COL1A1

Chr 17AD

collagen type I alpha 1 chain

Also known as: CAFYD, EDSARTH1, EDSC, OI1, OI2, OI3, OI4

NCBI Gene: 1277ENSG00000108821UniProt: P02452

This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

Primary Disease Associations & Inheritance

{Bone mineral density variation QTL, osteoporosis}MIM #166710
AD
Caffey diseaseMIM #114000
AD
Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1MIM #619115
AD
Ehlers-Danlos syndrome, arthrochalasia type, 1MIM #130060
AD
Osteogenesis imperfecta, type IMIM #166200
AD
Osteogenesis imperfecta, type IIMIM #166210
AD
Osteogenesis imperfecta, type IIIMIM #259420
AD
Osteogenesis imperfecta, type IVMIM #166220
AD
4
Active trials
161
Pathogenic / LP
438
ClinVar variants
7
Pubs (1 yr)
3.5
Missense Z· constrained
0.10
LOEUF· LoF intolerant
Clinical Summary— COL1A1
🧬
Gene-Disease Validity (ClinGen)
osteogenesis imperfecta · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
161 Pathogenic / Likely Pathogenic· 123 VUS of 438 total submissions
💊
Clinical Trials
4 active or recruiting trials — potential therapeutic options may be available
📖
GeneReview available — COL1A1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.10LOEUF
pLI 1.000
Z-score 8.23
OE 0.05 (0.02–0.10)
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.
3.53Z-score
OE missense 0.67 (0.62–0.71)
600 obs / 897.8 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.05 (0.02–0.10)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.67 (0.62–0.71)
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.1.07
0≤1.21.6
LoF obs/exp: 4 / 86.8Missense obs/exp: 600 / 897.8Syn Z: -1.00
DN
0.4785th %ile
GOF
0.3491th %ile
LOF
0.73top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · 45% of P/LP variants are LoF · LOEUF 0.10
DN1 literature citation

Literature Evidence

DNAround 90% of patients with OI harbor loss-of-function or dominant negative pathogenic variants in the COL1A1 and COL1A2 genes, which code for collagen type I a1 and a2 chains.PMID:32166892
LOFCOL1A1 haploinsufficiency mutations lead to the mildest form of osteogenesis imperfecta (OI), OI type I.PMID:23529829

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic113
Likely Pathogenic48
VUS123
Likely Benign149
Benign2
Conflicting3
113
Pathogenic
48
Likely Pathogenic
123
VUS
149
Likely Benign
2
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
58
34
21
0
113
Likely Pathogenic
15
26
7
0
48
VUS
0
100
20
3
123
Likely Benign
0
8
81
60
149
Benign
0
0
1
1
2
Conflicting
—3
Total7316813064438

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

View in ClinVar →

Protein Context — Lollipop Plot

COL1A1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL1A1-related osteogenesis imperfecta spectrum

definitive
ADDominant NegativeAltered Gene Product Structure
Dev. DisordersSkinSkeletal
G2P ↗

COL1A1-related Caffey disease

definitive
ADUndeterminedUncertain
Dev. DisordersSkinSkeletal
G2P ↗

COL1A1-related classical Ehlers Danlos syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Skin
G2P ↗

COL1A1-related arthrochalasia Ehlers-Danlos syndrome

definitive
ADDominant NegativeAltered Gene Product Structure
Skin
G2P ↗

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

Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
COL1A1-induced LOXL2 promotes ovarian cancer metastasis via a feedback loop upon inhibiting EGFR lysosomal degradation.
Shen Z et al.·Exp Mol Med
2026
Exploratory identification of COL1A1 as a potential gene linking endocrine-disrupting chemicals and lung adenocarcinoma: a bioinformatics and machine learning analysis.
She T et al.·BMC Pharmacol Toxicol
2026Open Access
Atypical Gene Rearrangement of the COL1A1::PDGFB Fusion in Dermatofibrosarcoma Protuberans of the Abdominal Wall: A Case Report.
Bejbl J et al.·Clin Case Rep
2026Open AccessCase report
The Role of COL1A1, COL5A1, ACTN3, MMP3, and GDF5 Gene Variants in Common Sports Injuries: Systematic Review of ACL Rupture, Achilles Tendinopathy, and Stress Fractures.
Abboud S et al.·Genes (Basel)
2026Review
Identification and functional characterization of a novel pathogenic COL1A1 splicing variant in a Chinese family with osteogenesis imperfecta.
Nie H et al.·Front Genet
2026Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients