COL4A2

Chr 13ADAR

collagen type IV alpha 2 chain

ENSG00000134871 UniProt: P08572 OMIM: 120090

The protein is a subunit of type IV collagen, the major structural component of basement membranes including those in blood vessels and glomeruli. Mutations cause brain small vessel disease with intracerebral hemorrhage susceptibility, inherited in either autosomal dominant or autosomal recessive patterns depending on the specific variant. This gene is highly constrained against loss-of-function variants, indicating that such mutations are likely to be pathogenic.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Type IV collagen is the major structural component of glomerular basement membranes (GBM), forming a 'chicken-wire' meshwork together with laminins, proteoglycans and entactin/nidogen

OMIM ResearchGenerating clinical summary…

DNmechanismAD/ARLOEUF 0.583 OMIM phenotypes

Clinical Summary— COL4A2

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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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Clinical Trials

2 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.58LOEUF

pLI 0.000

Z-score 4.81

OE 0.45 (0.35–0.58)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.19Z-score

OE missense 0.81 (0.76–0.86)

842 obs / 1040.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.45 (0.35–0.58)

0≤0.351.4

Missense OE?0.81 (0.76–0.86)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 40 / 89.0Missense obs/exp: 842 / 1040.4Syn Z: 0.83

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateCOL4A2-related porencephalyDNAD

This gene — mechanism propensity

0.78top 25%

GOF

0.6053th %ile

LOF

0.3452th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 literature citation

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.

Literature Evidence

DNTogether, our findings suggest that patients with COL4A1 and COL4A2 mutations may be at elevated risk of retinal hemorrhages and that retinal examinations may be useful for identifying patients with COL4A1 and COL4A2 mutations who are also at elevated risk of hemorrhagic strokes.1

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

References