GNE

Chr 9ARAD

glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase

Also known as: DMRV, GLCNE, IBM2, NM, THC12, Uae1

NCBI Gene: 10020 ENSG00000159921 UniProt: Q9Y223 OMIM: 603824

This bifunctional enzyme initiates and regulates the biosynthesis of N-acetylneuraminic acid, serving as the rate-limiting enzyme in the sialic acid biosynthetic pathway that is crucial for cell surface molecule function in adhesion and signal transduction. Mutations cause autosomal recessive Nonaka myopathy and inclusion body myopathy, autosomal dominant sialuria, and thrombocytopenia with or without myopathy. The pathogenic mechanism involves disrupted sialylation of cell surface molecules due to impaired sialic acid biosynthesis.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a bifunctional enzyme that initiates and regulates the biosynthesis of N-acetylneuraminic acid (NeuAc), a precursor of sialic acids. It is a rate-limiting enzyme in the sialic acid biosynthetic pathway. Sialic acid modification of cell surface molecules is crucial for their function in many biologic processes, including cell adhesion and signal transduction. Differential sialylation of cell surface molecules is also implicated in the tumorigenicity and metastatic behavior of malignant cells. Mutations in this gene are associated with sialuria, autosomal recessive inclusion body myopathy, and Nonaka myopathy. Alternative splicing of this gene results in transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Nonaka myopathyMIM #605820

SialuriaMIM #269921

Thrombocytopenia 12 with or without myopathyMIM #620757

Clinical highlights

Gene–disease validity (ClinGen · GenCC)

Definitive · thrombocytopenia 12 with or without myopathy · AR · ClinGen 2025
Definitive · GNE myopathy · AR · Myriad Women's Health
Strong · sialuria · AD · Genomics England PanelApp
Supportive · platelet-type bleeding disorder 19 · AR · Orphanet

Active trials

127

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

—

Mechanism

📖

GeneReview available — GNE

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?

1.16LOEUF

pLI 0.000

Z-score 0.83

OE 0.84 (0.62–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

2.59Z-score

OE missense 0.64 (0.58–0.71)

271 obs / 420.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.84 (0.62–1.16)

0≤0.351.4

Missense OE?0.64 (0.58–0.71)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 27 / 32.1Missense obs/exp: 271 / 420.5Syn Z: 1.59

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

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 110

691 rare PASS variants

Rare truncating (LoF)

1 in 1,600

124 rare PASS variants

Rare synonymous (reference)

1 in 170

288 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GNE. 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 160	1 in 1,700
South Asian	~43k	1 in 100	1 in 1,200
Remaining (unassigned)	~30k	1 in 83	1 in 840
European (Finnish)	~27k	1 in 340	≈ 1 in 6,700
Admixed American	~22k	1 in 110	1 in 2,300
African / African American	~21k	1 in 150	1 in 1,300
East Asian	~20k	1 in 98	1 in 350
Ashkenazi Jewish	~13k	1 in 1,000	≈ 1 in 6,500
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): 10 of 11 coding exons well covered in gnomAD exomes; exon 6 marginal. Genomes: all 11.? see exons ↓