GNPTAB

Chr 12AR

N-acetylglucosamine-1-phosphate transferase subunits alpha and beta

Also known as: GNPTA, ICD

NCBI Gene: 79158 ENSG00000111670 UniProt: Q3T906 OMIM: 607840

The protein catalyzes the formation of mannose 6-phosphate markers on oligosaccharides in the Golgi apparatus, which are essential for proper trafficking of lysosomal enzymes to lysosomes. Mutations cause mucolipidosis II (I-cell disease) and the milder mucolipidosis IIIA (pseudo-Hurler polydystrophy), both presenting with skeletal dysplasia, coarse facial features, and developmental delay with earlier and more severe manifestations in mucolipidosis II. Inheritance is autosomal recessive.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes two of three subunit types of the membrane-bound enzyme N-acetylglucosamine-1-phosphotransferase, a heterohexameric complex composed of two alpha, two beta, and two gamma subunits. The encoded protein is proteolytically cleaved at the Lys928-Asp929 bond to yield mature alpha and beta polypeptides while the gamma subunits are the product of a distinct gene (GeneID 84572). In the Golgi apparatus, the heterohexameric complex catalyzes the first step in the synthesis of mannose 6-phosphate recognition markers on certain oligosaccharides of newly synthesized lysosomal enzymes. These recognition markers are essential for appropriate trafficking of lysosomal enzymes. Mutations in this gene have been associated with both mucolipidosis II and mucolipidosis IIIA.[provided by RefSeq, May 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.822 OMIM phenotypes

Clinical Summary— GNPTAB

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Gene-Disease Validity (ClinGen)

GNPTAB-mucolipidosis · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

454 unique Pathogenic / Likely Pathogenic· 413 VUS of 1794 total submissions

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GeneReview available — GNPTAB

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.82LOEUF

pLI 0.000

Z-score 2.71

OE 0.63 (0.49–0.82)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.19Z-score

OE missense 0.87 (0.81–0.93)

572 obs / 657.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.63 (0.49–0.82)

0≤0.351.4

Missense OE?0.87 (0.81–0.93)

0≤0.61.4

Synonymous OE?1.06

0≤1.21.6

LoF obs/exp: 39 / 62.0Missense obs/exp: 572 / 657.7Syn Z: -0.70

ClinVar Variant Classifications

1794 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic213

Likely Pathogenic241

VUS413

Likely Benign763

Benign55

Conflicting57

213

Pathogenic

241

Likely Pathogenic

413

VUS

763

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	187	13	13	0	213
Likely Pathogenic	207	26	7	1	241
VUS	3	347	51	12	413
Likely Benign	1	15	293	454	763
Benign	0	0	49	6	55
Conflicting	—				57
Total	398	401	413	473	1,742

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap GNPTAB — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →