LRSAM1
Chr 9ADARleucine rich repeat and sterile alpha motif containing 1
Also known as: CMT2P, RIFLE, TAL
The protein functions as an E3 ubiquitin-protein ligase that regulates cargo sorting during endocytosis and serves as a bacterial recognition protein that promotes autophagy-mediated clearance of intracellular pathogens. Mutations cause Charcot-Marie-Tooth disease, axonal type 2P, a peripheral neuropathy that can be inherited in either autosomal dominant or autosomal recessive patterns. This gene is not highly constrained against loss-of-function variants (LOEUF 0.754).
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Typical tolerance to LoF variation
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative 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 dominant-negative. 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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
500 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 | 16 | 1 | 8 | 0 | 25 |
Likely Pathogenic | 18 | 1 | 4 | 0 | 23 |
VUS | 2 | 196 | 23 | 1 | 222 |
Likely Benign | 0 | 0 | 109 | 87 | 196 |
Benign | 0 | 0 | 17 | 0 | 17 |
Conflicting | — | 17 | |||
| Total | 36 | 198 | 161 | 88 | 500 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
LRSAM1 · 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