COL11A1

Chr 1ADAR

collagen type XI alpha 1 chain

Also known as: CO11A1, COLL6, DFNA37, STL2

NCBI Gene: 1301 ENSG00000060718 UniProt: P12107 OMIM: 120280

This gene encodes the alpha-1 chain of type XI collagen, which controls lateral growth of collagen II fibrils during fibrillogenesis. Mutations cause autosomal dominant conditions including Stickler syndrome type II, Marshall syndrome, and hereditary hearing loss, as well as autosomal recessive fibrochondrogenesis affecting skeletal development, vision, and hearing. The gene is highly constrained against loss-of-function variants (pLI 1.0, LOEUF 0.22), reflecting its critical role in connective tissue development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAD/ARLOEUF 0.225 OMIM phenotypes

Clinical Summary— COL11A1

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Gene-Disease Validity (ClinGen)

autosomal dominant nonsyndromic hearing loss · ADModerate

Moderate evidence — consider for supplementary testing

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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

9 unique Pathogenic / Likely Pathogenic· 56 VUS of 100 total submissions

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GeneReview available — COL11A1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint

0.22LOEUF

pLI 1.000

Z-score 8.61

OE 0.14 (0.10–0.22)

Highly constrained

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

Missense Constraint

1.02Z-score

OE missense 0.91 (0.86–0.96)

903 obs / 993.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios

LoF OE0.14 (0.10–0.22)

0≤0.351.4

Missense OE0.91 (0.86–0.96)

0≤0.61.4

Synonymous OE1.09

0≤1.21.6

LoF obs/exp: 17 / 118.0Missense obs/exp: 903 / 993.9Syn Z: -1.26

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOL11A1-related Stickler syndromeDNAD

definitiveCOL11A1-related fibrochondrogenesisLOFAR

definitiveCOL11A1-related Marshall syndromeOTHERAR

0.5082th %ile

GOF

0.3986th %ile

LOF

0.66top 25%

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 · 78% of P/LP variants are LoF · LOEUF 0.22

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

DNIn one family with the type 2 vitreous phenotype, we have demonstrated linkage to COL11A113 and shown the causative mutation to be substitution of a glycine residue in the collagen helix, likely to have a dominant negative effect.PMID:10573014

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