COL9A3

Chr 20ADAR

collagen type IX alpha 3 chain

Also known as: DJ885L7.4.1, EDM3, IDD, MED, STL6

NCBI Gene: 1299 ENSG00000092758 UniProt: Q14050 OMIM: 120270

This gene encodes the alpha-3 chain of type IX collagen, a structural component of hyaline cartilage and vitreous of the eye that forms heterotrimeric molecules typically found alongside type II collagen. Mutations cause multiple epiphyseal dysplasia type 3 (with or without myopathy), Stickler syndrome type VI, and susceptibility to intervertebral disc disease, affecting skeletal and ocular systems. The gene shows both autosomal dominant and autosomal recessive inheritance patterns and is not highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes one of the three alpha chains of type IX collagen, the major collagen component of hyaline cartilage. Type IX collagen, a heterotrimeric molecule, is usually found in tissues containing type II collagen, a fibrillar collagen. Mutations in this gene are associated with multiple epiphyseal dysplasia type 3. [provided by RefSeq, Jan 2010]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Intervertebral disc disease, susceptibility to}MIM #603932

Epiphyseal dysplasia, multiple, 3, with or without myopathyMIM #600969

Stickler syndrome, type VIMIM #620022

UniProtMultiple epiphyseal dysplasia 3

UniProtStickler syndrome 6

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Stickler syndrome · AR · ClinGen 2022

Interpreting a novel variant

The dominant disease is caused by dominant-negative changes and the recessive disease by loss of function (Gene2Phenotype). A single heterozygous truncating variant therefore fits the recessive disease and does not by itself explain a dominant presentation; a novel missense has to be read against the dominant mechanism.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.75

LOEUF

Multiple*

Mechanism· G2P

📖

GeneReview available — COL9A3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 3.00

OE 0.54 (0.40–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.38Z-score

OE missense 1.05 (0.97–1.13)

471 obs / 448.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.54 (0.40–0.75)

0≤0.351.4

Missense OE?1.05 (0.97–1.13)

0≤0.61.4

Synonymous OE?1.21

0≤1.21.6

LoF obs/exp: 27 / 49.9Missense obs/exp: 471 / 448.2Syn Z: -2.33

Background carrier burden — how many people carry a rare variant somewhere in COL9A3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 38

1,167 rare PASS variants

Rare truncating (LoF)

1 in 790

227 rare PASS variants

Rare synonymous (reference)

1 in 63

523 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for COL9A3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 45	1 in 800
South Asian	~43k	1 in 41	1 in 650
Remaining (unassigned)	~30k	1 in 26	1 in 790
European (Finnish)	~27k	1 in 89	1 in 870
Admixed American	~22k	1 in 33	1 in 550
African / African American	~21k	1 in 33	1 in 580
East Asian	~20k	1 in 39	1 in 800
Ashkenazi Jewish	~13k	1 in 170	1 in 1,400
Middle Eastern	~2,884	1 in 34	≈ 1 in 940

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 30 of 32 coding exons well covered in gnomAD exomes; exons 1, 9 marginal. Genomes: 31 of 32 (exon 12 below).? see exons ↓