TMEM63B

Chr 6AD

transmembrane protein 63B

Also known as: C6orf110, DEE118, hTMEM63B

NCBI Gene: 55362ENSG00000137216UniProt: Q5T3F8

Enables mechanosensitive monoatomic cation channel activity. Predicted to be involved in sensory perception of sound and surfactant secretion. Located in actin cytoskeleton; cytoplasmic vesicle membrane; and plasma membrane. [provided by Alliance of Genome Resources, Apr 2025]

Primary Disease Associations & Inheritance

Developmental and epileptic encephalopathy 118MIM #621250
AD
121
ClinVar variants
16
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— TMEM63B
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 92 VUS of 121 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.17LOEUF
pLI 1.000
Z-score 5.88
OE 0.07 (0.03–0.17)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
4.22Z-score
OE missense 0.48 (0.43–0.53)
243 obs / 511.4 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.07 (0.03–0.17)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.48 (0.43–0.53)
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.1.10
0≤1.21.6
LoF obs/exp: 3 / 46.1Missense obs/exp: 243 / 511.4Syn Z: -1.14

ClinVar Variant Classifications

121 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic4
VUS92
Likely Benign11
Benign1
Conflicting1
12
Pathogenic
4
Likely Pathogenic
92
VUS
11
Likely Benign
1
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
8
0
12
Likely Pathogenic
0
3
1
0
4
VUS
4
81
7
0
92
Likely Benign
0
4
2
5
11
Benign
0
0
0
1
1
Conflicting
—1
Total492186121

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

View in ClinVar →

Protein Context — Lollipop Plot

TMEM63B · protein map & ClinVar variants

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

Gene2Phenotype Curations

TMEM63B-related developmental and epileptic encephalopathy with anemia

moderate
ADGain Of FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Developmental and epileptic encephalopathy 118

MIM #621250

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.
Vetro A et al.·Am J Hum Genet
2023
TMEM63B functions as a mammalian hyperosmolar sensor for thirst.
Zou W et al.·Neuron
2025
The epilepsy-autism phenotype associated with developmental and epileptic encephalopathies: New mechanism-based therapeutic options.
Specchio N et al.·Epilepsia
2025Review
Membrane structure-responsive lipid scramblase activity of the TMEM63/OSCA family.
Miyata Y et al.·FEBS Lett
2025
Epileptic encephalopathies and progressive neurodegeneration.
Guerrini R et al.·Rev Neurol (Paris)
2024Review
TMEM63 mechanosensitive ion channels: Activation mechanisms, biological functions and human genetic disorders.
Chen X et al.·Biochem Biophys Res Commun
2023Review
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools