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…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.00

LOEUF

GOF

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in MMEL1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 37

1,085 rare PASS variants

Rare truncating (LoF)

1 in 500

200 rare PASS variants

Rare synonymous (reference)

1 in 73

413 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for MMEL1. 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 46	1 in 500
South Asian	~43k	1 in 35	1 in 430
Remaining (unassigned)	~30k	1 in 32	1 in 680
European (Finnish)	~27k	1 in 140	1 in 540
Admixed American	~22k	1 in 27	1 in 600
African / African American	~21k	1 in 34	1 in 650
East Asian	~20k	1 in 52	1 in 690
Ashkenazi Jewish	~13k	1 in 150	1 in 930
Middle Eastern	~2,884	1 in 41	≈ 1 in 680

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): 22 of 23 coding exons well covered in gnomAD exomes; exon 4 marginal. Genomes: 22 of 23 (exon 21 below).? see exons ↓