HSPG2

Chr 1AR

heparan sulfate proteoglycan 2

NCBI Gene: 3339 ENSG00000142798 UniProt: P98160

Integral component of basement membranes. Component of the glomerular basement membrane (GBM), responsible for the fixed negative electrostatic membrane charge, and which provides a barrier which is both size- and charge-selective. It serves as an attachment substrate for cells. Plays essential roles in vascularization. Critical for normal heart development and for regulating the vascular response to injury. Also required for avascular cartilage development (PubMed:12435733, PubMed:15591058, PubMed:19789387). In muscle, it is essential for localizing acetylcholinesterase (AChE) at the neuromuscular junctions (NMJ), most probably acting as an adapter that links the acetylcholinesterase collagenic tail peptide (COLQ) to alpha-dystroglycan, and is therefore involved in the down-regulation of colinergic synaptic transmission (By similarity)

Primary Disease Associations & Inheritance

Dyssegmental dysplasia, Silverman-Handmaker typeMIM #224410

Schwartz-Jampel syndrome, type 1MIM #255800

574

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— HSPG2

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Gene-Disease Validity (ClinGen)

Schwartz-Jampel syndrome type 1 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

25 Pathogenic / Likely Pathogenic· 246 VUS of 574 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

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.

0.41LOEUF

pLI 0.000

Z-score 9.23

OE 0.34 (0.28–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

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.

1.14Z-score

OE missense 0.94 (0.91–0.97)

2571 obs / 2738.4 exp

Tolerant

Mild missense constraint

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.0.34 (0.28–0.41)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.91–0.97)

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.1.05

0≤1.21.6

LoF obs/exp: 78 / 228.6Missense obs/exp: 2571 / 2738.4Syn Z: -1.39