COL1A2

Chr 7ADAR

collagen type I alpha 2 chain

Also known as: EDSARTH2, EDSCV, OI4

NCBI Gene: 1278 ENSG00000164692 UniProt: P08123

This gene encodes the pro-alpha2 chain 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 VIIB, recessive Ehlers-Danlos syndrome Classical type, idiopathic osteoporosis, and atypical Marfan syndrome. Symptoms associated with mutations in this gene, however, tend to be less severe than mutations in the gene for the alpha1 chain of type I collagen (COL1A1) reflecting the different role of alpha2 chains in matrix integrity. Three 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

{Osteoporosis, postmenopausal}MIM #166710

Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 2MIM #619120

Ehlers-Danlos syndrome, arthrochalasia type, 2MIM #617821

Ehlers-Danlos syndrome, cardiac valvular typeMIM #225320

Osteogenesis imperfecta, type IIMIM #166210

Osteogenesis imperfecta, type IIIMIM #259420

Osteogenesis imperfecta, type IVMIM #166220

626

ClinVar variants

154

Pathogenic / LP

1.00

pLI score· haploinsufficient

Active trials

Clinical Summary— COL1A2

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Gene-Disease Validity (ClinGen)

congenital heart disease · UDDisputed

Disputed — evidence questions this relationship

4 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.

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ClinVar Variants

154 Pathogenic / Likely Pathogenic· 240 VUS of 626 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

LoF intolerant — likely haploinsufficient

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.

0.20LOEUF

pLI 1.000

Z-score 7.22

OE 0.12 (0.07–0.20)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.

2.15Z-score

OE missense 0.79 (0.74–0.84)

641 obs / 813.5 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.12 (0.07–0.20)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.74–0.84)

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.1.11

0≤1.21.6

LoF obs/exp: 9 / 77.6Missense obs/exp: 641 / 813.5Syn Z: -1.44

ClinVar Variant Classifications

626 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic100

Likely Pathogenic54

VUS240

Likely Benign228

Benign2

Conflicting2

100

Pathogenic

Likely Pathogenic

240

VUS

228

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	18	72	10	0	100
Likely Pathogenic	6	43	5	0	54
VUS	5	193	40	2	240
Likely Benign	0	0	120	108	228
Benign	0	0	2	0	2
Conflicting	—				2
Total	29	308	177	110	626

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

View in ClinVar →

Protein Context — Lollipop Plot

COL1A2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

COL1A2-related osteogenesis imperfecta congenita type II

definitive

ADDominant NegativeAltered Gene Product Structure

Skin

G2P ↗

COL1A2-related osteogenesis imperfecta

definitive

ADDominant NegativeAltered Gene Product Structure

Skin

G2P ↗

COL1A2-related Ehlers-Danlos syndrome, cardiac valvular type

definitive

ARLoss Of FunctionAbsent Gene Product

Skin

G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

COLLAGEN, TYPE I, ALPHA-2; COL1A2

MIM #120160 · *

{Osteoporosis, postmenopausal}

MIM #166710