ITGAL

Chr 16

integrin subunit alpha L

ENSG00000005844 UniProt: P20701 OMIM: 153370

The integrin alpha L chain combines with integrin beta 2 to form LFA-1, which mediates leukocyte adhesion, migration, and immune cell interactions through binding to intercellular adhesion molecules. Mutations cause leukocyte adhesion deficiency type 1, an autosomal recessive primary immunodeficiency characterized by recurrent severe bacterial infections, delayed wound healing, and absent pus formation due to impaired neutrophil migration. The gene is highly constrained against loss-of-function variants, reflecting its essential role in immune function.

OMIM ResearchSummary from RefSeq, UniProt

MultiplemechanismLOEUF 0.411 OMIM phenotype

Clinical Summary— ITGAL

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint

0.41LOEUF

pLI 0.004

Z-score 5.29

OE 0.27 (0.19–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint

2.18Z-score

OE missense 0.76 (0.71–0.82)

521 obs / 681.3 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios

LoF OE0.27 (0.19–0.41)

0≤0.351.4

Missense OE0.76 (0.71–0.82)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 17 / 62.0Missense obs/exp: 521 / 681.3Syn Z: 0.79

0.6646th %ile

GOF

0.6833th %ile

LOF

0.2776th %ile

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

GOFprediction above median

DNprediction above median

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.