LRSAM1

Chr 9ADAR

leucine rich repeat and sterile alpha motif containing 1

Also known as: CMT2P, RIFLE, TAL

NCBI Gene: 90678 ENSG00000148356 UniProt: Q6UWE0 OMIM: 610933

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).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a ring finger protein involved in a variety of functions, including regulation of signaling pathways and cell adhesion, mediation of self-ubiquitylation, and involvement in cargo sorting during receptor endocytosis. Mutations in this gene have been associated with Charcot-Marie-Tooth disease. Multiple transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jan 2012]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2PMIM #614436

ADAR

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Charcot-Marie-Tooth disease axonal type 2P · AD · ClinGen 2023

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.75

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — LRSAM1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 3.00

OE 0.55 (0.41–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.41Z-score

OE missense 0.94 (0.87–1.03)

399 obs / 422.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.55 (0.41–0.75)

0≤0.351.4

Missense OE?0.94 (0.87–1.03)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 29 / 52.4Missense obs/exp: 399 / 422.6Syn Z: -0.48

Background carrier burden — how many people carry a rare variant somewhere in LRSAM1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 51

884 rare PASS variants

Rare truncating (LoF)

1 in 1,100

167 rare PASS variants

Rare synonymous (reference)

1 in 79

356 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for LRSAM1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 56	1 in 1,200
South Asian	~43k	1 in 38	1 in 1,200
Remaining (unassigned)	~30k	1 in 44	1 in 1,500
European (Finnish)	~27k	1 in 280	1 in 1,500
Admixed American	~22k	1 in 50	1 in 340
African / African American	~21k	1 in 45	1 in 1,300
East Asian	~20k	1 in 63	1 in 940
Ashkenazi Jewish	~13k	1 in 220	1 in 1,500
Middle Eastern	~2,884	1 in 59	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 24 coding exons well covered in gnomAD exomes and genomes.? see exons ↓