TM4SF19
Chr 3transmembrane 4 L six family member 19
Also known as: OCTM4
The protein encoded by TM4SF19 is a four-transmembrane domain protein that negatively regulates vacuolar H+-ATPase activity by inhibiting V1-V0 complex assembly and is required for osteoclast multinucleation. Mutations cause autosomal recessive developmental and epileptic encephalopathy with movement abnormalities, typically presenting in early infancy with severe seizures and developmental delays. This gene is extremely intolerant to loss-of-function variation (pLI near 1.0), suggesting complete loss of protein function may be incompatible with normal development.
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
152 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 | 84 | 0 | 84 |
Likely Pathogenic | 0 | 0 | 2 | 0 | 2 |
VUS | 1 | 32 | 20 | 0 | 53 |
Likely Benign | 0 | 7 | 4 | 0 | 11 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 1 | |||
| Total | 1 | 39 | 110 | 0 | 151 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TM4SF19 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
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