COL5A1

Chr 9AD

collagen type V alpha 1 chain

Also known as: EDSC, EDSCL1, FMDMF

NCBI Gene: 1289 ENSG00000130635 UniProt: P20908 OMIM: 120215

The protein is an alpha chain of type V collagen, a fibrillar collagen that regulates assembly of heterotypic fibers containing both type I and type V collagen and is found throughout connective tissues. Mutations cause Ehlers-Danlos syndrome classic type and fibromuscular dysplasia through autosomal dominant inheritance. This gene is highly constrained against loss-of-function variants (pLI = 1, LOEUF = 0.055), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.062 OMIM phenotypes

Clinical Summary— COL5A1

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Gene-Disease Validity (ClinGen)

Ehlers-Danlos syndrome, classic type · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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

10 unique Pathogenic / Likely Pathogenic· 129 VUS of 300 total submissions

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Clinical Trials

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

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GeneReview available — COL5A1

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

0.06LOEUF

pLI 1.000

Z-score 9.75

OE 0.02 (0.01–0.06)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint

2.07Z-score

OE missense 0.83 (0.78–0.87)

937 obs / 1132.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.02 (0.01–0.06)

0≤0.351.4

Missense OE0.83 (0.78–0.87)

0≤0.61.4

Synonymous OE1.11

0≤1.21.6

LoF obs/exp: 2 / 114.6Missense obs/exp: 937 / 1132.9Syn Z: -1.82

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveCOL5A1-related classical Ehlers Danlos syndromeLOFAD

0.4884th %ile

GOF

0.4382th %ile

LOF

0.68top 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 · 1 literature citation · 90% of P/LP variants are LoF · LOEUF 0.06

DN1 literature citation

Literature Evidence

DNVery probably, the resulting in-frame exon skip has a dominant-negative effect due to incorporation of the mutant proalpha chain into the triple-helical molecule.PMID:9683580

LOFMETHODS: Seven patients with classic Ehlers-Danlos syndrome (EDS) due to COL5A1 haploinsufficiency and one with an exon-skipping mutation in COL5A2 underwent an ocular examination, corneal topography, pachymetry, and specular microscopy.PMID:16431952

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