TMEM175
Chr 4transmembrane protein 175
Also known as: hTMEM175
TMEM175 encodes a proton-activated channel that maintains pH homeostasis in lysosomes and endosomes by mediating proton efflux at low pH and potassium conductance at higher pH, which is essential for autophagosome-lysosome fusion and protecting neurons against stress-induced damage. Mutations cause autosomal recessive spastic paraplegia and early-onset parkinsonism, typically presenting in childhood to early adulthood. The gene shows very low constraint against loss-of-function variants (pLI near zero), consistent with recessive inheritance where heterozygous carriers are typically unaffected.
Primary Disease Associations & Inheritance
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative 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
295 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 | 138 | 0 | 138 |
Likely Pathogenic | 0 | 0 | 5 | 0 | 5 |
VUS | 0 | 95 | 23 | 0 | 118 |
Likely Benign | 0 | 5 | 1 | 2 | 8 |
Benign | 1 | 1 | 0 | 2 | 4 |
| Total | 1 | 101 | 167 | 4 | 273 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
TMEM175 · 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