ITGA8

Chr 10AR

integrin subunit alpha 8

NCBI Gene: 8516 ENSG00000077943 UniProt: P53708 OMIM: 604063

The integrin alpha-8 subunit forms heterodimeric integrin alpha8beta1 receptors that regulate recruitment of mesenchymal cells into epithelial structures during kidney development and mediate neurite outgrowth of sensory and motor neurons. Mutations cause autosomal recessive renal hypodysplasia/aplasia, a congenital kidney malformation disorder. The gene shows low constraint to loss-of-function variation (pLI near zero), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Integrins are heterodimeric transmembrane receptor proteins that mediate numerous cellular processes including cell adhesion, cytoskeletal rearrangement, and activation of cell signaling pathways. Integrins are composed of alpha and beta subunits. This gene encodes the alpha 8 subunit of the heterodimeric integrin alpha8beta1 protein. The encoded protein is a single-pass type 1 membrane protein that contains multiple FG-GAP repeats. This repeat is predicted to fold into a beta propeller structure. This gene regulates the recruitment of mesenchymal cells into epithelial structures, mediates cell-cell interactions, and regulates neurite outgrowth of sensory and motor neurons. The integrin alpha8beta1 protein thus plays an important role in wound-healing and organogenesis. Mutations in this gene have been associated with renal hypodysplasia/aplasia-1 (RHDA1) and with several animal models of chronic kidney disease. Alternate splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Apr 2014]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Renal hypodysplasia/aplasia 1MIM #191830

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Renal hypodysplasia/aplasia 1; no ClinGen or GenCC tier

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.66

LOEUF

LOF

Mechanism· G2P

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.66LOEUF

pLI 0.000

Z-score 3.74

OE 0.49 (0.37–0.66)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.27Z-score

OE missense 1.03 (0.96–1.10)

593 obs / 574.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.49 (0.37–0.66)

0≤0.351.4

Missense OE?1.03 (0.96–1.10)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 31 / 63.0Missense obs/exp: 593 / 574.7Syn Z: -1.00

Background carrier burden — how many people carry a rare variant somewhere in ITGA8?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 34

1,521 rare PASS variants

Rare truncating (LoF)

1 in 1,300

184 rare PASS variants

Rare synonymous (reference)

1 in 56

538 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for ITGA8. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 1,700
South Asian	~43k	1 in 34	1 in 590
Remaining (unassigned)	~30k	1 in 34	1 in 2,000
European (Finnish)	~27k	1 in 160	1 in 4,300
Admixed American	~22k	1 in 39	1 in 700
African / African American	~21k	1 in 38	1 in 990
East Asian	~20k	1 in 41	1 in 760
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 3,200
Middle Eastern	~2,884	1 in 37	≈ 1 in 720

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 24 of 30 coding exons well covered in gnomAD exomes; exons 1, 5, 10, 16, 23, 28 marginal. Genomes: all 30.? see exons ↓