MMEL1

Chr 1

membrane metalloendopeptidase like 1

Also known as: MMEL2, NEP2, NEPII, NL1, NL2, SEP

NCBI Gene: 79258 ENSG00000142606 UniProt: Q495T6 OMIM: 618104

This gene encodes a membrane metalloprotease that degrades small peptides and is involved in sperm function and early embryonic development. Mutations cause autosomal recessive male infertility due to multiple morphological abnormalities of the flagella (MMAF), resulting in asthenozoospermia and reduced fertility. The gene shows no intolerance to loss-of-function variants in the general population, consistent with its reproductive-specific phenotype.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is a member of the neutral endopeptidase (NEP) or membrane metallo-endopeptidase (MME) family. Family members play important roles in pain perception, arterial pressure regulation, phosphate metabolism and homeostasis. This protein is a type II transmembrane protein and is thought to be expressed as a secreted protein. This gene is expressed mainly in testis with weak expression in the brain, kidney, and heart. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

GOFmechanismLOEUF 1.00

Clinical Summary— MMEL1

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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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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.00LOEUF

pLI 0.000

Z-score 1.57

OE 0.77 (0.60–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.13Z-score

OE missense 0.98 (0.91–1.06)

480 obs / 487.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.77 (0.60–1.00)

0≤0.351.4

Missense OE?0.98 (0.91–1.06)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 41 / 53.4Missense obs/exp: 480 / 487.8Syn Z: 0.10

This gene — mechanism propensity

0.6164th %ile

GOF

0.74top 25%

LOF

0.2679th %ile

The highest-scoring mechanism for this gene is gain-of-function.

GOFprediction above median

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.