GNS

Chr 12AR

glucosamine (N-acetyl)-6-sulfatase

Also known as: G6S

NCBI Gene: 2799 ENSG00000135677 UniProt: P15586 OMIM: 607664

This gene encodes a lysosomal enzyme that catabolizes heparin, heparan sulfate, and keratan sulfate. Mutations cause mucopolysaccharidosis type IIID (Sanfilippo D syndrome), the rarest subtype of Sanfilippo syndrome, through autosomal recessive inheritance. Enzyme deficiency leads to accumulation of undegraded substrate in lysosomes, resulting in progressive neurodegeneration.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

The product of this gene is a lysosomal enzyme found in all cells. It is involved in the catabolism of heparin, heparan sulphate, and keratan sulphate. Deficiency of this enzyme results in the accumulation of undegraded substrate and the lysosomal storage disorder mucopolysaccharidosis type IIID (Sanfilippo D syndrome). Mucopolysaccharidosis type IIID is the least common of the four subtypes of Sanfilippo syndrome. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.611 OMIM phenotype

Clinical Summary— GNS

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Gene-Disease Validity (ClinGen)

mucopolysaccharidosis type 3D · 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

87 unique Pathogenic / Likely Pathogenic· 262 VUS of 850 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GNS

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?

0.61LOEUF

pLI 0.001

Z-score 3.22

OE 0.37 (0.23–0.61)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.37Z-score

OE missense 0.78 (0.70–0.87)

234 obs / 301.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.37 (0.23–0.61)

0≤0.351.4

Missense OE?0.78 (0.70–0.87)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 11 / 30.1Missense obs/exp: 234 / 301.1Syn Z: 0.33

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGNS-related mucopolysaccharidosisLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6937th %ile

GOF

0.5955th %ile

LOF

0.3261th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

850 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic54

Likely Pathogenic33

VUS262

Likely Benign430

Benign44

Conflicting17

Pathogenic

Likely Pathogenic

262

VUS

430

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	52	1	1	0	54
Likely Pathogenic	29	1	3	0	33
VUS	5	191	55	11	262
Likely Benign	0	4	185	241	430
Benign	0	0	39	5	44
Conflicting	—				17
Total	86	197	283	257	840

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 13) ClinVar copy-number / structural variants overlap GNS — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →