MME

Chr 3ADAR

membrane metalloendopeptidase

Also known as: CALLA, CD10, CMT2T, NEP, SCA43, SFE

NCBI Gene: 4311 ENSG00000196549 UniProt: P08473 OMIM: 120520

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.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a type II transmembrane glycoprotein and a common acute lymphocytic leukemia antigen that is an important cell surface marker in the diagnosis of human acute lymphocytic leukemia (ALL). The encoded protein is present on leukemic cells of pre-B phenotype, which represent 85% of cases of ALL. This protein is not restricted to leukemic cells, however, and is found on a variety of normal tissues. The protein is a neutral endopeptidase that cleaves peptides at the amino side of hydrophobic residues and inactivates several peptide hormones including glucagon, enkephalins, substance P, neurotensin, oxytocin, and bradykinin. [provided by RefSeq, Aug 2017]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.922 OMIM phenotypes

Clinical Summary— MME

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease axonal type 2T · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

110 unique Pathogenic / Likely Pathogenic· 333 VUS of 802 total submissions

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Clinical Trials

5 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — MME

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?

0.92LOEUF

pLI 0.000

Z-score 2.00

OE 0.70 (0.54–0.92)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.36Z-score

OE missense 0.95 (0.87–1.03)

374 obs / 394.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.70 (0.54–0.92)

0≤0.351.4

Missense OE?0.95 (0.87–1.03)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 36 / 51.5Missense obs/exp: 374 / 394.0Syn Z: 0.67

This gene — mechanism propensity

0.5772th %ile

GOF

0.6735th %ile

LOF

0.2582th %ile

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.

GOFprediction above median

LOF1 literature citation · 86% of P/LP variants are LoF

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

LOFTransfection of the mutation into HEK293 cells showed that the mutant protein had significantly decreased neprilysin activity, consistent with a loss of function and haploinsufficiency.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 27588448 ↗

ClinVar Variant Classifications

802 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59

Likely Pathogenic51

VUS333

Likely Benign272

Benign60

Conflicting16

Pathogenic

Likely Pathogenic

333

VUS

272

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	50	1	8	0	59
Likely Pathogenic	45	6	0	0	51
VUS	5	289	35	4	333
Likely Benign	0	6	152	114	272
Benign	0	1	56	3	60
Conflicting	—				16
Total	100	303	251	121	791

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

17 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap MME — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →