COL5A1

Chr 9AD

collagen type V alpha 1 chain

Also known as: EDSC, EDSCL1, FMDMF

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.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismADLOEUF 0.062 OMIM phenotypes
Clinical SummaryCOL5A1
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Gene-Disease Validity (ClinGen)
Ehlers-Danlos syndrome, classic type · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

LoF intolerant — likely haploinsufficient
LoF Constraint
0.06LOEUF
pLI 1.000
Z-score 9.75
OE 0.02 (0.010.06)
Highly constrained

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

Missense Constraint
2.07Z-score
OE missense 0.83 (0.780.87)
937 obs / 1132.9 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios
LoF OE0.02 (0.010.06)
00.351.4
Missense OE0.83 (0.780.87)
00.61.4
Synonymous OE1.11
01.21.6
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
DN
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.

ClinVar Variant Classifications

300 submitted variants in ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic5
VUS129
Likely Benign141
Benign14
Conflicting3
5
Pathogenic
5
Likely Pathogenic
129
VUS
141
Likely Benign
14
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
0
0
0
5
Likely Pathogenic
4
0
0
1
5
VUS
1
114
13
1
129
Likely Benign
0
14
74
53
141
Benign
0
10
0
4
14
Conflicting
3
Total101388759297

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

View in ClinVar →

Protein Context — Lollipop Plot

COL5A1 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
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