COL2A1
Chr 12ADcollagen type II alpha 1 chain
Also known as: ACG2, ANFH, ANFH1, AOM, COL11A3, EDMMD, LCPD, OSCDP
This gene encodes the alpha-1 chain of type II collagen, which is essential for cartilage development and the ability to resist compressive forces. Mutations cause a spectrum of skeletal dysplasias including achondrogenesis, Kniest dysplasia, spondyloepiphyseal dysplasia congenita, and Stickler syndrome type I, with phenotypes ranging from perinatal lethal to milder forms with joint problems and sensory impairments. The gene follows autosomal dominant inheritance and is highly constrained against loss-of-function variants.
Moderate evidence — consider for supplementary testing
8 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Among the most LoF-intolerant genes (~top 3%)
Highly missense-constrained (top ~0.1%)
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.
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
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
500 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 64 | 16 | 5 | 0 | 85 |
Likely Pathogenic | 18 | 50 | 2 | 2 | 72 |
VUS | 4 | 90 | 20 | 3 | 117 |
Likely Benign | 0 | 29 | 59 | 45 | 133 |
Benign | 0 | 9 | 3 | 0 | 12 |
Conflicting | — | 80 | |||
| Total | 86 | 194 | 89 | 50 | 499 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
COL2A1 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
External Resources
Links to major genomics databases and tools