COL4A2

Chr 13ADAR

collagen type IV alpha 2 chain

Also known as: BSVD2, BSVD2A, BSVD2B, ICH, POREN2

NCBI Gene: 1284ENSG00000134871UniProt: P08572

This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. The C-terminal portion of the protein, known as canstatin, is an inhibitor of angiogenesis and tumor growth. Like the other members of the type IV collagen gene family, this gene is organized in a head-to-head conformation with another type IV collagen gene so that each gene pair shares a common promoter. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

{Hemorrhage, intracerebral, susceptibility to}MIM #614519
Brain small vessel disease 2A, autosomal dominantMIM #614483
AD
Brain small vessel disease 2B, autosomal recessiveMIM #621414
AR
UniProtIntracerebral hemorrhage
1986
ClinVar variants
70
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— COL4A2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
70 Pathogenic / Likely Pathogenic· 221 VUS of 1986 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

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.
0.58LOEUF
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?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.
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?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.0.45 (0.35–0.58)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.76–0.86)
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.0.95
0≤1.21.6
LoF obs/exp: 40 / 89.0Missense obs/exp: 842 / 1040.4Syn Z: 0.83

ClinVar Variant Classifications

1986 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic62
Likely Pathogenic8
VUS221
Likely Benign120
Benign18
Conflicting8
62
Pathogenic
8
Likely Pathogenic
221
VUS
120
Likely Benign
18
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
3
52
0
62
Likely Pathogenic
4
4
0
0
8
VUS
11
184
25
1
221
Likely Benign
0
12
46
62
120
Benign
0
1
10
7
18
Conflicting
—8
Total2220413370437

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

View in ClinVar →

Protein Context — Lollipop Plot

COL4A2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL4A2-related porencephaly

moderate
ADDominant NegativeAltered Gene Product Structure
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{Hemorrhage, intracerebral, susceptibility to}

MIM #614519

Molecular basis of disorder known

Brain small vessel disease 2A, autosomal dominant

MIM #614483

Molecular basis of disorder known

Autosomal dominant

Brain small vessel disease 2B, autosomal recessive

MIM #621414

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The expanding phenotype of COL4A1 and COL4A2 mutations: clinical data on 13 newly identified families and a review of the literature.
Meuwissen ME et al.·Genet Med
2015Review
Multiorgan manifestations of COL4A1 and COL4A2 variants and proposal for a clinical management protocol.
Gasparini S et al.·Am J Med Genet C Semin Med Genet
2024
Neurologic phenotypes associated with COL4A1/2 mutations: Expanding the spectrum of disease.
Zagaglia S et al.·Neurology
2018
COL4A1 and COL4A2-related disorders: Clinical features, diagnostic guidelines, and management.
Tambala D et al.·Genet Med
2025
COL4A1 and COL4A2 mutations and disease: insights into pathogenic mechanisms and potential therapeutic targets.
Kuo DS et al.·Hum Mol Genet
2012Review
Systematic Review of Cerebral Phenotypes Associated With Monogenic Cerebral Small-Vessel Disease.
Whittaker E et al.·J Am Heart Assoc
2022Review
Monogenic causes of cerebral small vessel disease and stroke.
Guey S et al.·Handb Clin Neurol
2024Review
COL4A2 is associated with lacunar ischemic stroke and deep ICH: Meta-analyses among 21,500 cases and 40,600 controls.
Rannikmäe K et al.·Neurology
2017Meta-analysis
Phenotype and surgical management of drug-resistant epilepsy in patients with COL4A1 and COL4A2 variants.
Shi J et al.·Epilepsia Open
2025Cohort
Type IV Collagens and Basement Membrane Diseases: Cell Biology and Pathogenic Mechanisms.
Mao M et al.·Curr Top Membr
2015Review
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
CRC (Colorectal Cancer)Adenoma Colon

An Exploratory Study on Gene Methylation Detection of Colorectal Cancer

RECRUITING
NCT07033156Zhejiang Provincial People's HospitalStarted 2024-12-24
This study does not require intervention trials
COL4A1\2COL4A1-Related Brain Small Vessel Disease With Haemorrhage

COL4A1COL4A2: Study of Pathological Conditions Involving Multiple Organs Caused by Mutations in the COL4A1 and COL4A2 Genes

RECRUITING
NCT07374913Phase NAMeyer Children's Hospital IRCCSStarted 2021-05-01
Ophtalmological and cardiological screening

External Resources

Links to major genomics databases and tools