FBLN5

Chr 14ADAR

fibulin 5

Also known as: ADCL2, ARCL1A, ARMD3, CMT1H, DANCE, EVEC, FIBL-5, HNARMD

NCBI Gene: 10516 ENSG00000140092 UniProt: Q9UBX5 OMIM: 604580

This protein is essential for elastic fiber formation and promotes the assembly of elastin polymer while stabilizing elastic fibers in skin, lung, and vasculature. Mutations cause cutis laxa (both autosomal dominant and recessive forms), Charcot-Marie-Tooth disease type 1H, and age-related macular degeneration, affecting connective tissue, peripheral nerves, and retina. The gene is highly constrained against loss-of-function variants (pLI = 1.0, LOEUF = 0.17), indicating that complete loss of protein function is typically not tolerated.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a secreted, extracellular matrix protein containing an Arg-Gly-Asp (RGD) motif and calcium-binding EGF-like domains. It promotes adhesion of endothelial cells through interaction of integrins and the RGD motif. It is prominently expressed in developing arteries but less so in adult vessels. However, its expression is reinduced in balloon-injured vessels and atherosclerotic lesions, notably in intimal vascular smooth muscle cells and endothelial cells. Therefore, the protein encoded by this gene may play a role in vascular development and remodeling. Defects in this gene are a cause of autosomal dominant cutis laxa, autosomal recessive cutis laxa type I (CL type I), and age-related macular degeneration type 3 (ARMD3). [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.174 OMIM phenotypes

Clinical Summary— FBLN5

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Gene-Disease Validity (ClinGen)

demyelinating hereditary motor and sensory neuropathy · 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

8 unique Pathogenic / Likely Pathogenic· 330 VUS of 689 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — FBLN5

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?

0.17LOEUF

pLI 1.000

Z-score 4.70

OE 0.04 (0.01–0.17)

Highly constrained

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

Missense Constraint?

1.56Z-score

OE missense 0.73 (0.65–0.83)

199 obs / 271.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.04 (0.01–0.17)

0≤0.351.4

Missense OE?0.73 (0.65–0.83)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 1 / 27.6Missense obs/exp: 199 / 271.1Syn Z: 0.42

ClinVar Variant Classifications

689 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5

Likely Pathogenic3

VUS330

Likely Benign272

Benign43

Conflicting25

Pathogenic

Likely Pathogenic

330

VUS

272

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	1	1	0	5
Likely Pathogenic	2	1	0	0	3
VUS	15	279	31	5	330
Likely Benign	0	4	148	120	272
Benign	0	2	39	2	43
Conflicting	—				25
Total	20	287	219	127	678

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap FBLN5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →