COL18A1

Chr 21

collagen type XVIII alpha 1 chain

Also known as: GLCC, KNO, KNO1, KS

NCBI Gene: 80781ENSG00000182871UniProt: P39060

This gene encodes the alpha chain of type XVIII collagen. This collagen is one of the multiplexins, extracellular matrix proteins that contain multiple triple-helix domains (collagenous domains) interrupted by non-collagenous domains. A long isoform of the protein has an N-terminal domain that is homologous to the extracellular part of frizzled receptors. Proteolytic processing at several endogenous cleavage sites in the C-terminal domain results in production of endostatin, a potent antiangiogenic protein that is able to inhibit angiogenesis and tumor growth. Mutations in this gene are associated with Knobloch syndrome. The main features of this syndrome involve retinal abnormalities, so type XVIII collagen may play an important role in retinal structure and in neural tube closure. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Primary Disease Associations & Inheritance

UniProtKnobloch syndrome 1
UniProtGlaucoma, primary closed-angle
3400
ClinVar variants
42
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— COL18A1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 70 VUS of 3400 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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.
0.54LOEUF
pLI 0.000
Z-score 4.94
OE 0.40 (0.30–0.54)
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.
-0.80Z-score
OE missense 1.07 (1.02–1.13)
1057 obs / 986.5 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.0.40 (0.30–0.54)
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 (1.02–1.13)
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: 31 / 78.2Missense obs/exp: 1057 / 986.5Syn Z: -5.14

ClinVar Variant Classifications

3400 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27
Likely Pathogenic15
VUS70
Likely Benign312
Benign2
Conflicting2
27
Pathogenic
15
Likely Pathogenic
70
VUS
312
Likely Benign
2
Benign
2
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
21
0
6
0
27
Likely Pathogenic
15
0
0
0
15
VUS
2
58
9
1
70
Likely Benign
0
10
147
155
312
Benign
0
0
1
1
2
Conflicting
—2
Total3868163157428

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

View in ClinVar →

Protein Context — Lollipop Plot

COL18A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL18A1-related Knobloch syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Spatial transcriptomics combined with single-cell RNA-sequencing unravels the complex inflammatory cell network in atopic dermatitis.
Mitamura Y et al.·Allergy
2023
Large-Scale Plasma Proteomics to Profile Pathways and Prognosis of Chronic Pain.
Li ZY et al.·Adv Sci (Weinh)
2025
Genetics and Clinical Findings Associated with Early-Onset Myopia and Retinal Detachment in Saudi Arabia.
AlEissa MM et al.·Genes (Basel)
2025Review
Fetal and neonatal outcomes of posterior fossa anomalies: a retrospective cohort study.
Alsehli H et al.·Sci Rep
2024Cohort
Acute Angle Closure in Knobloch Syndrome.
Wawrzynski J et al.·J Glaucoma
2021
Ophthalmological and Genetic Profile in Knobloch Syndrome.
Ozdek S et al.·Am J Ophthalmol
2025
Single-cell RNA sequencing analysis reveals the dynamic changes in the tumor microenvironment during NMIBC recurrence.
Chen Z et al.·Apoptosis
2025
Inherited Retinal Diseases with High Myopia: A Review.
Liu C et al.·Genes (Basel)
2025Review
Knobloch Syndrome Associated with Novel COL18A1 Variants in Chinese Population.
Li S et al.·Genes (Basel)
2021
[Clinical and genetic analysis of two children with Knobloch syndrome due to variants of COL18A1 gene].
Gao X et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2025Case report
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