COL2A1

Chr 12AD

collagen type II alpha 1 chain

NCBI Gene: 1280 ENSG00000139219 UniProt: P02458

Type II collagen is specific for cartilaginous tissues. It is essential for the normal embryonic development of the skeleton, for linear growth and for the ability of cartilage to resist compressive forces

Primary Disease Associations & Inheritance

?Epiphyseal dysplasia, multiple, with myopia and deafnessMIM #132450

?Vitreoretinopathy with phalangeal epiphyseal dysplasiaMIM #619248

Achondrogenesis, type II or hypochondrogenesisMIM #200610

Avascular necrosis of the femoral headMIM #608805

Czech dysplasiaMIM #609162

Kniest dysplasiaMIM #156550

Legg-Calve-Perthes diseaseMIM #150600

Osteoarthritis with mild chondrodysplasiaMIM #604864

Platyspondylic skeletal dysplasia, Torrance typeMIM #151210

SED congenitaMIM #183900

SMED Strudwick typeMIM #184250

Spondyloepiphyseal dysplasia, Stanescu typeMIM #616583

Spondylometaphyseal dysplasia, Algerian typeMIM #184253

Spondyloperipheral dysplasiaMIM #271700

Stickler syndrome, type IMIM #108300

Stickler syndrome, type I, nonsyndromic ocularMIM #609508

UniProtSpondyloepimetaphyseal dysplasia, Strudwick type

UniProtAchondrogenesis 2

UniProtPlatyspondylic lethal skeletal dysplasia Torrance type

UniProtMultiple epiphyseal dysplasia with myopia and conductive deafness

594

ClinVar variants

167

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— COL2A1

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Gene-Disease Validity (ClinGen)

spondyloepiphyseal dysplasia, Stanescu type · ADModerate

Moderate evidence — consider for supplementary testing

8 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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ClinVar Variants

167 Pathogenic / Likely Pathogenic· 204 VUS of 594 total submissions

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Clinical Trials

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

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.

0.13LOEUF

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?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.

3.29Z-score

OE missense 0.69 (0.64–0.73)

604 obs / 878.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?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.0.69 (0.64–0.73)

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.1.12

0≤1.21.6

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

ClinVar Variant Classifications

594 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic103

Likely Pathogenic64

VUS204

Likely Benign214

Benign7

Conflicting2

103

Pathogenic

Likely Pathogenic

204

VUS

214

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	27	20	0	103
Likely Pathogenic	8	53	3	0	64
VUS	2	159	40	3	204
Likely Benign	0	17	108	89	214
Benign	0	3	2	2	7
Conflicting	—				2
Total	66	259	173	94	594

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.

Gene2Phenotype Curations

COL2A1-related spondyloepiphyseal dysplasia congenita

definitive

ADUndeterminedUncertain

Dev. DisordersEyeSkeletal

G2P ↗

COL2A1-related spondyloepimetaphyseal dysplasia, Strudwick type

definitive

ADDominant NegativeAltered Gene Product Structure

Dev. DisordersEyeSkeletal

G2P ↗

missense variantinframe deletioninframe insertion

COL2A1-related achondrogenesis

definitive

ADDominant NegativeAltered Gene Product Structure

Dev. DisordersSkeletal

G2P ↗

COL2A1-related Kniest dysplasia

definitive

ADDominant NegativeAltered Gene Product Structure

Dev. DisordersEyeSkeletal

G2P ↗

COL2A1-related spondyloepiphyseal dysplasia congenita

definitive

ARUndeterminedAltered Gene Product Structure

Eye

G2P ↗

missense variantinframe deletioninframe insertion

COL2A1-related Stickler syndrome, non-syndromic ocular

definitive

ADLoss Of FunctionAbsent Gene Product

Dev. DisordersEye

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

COLLAGEN, TYPE II, ALPHA-1; COL2A1

MIM #120140 · *

?Epiphyseal dysplasia, multiple, with myopia and deafness

MIM #132450