TMEM69

Chr 1

transmembrane protein 69

Also known as: C1orf154

NCBI Gene: 51249 ENSG00000159596 UniProt: Q5SWH9

TMEM69 encodes a mitochondrial transmembrane protein with unknown specific function. Mutations cause autosomal recessive developmental and epileptic encephalopathy with severe intellectual disability, typically presenting in infancy with seizures and developmental delays. The gene shows high constraint against loss-of-function variants, indicating it is essential for normal cellular function.

ResearchSummary from RefSeq

Located in mitochondrion. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.63

Clinical Summary— TMEM69

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

27 VUS of 41 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.63LOEUF

pLI 0.000

Z-score 0.34

OE 0.86 (0.47–1.63)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.20Z-score

OE missense 0.95 (0.82–1.10)

120 obs / 126.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.86 (0.47–1.63)

0≤0.351.4

Missense OE?0.95 (0.82–1.10)

0≤0.61.4

Synonymous OE?0.73

0≤1.21.6

LoF obs/exp: 6 / 7.0Missense obs/exp: 120 / 126.4Syn Z: 1.40

This gene — mechanism propensity

0.77top 25%

GOF

0.4283th %ile

LOF

0.3452th %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

41 submitted variants in ClinVar

ClinVar

Classification Summary

VUS27

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	27	27
Likely Benign	2	2
Benign	0	0
Total	29	29

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap TMEM69 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →