GNPDA2

Chr 4

glucosamine-6-phosphate deaminase 2

Also known as: GNP2, SB52

NCBI Gene: 132789 ENSG00000163281 UniProt: Q8TDQ7 OMIM: 613222

The protein catalyzes the reversible conversion of glucosamine-6-phosphate to fructose-6-phosphate and ammonium, regulating UDP-N-acetylglucosamine biosynthesis through the hexosamine pathway and influencing hyaluronan synthesis during tissue remodeling. GNPDA2 variants have been associated with body mass index regulation and obesity susceptibility, though the gene shows low constraint to loss-of-function variation. The inheritance pattern and specific neurological phenotypes associated with pathogenic variants in this gene are not well-established in the current literature.

OMIM ResearchSummary from RefSeq, UniProt

The protein encoded by this gene is an allosteric enzyme that catalyzes the reversible reaction converting D-glucosamine-6-phosphate into D-fructose-6-phosphate and ammonium. Variations of this gene have been reported to be associated with influencing body mass index and susceptibility to obesity. A pseudogene of this gene is located on chromosome 9. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Aug 2012]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.95

Clinical Summary— GNPDA2

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Population Constraint (gnomAD)

Low constraint (pLI 0.01) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

22 VUS of 33 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.95LOEUF

pLI 0.008

Z-score 1.68

OE 0.45 (0.24–0.95)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.09Z-score

OE missense 0.74 (0.63–0.87)

106 obs / 142.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.45 (0.24–0.95)

0≤0.351.4

Missense OE?0.74 (0.63–0.87)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 5 / 11.0Missense obs/exp: 106 / 142.6Syn Z: 0.06

This gene — mechanism propensity

0.77top 25%

GOF

0.76top 25%

LOF

0.2385th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

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.

ClinVar Variant Classifications

33 submitted variants in ClinVar

ClinVar

Classification Summary

VUS22

Likely Benign1

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	22	0	22
Likely Benign	0	1	1
Benign	0	1	1
Total	22	2	24

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

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17 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap GNPDA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →