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…

MultiplemechanismAD/ARLOEUF 0.753 OMIM phenotypes

Clinical Summary— COL9A3

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Gene-Disease Validity (ClinGen)

Stickler syndrome · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

55 unique Pathogenic / Likely Pathogenic· 778 VUS of 1767 total submissions

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCOL9A3-related Stickler syndromeLOFAR

definitiveCOL9A3-related multiple epiphyseal dysplasiaDNAD

This gene — mechanism propensity

0.86top 5%

GOF

0.6149th %ile

LOF

0.3164th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median · 1 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

DNThe novel phenotype of MED and mild myopathy is likely caused by a dominant-negative effect of the exon 3-skipping mutation in the COL9A3 gene.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

1.PMID 10655510 ↗

ClinVar Variant Classifications

1767 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38

Likely Pathogenic17

VUS778

Likely Benign758

Benign99

Conflicting59

Pathogenic

Likely Pathogenic

778

VUS

758

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	37	0	1	0	38
Likely Pathogenic	12	2	3	0	17
VUS	43	646	68	21	778
Likely Benign	0	22	460	276	758
Benign	0	1	90	8	99
Conflicting	—				59
Total	92	671	622	305	1,749

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

View in ClinVar →

31 pathogenic / likely-pathogenic (of 46) ClinVar copy-number / structural variants overlap COL9A3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →