GJA9

Chr 1

gap junction protein alpha 9

Also known as: CX58, CX59, GJA10

NCBI Gene: 81025 ENSG00000131233 UniProt: Q9UKL4 OMIM: 611923

GJA9 encodes connexin-59, a protein that forms gap junction channels allowing direct intercellular communication through the passage of small molecules between adjacent cells. Mutations cause oculodentodigital dysplasia, an autosomal dominant disorder affecting the eyes, teeth, and digits. The gene shows minimal constraint against loss-of-function variants, suggesting tolerance to reduced protein levels.

OMIM ResearchSummary from RefSeq, UniProt

Connexins, such as GJA9, are involved in the formation of gap junctions, intercellular conduits that directly connect the cytoplasms of contacting cells. Each gap junction channel is formed by docking of 2 hemichannels, each of which contains 6 connexin subunits (Sohl et al., 2003 [PubMed 12881038]).[supplied by OMIM, Mar 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 1.56

Clinical Summary— GJA9

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.56LOEUF

pLI 0.000

Z-score -0.17

OE 1.05 (0.71–1.56)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.94Z-score

OE missense 0.84 (0.75–0.94)

222 obs / 264.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.05 (0.71–1.56)

0≤0.351.4

Missense OE?0.84 (0.75–0.94)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 17 / 16.3Missense obs/exp: 222 / 264.8Syn Z: 1.03

This gene — mechanism propensity

0.77top 25%

GOF

0.83top 5%

LOF

0.3746th %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.