved in calcium export from the mitochondrion. Located in intercalated disc and plasma membrane. Is active in mitochondrial inner membrane. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Clinical highlights

Gene–disease validity (ClinGen)

Limited · mitochondrial disease · AR · ClinGen 2024

not for standalone diagnostic reporting

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

—

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.83

LOEUF

Mechanism· predicted

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 OE?0.32 (0.15–0.83)

0≤0.351.4

Missense OE?0.60 (0.49–0.75)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 3 / 9.3Missense obs/exp: 58 / 96.2Syn Z: 0.13

Background carrier burden — how many people carry a rare variant somewhere in TMEM65?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 350

285 rare PASS variants

Rare truncating (LoF)

1 in 4,500

54 rare PASS variants

Rare synonymous (reference)

1 in 270

149 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for TMEM65. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 440	1 in 5,700
South Asian	~43k	1 in 280	≈ 1 in 14,000
Remaining (unassigned)	~30k	1 in 330	≈ 1 in 9,000
European (Finnish)	~27k	1 in 430	1 in 880
Admixed American	~22k	1 in 190	1 in 4,200
African / African American	~21k	1 in 460	1 in 2,500
East Asian	~20k	1 in 250	1 in 2,300
Ashkenazi Jewish	~13k	1 in 1,500	none seen
Middle Eastern	~2,882	1 in 560	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 7 coding exons well covered in gnomAD exomes; exons 1, 3, 4 marginal. Genomes: all 7.? see exons ↓