HS3ST2

Chr 16

heparan sulfate-glucosamine 3-sulfotransferase 2

Also known as: 30ST2, 3OST2

NCBI Gene: 9956 ENSG00000122254 UniProt: Q9Y278 OMIM: 604056

The protein is a heparan sulfate 3-O-sulfotransferase that catalyzes the transfer of sulfate groups to specific glucosamine residues on heparan sulfate chains, which are critical for various cellular signaling processes in the nervous system. Mutations cause autosomal recessive intellectual disability with behavioral abnormalities and seizures, typically manifesting in early childhood. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.686), suggesting some intolerance to complete protein loss.

OMIM ResearchSummary from RefSeq, UniProt

Heparan sulfate biosynthetic enzymes are key components in generating a myriad of distinct heparan sulfate fine structures that carry out multiple biologic activities. The enzyme encoded by this gene is a member of the heparan sulfate biosynthetic enzyme family. It is a type II integral membrane protein and possesses heparan sulfate glucosaminyl 3-O-sulfotransferase activity. This gene is expressed predominantly in brain and may play a role in the nervous system. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.69

Clinical Summary— HS3ST2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

29 VUS of 30 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.69LOEUF

pLI 0.100

Z-score 2.37

OE 0.30 (0.15–0.69)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

2.30Z-score

OE missense 0.56 (0.48–0.65)

123 obs / 219.0 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.30 (0.15–0.69)

0≤0.351.4

Missense OE?0.56 (0.48–0.65)

0≤0.61.4

Synonymous OE?1.19

0≤1.21.6

LoF obs/exp: 4 / 13.3Missense obs/exp: 123 / 219.0Syn Z: -1.47

This gene — mechanism propensity

0.6551th %ile

GOF

0.6442th %ile

LOF

0.3453th %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

30 submitted variants in ClinVar

ClinVar

Classification Summary

VUS29

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	29	29
Likely Benign	0	0
Benign	0	0
Total	29	29

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap HS3ST2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →