MME
Chr 3ADARmembrane metalloendopeptidase
Also known as: CALLA, CD10, CMT2T, NEP, SCA43, SFE
The encoded neutral endopeptidase cleaves and inactivates multiple neuropeptides including enkephalins, substance P, bradykinin, and natriuretic peptides. Mutations cause spinocerebellar ataxia 43 and Charcot-Marie-Tooth disease type 2T, affecting both central and peripheral nervous systems with both autosomal dominant and recessive inheritance patterns reported. The gene shows tolerance to loss-of-function variants (LOEUF 0.923), suggesting different pathogenic mechanisms may underlie the distinct neurological phenotypes.
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 (gain-of-function and loss-of-function). 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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
100 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 | 9 | 0 | 2 | 0 | 11 |
Likely Pathogenic | 11 | 0 | 0 | 0 | 11 |
VUS | 0 | 27 | 4 | 0 | 31 |
Likely Benign | 0 | 1 | 21 | 23 | 45 |
Benign | 0 | 0 | 2 | 0 | 2 |
| Total | 20 | 28 | 29 | 23 | 100 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
MME · 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
Bradykinin-degradating Enzymes Activities in Angiotensin-Converting Enzyme Inhibitors-associated Angioedema
RECRUITINGNon-interventional Study of Patients With Transthyretin (ATTR) Amyloidosis
RECRUITINGTo Assess Safety and Efficacy of Agents Targeting DNA Damage Repair With Olaparib Versus Olaparib Monotherapy.
ACTIVE NOT RECRUITINGPredictive Value of Transcriptome-based OncoTreat/Oncotarget and Organoid Testing in Metastatic Pancreatic Cancer.
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools