GPC4

Chr XXLR

glypican 4

Also known as: K-glypican, KPTS

NCBI Gene: 2239ENSG00000076716UniProt: O75487

Cell surface heparan sulfate proteoglycans are composed of a membrane-associated protein core substituted with a variable number of heparan sulfate chains. Members of the glypican-related integral membrane proteoglycan family (GRIPS) contain a core protein anchored to the cytoplasmic membrane via a glycosyl phosphatidylinositol linkage. These proteins may play a role in the control of cell division and growth regulation. The GPC4 gene is adjacent to the 3' end of GPC3 and may also play a role in Simpson-Golabi-Behmel syndrome. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Keipert syndromeMIM #301026
XLR
215
ClinVar variants
92
Pathogenic / LP
0.93
pLI score· haploinsufficient
0
Active trials
Clinical Summary— GPC4
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.93). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
92 Pathogenic / Likely Pathogenic· 91 VUS of 215 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.37LOEUF
pLI 0.926
Z-score 3.39
OE 0.12 (0.05–0.37)
Highly 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.
1.66Z-score
OE missense 0.69 (0.61–0.79)
159 obs / 229.6 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.0.12 (0.05–0.37)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.69 (0.61–0.79)
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.0.93
0≤1.21.6
LoF obs/exp: 2 / 17.1Missense obs/exp: 159 / 229.6Syn Z: 0.55

ClinVar Variant Classifications

215 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic82
Likely Pathogenic10
VUS91
Likely Benign19
Benign8
Conflicting5
82
Pathogenic
10
Likely Pathogenic
91
VUS
19
Likely Benign
8
Benign
5
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
77
0
82
Likely Pathogenic
3
0
7
0
10
VUS
0
74
17
0
91
Likely Benign
0
7
5
7
19
Benign
0
2
6
0
8
Conflicting
—5
Total8831127215

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

View in ClinVar →

Protein Context — Lollipop Plot

GPC4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GPC4-related Keipert syndrome

definitive
Monoallelic X HemizygousLoss Of FunctionAbsent Gene Product
Dev. DisordersSkeletal
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
GLYPICAN 4; GPC4
MIM #300168 · *

Keipert syndrome

MIM #301026

Molecular basis of disorder known

X-linked recessive
📖
GeneReview available — GPC4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GPC4 truncating variant associated with Keipert syndrome and lacrimal punctal agenesis.
Kuroda Y et al.·Am J Med Genet A
2024Case report
Pathogenic Variants in GPC4 Cause Keipert Syndrome.
Amor DJ et al.·Am J Hum Genet
2019
Clinical-Genetic Approach to Conditions with Macrocephaly and ASD/Behaviour Abnormalities: Variants in PTEN and PPP2R5D Are the Most Recurrent Gene Mutations in a Patient-Oriented Diagnostic Strategy.
L'Erario FF et al.·Genes (Basel)
2025
Duplications of GPC3 and GPC4 genes in symptomatic female carriers of Simpson-Golabi-Behmel syndrome type 1.
Schirwani S et al.·Eur J Med Genet
2019Case report
Circulating glypican-4 is a new predictor of all-cause mortality in patients with heart failure.
Muendlein A et al.·Clin Biochem
2023Cohort
For Debate: The Significance of Etiologic Diagnosis in Neonates with Overgrowth Syndromes. Lesson Learned from the Simpson-Golabi-Behmel Syndrome.
Plachý L et al.·Pediatr Endocrinol Rev
2018
GPC4, the gene for human K-glypican, flanks GPC3 on xq26: deletion of the GPC3-GPC4 gene cluster in one family with Simpson-Golabi-Behmel syndrome.
Veugelers M et al.·Genomics
1998
Circulating Glypican-4 Is a Predictor of 24-Month Overall Survival in Metastatic Breast Cancer.
Muendlein A et al.·Oncol Res Treat
2023
The Shear Stress-Regulated Expression of Glypican-4 in Endothelial Dysfunction In Vitro and Its Clinical Significance in Atherosclerosis.
Urschel K et al.·Int J Mol Sci
2023
Serum glypican-4 is a marker of future vascular risk and mortality in coronary angiography patients.
Muendlein A et al.·Atherosclerosis
2022Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools