COL4A4

Chr 2ARAD

collagen type IV alpha 4 chain

Also known as: ATS2, BFH, BFH1, CA44

NCBI Gene: 1286ENSG00000081052UniProt: P53420

This gene encodes one of the six subunits of type IV collagen, the major structural component of basement membranes. This particular collagen IV subunit, however, is only found in a subset of basement membranes. 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. Mutations in this gene are associated with type II autosomal recessive Alport syndrome (hereditary glomerulonephropathy) and with familial benign hematuria (thin basement membrane disease). Two transcripts, differing only in their transcription start sites, have been identified for this gene and, as is common for collagen genes, multiple polyadenylation sites are found in the 3' UTR. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Alport syndrome 2, autosomal recessiveMIM #203780
AR
Hematuria, familial benign, 1MIM #141200
AD
UniProtHematuria, benign familial, 1
585
ClinVar variants
163
Pathogenic / LP
0.00
pLI score
4
Active trials
Clinical Summary— COL4A4
🧬
Gene-Disease Validity (ClinGen)
Alport syndrome · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
163 Pathogenic / Likely Pathogenic· 334 VUS of 585 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.62LOEUF
pLI 0.000
Z-score 4.49
OE 0.47 (0.37–0.62)
Tolerant

Typical tolerance to LoF variation

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.
1.02Z-score
OE missense 0.91 (0.86–0.96)
874 obs / 962.6 exp
Tolerant

Mild missense constraint

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.0.47 (0.37–0.62)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.91 (0.86–0.96)
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.1.08
0≤1.21.6
LoF obs/exp: 40 / 84.5Missense obs/exp: 874 / 962.6Syn Z: -1.18

ClinVar Variant Classifications

585 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic43
Likely Pathogenic120
VUS334
Likely Benign80
Benign1
Conflicting7
43
Pathogenic
120
Likely Pathogenic
334
VUS
80
Likely Benign
1
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
31
2
10
0
43
Likely Pathogenic
49
64
7
0
120
VUS
1
271
50
12
334
Likely Benign
0
2
41
37
80
Benign
0
0
1
0
1
Conflicting
—7
Total8133910949585

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

View in ClinVar →

Protein Context — Lollipop Plot

COL4A4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL4A4-related Alport syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEyeSkinEar
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Alport syndrome 2, autosomal recessive

MIM #203780

Molecular basis of disorder known

Autosomal recessive

Hematuria, familial benign, 1

MIM #141200

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — COL4A4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Guidelines for Genetic Testing and Management of Alport Syndrome.
Savige J et al.·Clin J Am Soc Nephrol
2022
Digenic Alport Syndrome.
Savige J et al.·Clin J Am Soc Nephrol
2022Review
Clinical utility of genetic testing in early-onset kidney disease: seven genes are the main players.
Domingo-Gallego A et al.·Nephrol Dial Transplant
2022
Alport syndrome and Alport kidney diseases - elucidating the disease spectrum.
Puapatanakul P et al.·Curr Opin Nephrol Hypertens
2024Review
Genetic Etiologies for Chronic Kidney Disease Revealed through Next-Generation Renal Gene Panel.
Bleyer AJ et al.·Am J Nephrol
2022
Genotype-phenotype correlations and nephroprotective effects of RAAS inhibition in patients with autosomal recessive Alport syndrome.
Zhang Y et al.·Pediatr Nephrol
2021Cohort
Genetic Variants of the COL4A3 , COL4A4 , and COL4A5 Genes Contribute to Thinned Glomerular Basement Membrane Lesions in Sporadic IgA Nephropathy Patients.
Yuan X et al.·J Am Soc Nephrol
2023Cohort
X-Linked and Autosomal Recessive Alport Syndrome: Pathogenic Variant Features and Further Genotype-Phenotype Correlations.
Savige J et al.·PLoS One
2016
Clinical and Genetic Features of Autosomal Dominant Alport Syndrome: A Cohort Study.
Furlano M et al.·Am J Kidney Dis
2021Cohort
Toripalimab Plus Chemotherapy as a First-Line Therapy for Extensive-Stage Small Cell Lung Cancer: The Phase 3 EXTENTORCH Randomized Clinical Trial.
Cheng Y et al.·JAMA Oncol
2025Clinical trial
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Clinical features of hearing loss and genotype-phenotype correlations in Alport syndrome caused by COL4A4 or COL4A5 variants.
Matsuzaki S et al.·Sci Rep
2025🔓 Open Access
Case Report: A novel TTN gene variant and a concurrent rare COL4A4 gene variant in a Chinese patient with dilated cardiomyopathy.
Han S et al.·Front Cardiovasc Med
2025🔓 Open AccessCase report
Expanding the COL4A4 variant spectrum: genotype-phenotype correlation in 19 Chinese children using updated Alport kidney disease classification.
Huang Y et al.·Ren Fail
2025🔓 Open Access
From screening to strategy: Clinical implications of COL4A3/COL4A4 variants found in reproductive genetic testing.
Butler G et al.·Eur J Hum Genet
2026
Age at disease onset and risk of chronic kidney disease in patients with heterozygous disease-causing variants in COL4A3 and COL4A4.
Hu N et al.·Clin Kidney J
2025🔓 Open AccessCohort
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Alport Syndrome

Safety and Efficacy of ACEI in Alport Syndrome Patients With COL4A3/COL4A4/COL4A5 Variants

NOT YET RECRUITING
NCT05133050Phase NAXinhua Hospital, Shanghai Jiao Tong University School of MedicineStarted 2022-01-01
Ramipril
Keratoconus

The Collagen Factors of Rapid Progression of Keratoconus in Children.

RECRUITING
NCT06722937Zhongshan Ophthalmic Center, Sun Yat-sen UniversityStarted 2023-04-14
Observation
Alport Syndrome

BAY3401016; Biomarker Study Alport

NOT YET RECRUITING
NCT07211685Phase PHASE2BayerStarted 2025-12-02
BAY 3401016Placebo
Alport Syndrome

Genotype-Phenotype Correlations in Patients With Alport Syndrome

RECRUITING
NCT04947813Xinhua Hospital, Shanghai Jiao Tong University School of MedicineStarted 2021-01-01

External Resources

Links to major genomics databases and tools