ITGAL

Chr 16AR

integrin subunit alpha L

Also known as: CD11A, EV6, HNA-5, LFA-1, LFA1A

NCBI Gene: 3683 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

ITGAL encodes the integrin alpha L chain. Integrins are heterodimeric integral membrane proteins composed of an alpha chain and a beta chain. This I-domain containing alpha integrin combines with the beta 2 chain (ITGB2) to form the integrin lymphocyte function-associated antigen-1 (LFA-1), which is expressed on all leukocytes. LFA-1 plays a central role in leukocyte intercellular adhesion through interactions with its ligands, ICAMs 1-3 (intercellular adhesion molecules 1 through 3), and also functions in lymphocyte costimulatory signaling. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 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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ClinVar Variants

88 VUS of 126 total submissions

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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 OE?0.27 (0.19–0.41)

0≤0.351.4

Missense OE?0.76 (0.71–0.82)

0≤0.61.4

Synonymous OE?0.94

0≤1.21.6

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

This gene — mechanism propensity

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.

ClinVar Variant Classifications

126 submitted variants in ClinVar

ClinVar

Classification Summary

VUS88

Likely Benign13

Benign6

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	88	0	0	88
Likely Benign	11	0	2	13
Benign	1	2	3	6
Total	100	2	5	107

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

View in ClinVar →

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