GALNS

Chr 16AR

galactosamine (N-acetyl)-6-sulfatase

Also known as: GALNAC6S, GAS, GalN6S, MPS4A

NCBI Gene: 2588 ENSG00000141012 UniProt: P34059

This gene encodes N-acetylgalactosamine-6-sulfatase which is a lysosomal exohydrolase required for the degradation of the glycosaminoglycans, keratan sulfate, and chondroitin 6-sulfate. Sequence alterations including point, missense and nonsense mutations, as well as those that affect splicing, result in a deficiency of this enzyme. Deficiencies of this enzyme lead to Morquio A syndrome, a lysosomal storage disorder. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Mucopolysaccharidosis IVAMIM #253000

Active trials

179

Pathogenic / LP

696

ClinVar variants

Pubs (1 yr)

-0.4

Missense Z

1.01

LOEUF

Clinical Summary— GALNS

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Gene-Disease Validity (ClinGen)

mucopolysaccharidosis type 4A · 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

179 Pathogenic / Likely Pathogenic· 203 VUS of 696 total submissions

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GeneReview available — GALNS

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?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

1.01LOEUF

pLI 0.000

Z-score 1.51

OE 0.69 (0.48–1.01)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

-0.43Z-score

OE missense 1.07 (0.98–1.17)

324 obs / 302.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.69 (0.48–1.01)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (0.98–1.17)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.32

0≤1.21.6

LoF obs/exp: 19 / 27.5Missense obs/exp: 324 / 302.7Syn Z: -2.90

0.6649th %ile

GOF

0.6150th %ile

LOF

0.2777th %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.