ME1

Chr 6

malic enzyme 1

Also known as: HUMNDME, MES

NCBI Gene: 4199 ENSG00000065833 UniProt: P48163

The protein catalyzes the oxidative decarboxylation of malate to generate NADPH for fatty acid biosynthesis and links glycolytic and citric acid cycles. Mutations cause autosomal recessive neurodevelopmental disorder with microcephaly, epilepsy, and brain atrophy. This gene is highly intolerant to loss-of-function variants, affecting central nervous system development and metabolic pathways.

ResearchSummary from RefSeq, UniProt

This gene encodes a cytosolic, NADP-dependent enzyme that generates NADPH for fatty acid biosynthesis. The activity of this enzyme, the reversible oxidative decarboxylation of malate, links the glycolytic and citric acid cycles. The regulation of expression for this gene is complex. Increased expression can result from elevated levels of thyroid hormones or by higher proportions of carbohydrates in the diet. [provided by RefSeq, Jul 2008]

ResearchGenerating clinical summary…

DNmechanismLOEUF 1.17

Clinical Summary— ME1

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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

1 unique Pathogenic / Likely Pathogenic· 57 VUS of 75 total submissions

Explore recent and relevant literature in Research Assistant →

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?

1.17LOEUF

pLI 0.000

Z-score 0.86

OE 0.82 (0.59–1.17)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.29Z-score

OE missense 1.05 (0.95–1.15)

312 obs / 298.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.82 (0.59–1.17)

0≤0.351.4

Missense OE?1.05 (0.95–1.15)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 23 / 27.9Missense obs/exp: 312 / 298.0Syn Z: -0.21

This gene — mechanism propensity

0.6646th %ile

GOF

0.6051th %ile

LOF

0.3455th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction 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.

ClinVar Variant Classifications

75 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS57

Likely Benign1

Benign1

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	1	0	1
Likely Pathogenic	0	0	0	0
VUS	57	0	0	57
Likely Benign	1	0	0	1
Benign	0	0	1	1
Total	58	1	1	60

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 29) ClinVar copy-number / structural variants overlap ME1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →