TMBIM4
Chr 12transmembrane BAX inhibitor motif containing 4
Also known as: CGI-119, GAAP, LFG4, S1R, ZPRO
The TMBIM4 protein functions as an anti-apoptotic protein that inhibits cell death and modulates calcium signaling through capacitative calcium entry and IP3-mediated calcium release from the endoplasmic reticulum and Golgi. Mutations in TMBIM4 cause autosomal recessive spinal muscular atrophy with congenital bone fractures, characterized by early-onset neuromuscular weakness and skeletal fragility. The gene shows tolerance to loss-of-function variants (LOEUF 1.487), suggesting that complete loss of protein function may be required for disease manifestation.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
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
65 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 15 | 0 | 15 |
Likely Pathogenic | 0 | 0 | 0 | 0 | 0 |
VUS | 2 | 28 | 4 | 0 | 34 |
Likely Benign | 0 | 2 | 0 | 1 | 3 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 2 | 30 | 19 | 1 | 52 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TMBIM4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools