COL2A1

Chr 12AD

collagen type II alpha 1 chain

Also known as: ACG2, ANFH, ANFH1, AOM, COL11A3, EDMMD, LCPD, OSCDP

NCBI Gene: 1280 ENSG00000139219 UniProt: P02458 OMIM: 120140

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the alpha-1 chain of type II collagen, a fibrillar collagen found in cartilage and the vitreous humor of the eye. Mutations in this gene are associated with achondrogenesis, chondrodysplasia, early onset familial osteoarthritis, SED congenita, Langer-Saldino achondrogenesis, Kniest dysplasia, Stickler syndrome type I, and spondyloepimetaphyseal dysplasia Strudwick type. In addition, defects in processing chondrocalcin, a calcium binding protein that is the C-propeptide of this collagen molecule, are also associated with chondrodysplasia. There are two transcripts identified for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.1316 OMIM phenotypes

Clinical Summary— COL2A1

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Gene-Disease Validity (ClinGen)

COL2A1-related spondyloepiphyseal dysplasia · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

7 total gene-disease associations curated

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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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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 8.12

OE 0.07 (0.04–0.13)

Highly constrained

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

Missense Constraint?

3.29Z-score

OE missense 0.69 (0.64–0.73)

604 obs / 878.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.07 (0.04–0.13)

0≤0.351.4

Missense OE?0.69 (0.64–0.73)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 6 / 88.4Missense obs/exp: 604 / 878.6Syn Z: -1.67

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOL2A1-related spondyloepiphyseal dysplasia congenitaOTHERAD

definitiveCOL2A1-related spondyloepimetaphyseal dysplasia, Strudwick typeDNAD

definitiveCOL2A1-related achondrogenesisDNAD

definitiveCOL2A1-related Kniest dysplasiaDNAD

definitiveCOL2A1-related spondyloepiphyseal dysplasia congenitaOTHERAR

definitiveCOL2A1-related Stickler syndrome, non-syndromic ocularLOFAD

This gene — mechanism propensity

0.5279th %ile

GOF

0.3788th %ile

LOF

0.69top 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 · LOEUF 0.13 · ClinGen HI: Sufficient evidence for dosage pathogenicity

DN1 literature citation

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

DNDominant negative mutations in the C-propeptide of COL2A1 cause platyspondylic lethal skeletal dysplasia, torrance type, and define a novel subfamily within the type 2 collagenopathies1

LOFPremature termination codons in COL2A1 that result in haploinsufficiency of type II collagen are a common finding.2

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

References