CHST6

Chr 16AR

carbohydrate sulfotransferase 6

Also known as: C-GlcNAc6ST, GST4-beta, MCDC1, glcNAc6ST-5, gn6st-5, hCGn6ST

NCBI Gene: 4166 ENSG00000183196 UniProt: Q9GZX3

The protein encoded by this gene is an enzyme that catalyzes the transfer of a sulfate group to the GlcNAc residues of keratan. Keratan sulfate helps maintain corneal transparency. Defects in this gene are a cause of macular corneal dystrophy (MCD). [provided by RefSeq, Jan 2010]

Primary Disease Associations & Inheritance

Macular corneal dystrophyMIM #217800

UniProtMacular dystrophy, corneal

Active trials

Pathogenic / LP

342

ClinVar variants

Pubs (1 yr)

-0.9

Missense Z

1.82

LOEUF

Clinical Summary— CHST6

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Gene-Disease Validity (ClinGen)

macular corneal dystrophy · 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

57 Pathogenic / Likely Pathogenic· 199 VUS of 342 total submissions

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.

1.82LOEUF

pLI 0.000

Z-score -0.62

OE 1.21 (0.77–1.82)

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.

-0.90Z-score

OE missense 1.15 (1.05–1.26)

334 obs / 290.8 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.1.21 (0.77–1.82)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.15 (1.05–1.26)

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.1.09

0≤1.21.6

LoF obs/exp: 12 / 9.9Missense obs/exp: 334 / 290.8Syn Z: -0.86

0.6161th %ile

GOF

0.6737th %ile

LOF

0.3261th %ile

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

GOFprediction above median

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.