TMEM63B

Chr 6AD

transmembrane protein 63B

Also known as: C6orf110, DEE118, hTMEM63B

NCBI Gene: 55362 ENSG00000137216 UniProt: Q5T3F8 OMIM: 619952

The TMEM63B protein functions as a mechanosensitive and osmosensitive cation channel that is essential for respiratory function, hearing, and cellular volume regulation, and also acts as a phospholipid scramblase in response to membrane structural changes. Mutations cause developmental and epileptic encephalopathy 118 with autosomal dominant inheritance. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.168), reflecting its critical role in early development and essential physiological processes.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

GOFmechanismADLOEUF 0.171 OMIM phenotype

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

7 unique Pathogenic / Likely Pathogenic· 92 VUS of 150 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.07 (0.03–0.17)

0≤0.351.4

Missense OE?0.48 (0.43–0.53)

0≤0.61.4

Synonymous OE?1.10

0≤1.21.6

LoF obs/exp: 3 / 46.1Missense obs/exp: 243 / 511.4Syn Z: -1.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateTMEM63B-related developmental and epileptic encephalopathy with anemiaGOFAD

This gene — mechanism propensity

0.4289th %ile

GOF

0.6932th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFLOEUF 0.17

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

150 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic3

VUS92

Likely Benign13

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	3	0	0	3
VUS	5	87	0	0	92
Likely Benign	0	4	1	8	13
Benign	0	0	0	1	1
Conflicting	—				1
Total	5	98	1	9	114

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap TMEM63B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →