ME3

Chr 11

malic enzyme 3

Also known as: NADP-ME

NCBI Gene: 10873 ENSG00000151376 UniProt: Q16798

Malic enzyme 3 is a mitochondrial enzyme that catalyzes the oxidative decarboxylation of malate to pyruvate using NADP+ as a cofactor, playing a key role in cellular metabolism. Mutations cause autosomal recessive developmental and epileptic encephalopathy with onset in early infancy, characterized by severe intellectual disability, seizures, and developmental regression. The gene is highly constrained against loss-of-function variants, indicating that complete loss of function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

Malic enzyme catalyzes the oxidative decarboxylation of malate to pyruvate using either NAD+ or NADP+ as a cofactor. Mammalian tissues contain 3 distinct isoforms of malic enzyme: a cytosolic NADP(+)-dependent isoform, a mitochondrial NADP(+)-dependent isoform, and a mitochondrial NAD(+)-dependent isoform. This gene encodes a mitochondrial NADP(+)-dependent isoform. Multiple alternatively spliced transcript variants have been found for this gene, but the biological validity of some variants has not been determined. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.07

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.07LOEUF

pLI 0.000

Z-score 1.24

OE 0.76 (0.55–1.07)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.33Z-score

OE missense 0.80 (0.73–0.89)

291 obs / 362.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.76 (0.55–1.07)

0≤0.351.4

Missense OE?0.80 (0.73–0.89)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 24 / 31.5Missense obs/exp: 291 / 362.3Syn Z: -0.83

Background carrier burden — how many people carry a rare variant somewhere in ME3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 120

764 rare PASS variants

Rare truncating (LoF)

1 in 1,200

108 rare PASS variants

Rare synonymous (reference)

1 in 140

359 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ME3. 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 130	1 in 1,200
South Asian	~43k	1 in 93	1 in 2,100
Remaining (unassigned)	~30k	1 in 100	1 in 940
European (Finnish)	~27k	1 in 400	none seen
Admixed American	~22k	1 in 96	1 in 1,500
African / African American	~21k	1 in 75	1 in 900
East Asian	~20k	1 in 100	1 in 960
Ashkenazi Jewish	~13k	1 in 470	≈ 1 in 4,300
Middle Eastern	~2,884	1 in 140	≈ 1 in 2,900

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 14 coding exons well covered in gnomAD exomes and genomes.? see exons ↓