ITGAV

Chr 2AR

integrin subunit alpha V

Also known as: CD51, IDNDC, MSK8, VNRA, VTNR

NCBI Gene: 3685 ENSG00000138448 UniProt: P06756 OMIM: 193210

The alpha-V integrin subunit forms heterodimeric cell surface receptors that bind multiple extracellular matrix proteins and growth factors, mediating cell adhesion, signaling, and TGF-beta activation. Biallelic mutations cause autosomal recessive immune dysregulation with neurodevelopmental defects and colitis. This gene is highly intolerant to loss-of-function variants in the general population, indicating that heterozygous loss alone is likely insufficient to cause disease.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The product of this gene belongs to the integrin alpha chain family. Integrins are heterodimeric integral membrane proteins composed of an alpha subunit and a beta subunit that function in cell surface adhesion and signaling. The encoded preproprotein is proteolytically processed to generate light and heavy chains that comprise the alpha V subunit. This subunit associates with beta 1, beta 3, beta 5, beta 6 and beta 8 subunits. The heterodimer consisting of alpha V and beta 3 subunits is also known as the vitronectin receptor. This integrin may regulate angiogenesis and cancer progression. Alternative splicing results in multiple transcript variants. Note that the integrin alpha 5 and integrin alpha V subunits are encoded by distinct genes. [provided by RefSeq, Oct 2015]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.441 OMIM phenotype

Clinical Summary— ITGAV

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 140 VUS of 205 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.44LOEUF

pLI 0.000

Z-score 5.13

OE 0.30 (0.21–0.44)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.89Z-score

OE missense 0.89 (0.83–0.96)

505 obs / 564.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.21–0.44)

0≤0.351.4

Missense OE?0.89 (0.83–0.96)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 19 / 62.9Missense obs/exp: 505 / 564.3Syn Z: 0.44

This gene — mechanism propensity

0.6939th %ile

GOF

0.6735th %ile

LOF

0.3164th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction above median

LOF67% of P/LP variants are LoF · LOEUF 0.44

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.

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

205 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS140

Likely Benign14

Benign5

Pathogenic

Likely Pathogenic

140

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	2	0	0	3
Likely Pathogenic	3	0	0	0	3
VUS	0	140	0	0	140
Likely Benign	0	4	5	5	14
Benign	0	0	1	4	5
Total	4	146	6	9	165

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

View in ClinVar →

26 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap ITGAV — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →