COL18A1

Chr 21

collagen type XVIII alpha 1 chain

Also known as: GLCC, KNO, KNO1, KS

NCBI Gene: 80781 ENSG00000182871 UniProt: P39060

The COL18A1 gene encodes the alpha chain of type XVIII collagen, an extracellular matrix protein that undergoes proteolytic processing to produce endostatin, an antiangiogenic protein, and plays a major role in determining retinal structure and neural tube closure. Mutations cause Knobloch syndrome type 1 (characterized by retinal abnormalities and occipital encephalocele) and primary closed-angle glaucoma, with both autosomal recessive and autosomal dominant inheritance patterns reported. The gene shows moderate constraint against loss-of-function variants (LOEUF 0.535), indicating some tolerance to complete gene disruption.

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.54

Clinical Summary— COL18A1

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Gene-Disease Validity (ClinGen)

Knobloch syndrome 1 · 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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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?

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?

-0.80Z-score

OE missense 1.07 (1.02–1.13)

1057 obs / 986.5 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.40 (0.30–0.54)

0≤0.351.4

Missense OE?1.07 (1.02–1.13)

0≤0.61.4

Synonymous OE?1.32

0≤1.21.6

LoF obs/exp: 31 / 78.2Missense obs/exp: 1057 / 986.5Syn Z: -5.14

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOL18A1-related Knobloch syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6743th %ile

GOF

0.5856th %ile

LOF

0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.