COL4A1

Chr 13AD

collagen type IV alpha 1 chain

Also known as: BSVD, BSVD1, COL4A1s, PADMAL, RATOR

NCBI Gene: 1282 ENSG00000187498 UniProt: P02462

This gene encodes a type IV collagen alpha protein. Type IV collagen proteins are integral components of basement membranes. This gene shares a bidirectional promoter with a paralogous gene on the opposite strand. The protein consists of an amino-terminal 7S domain, a triple-helix forming collagenous domain, and a carboxy-terminal non-collagenous domain. It functions as part of a heterotrimer and interacts with other extracellular matrix components such as perlecans, proteoglycans, and laminins. In addition, proteolytic cleavage of the non-collagenous carboxy-terminal domain results in a biologically active fragment known as arresten, which has anti-angiogenic and tumor suppressor properties. Mutations in this gene cause porencephaly, cerebrovascular disease, and renal and muscular defects. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2014]

Primary Disease Associations & Inheritance

?Retinal arteries, tortuosity ofMIM #180000

{Hemorrhage, intracerebral, susceptibility to}MIM #614519

Angiopathy, hereditary, with nephropathy, aneurysms, and muscle crampsMIM #611773

Brain small vessel disease with or without ocular anomaliesMIM #175780

Microangiopathy and leukoencephalopathy, pontine, autosomal dominantMIM #618564

UniProtHereditary angiopathy with nephropathy aneurysms and muscle cramps

UniProtIntracerebral hemorrhage

UniProtTortuosity of retinal arteries

UniProtSchizencephaly

555

ClinVar variants

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— COL4A1

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Gene-Disease Validity (ClinGen)

COL4A1-related disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

80 Pathogenic / Likely Pathogenic· 247 VUS of 555 total submissions

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Clinical Trials

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

Some data sources returned errors (1)

pubmed: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esummary.fcgi

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.

0.13LOEUF

pLI 1.000

Z-score 8.32

OE 0.07 (0.04–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

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.

3.02Z-score

OE missense 0.73 (0.68–0.77)

701 obs / 964.9 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.0.07 (0.04–0.13)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.68–0.77)

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.1.20

0≤1.21.6

LoF obs/exp: 6 / 92.3Missense obs/exp: 701 / 964.9Syn Z: -2.97

ClinVar Variant Classifications

555 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic33

Likely Pathogenic47

VUS247

Likely Benign222

Benign2

Conflicting4

Pathogenic

Likely Pathogenic

247

VUS

222

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	10	8	15	0	33
Likely Pathogenic	10	34	3	0	47
VUS	4	211	27	5	247
Likely Benign	0	2	132	88	222
Benign	0	0	2	0	2
Conflicting	—				4
Total	24	255	179	93	555

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

View in ClinVar →

Protein Context — Lollipop Plot

COL4A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL4A1-related porencephaly and brain small vessel disease with or without ocular anomalies

definitive

ADDominant NegativeAltered Gene Product Structure

Dev. DisordersEye

G2P ↗

missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

COLLAGEN, TYPE IV, ALPHA-1; COL4A1

MIM #120130 · *

?Retinal arteries, tortuosity of

MIM #180000