GJA8

Chr 1AD

gap junction protein alpha 8

Also known as: CAE, CAE1, CTRCT1, CX50, CZP1, MP70

NCBI Gene: 2703 ENSG00000121634 UniProt: P48165 OMIM: 600897

This gene encodes connexin 50, a transmembrane protein that forms gap junction channels connecting lens fiber cells and is essential for lens growth and maturation. Mutations cause autosomal dominant cataracts of multiple types, including zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. The gene shows minimal constraint against loss-of-function variants (pLI 0.002), suggesting tolerance to complete protein loss.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a transmembrane connexin protein that is necessary for lens growth and maturation of lens fiber cells. The encoded protein is a component of gap junction channels and functions in a calcium and pH-dependent manner. Mutations in this gene have been associated with zonular pulverulent cataracts, nuclear progressive cataracts, and cataract-microcornea syndrome. [provided by RefSeq, Dec 2009]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.001 OMIM phenotype

Clinical Summary— GJA8

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Population Constraint (gnomAD)

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

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ClinVar Variants

54 unique Pathogenic / Likely Pathogenic· 171 VUS of 302 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJA8

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.00LOEUF

pLI 0.002

Z-score 1.58

OE 0.51 (0.28–1.00)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.20Z-score

OE missense 1.03 (0.94–1.14)

270 obs / 261.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.51 (0.28–1.00)

0≤0.351.4

Missense OE?1.03 (0.94–1.14)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 6 / 11.9Missense obs/exp: 270 / 261.0Syn Z: -1.57

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGJA8-related cataractOTHERAD

This gene — mechanism propensity

0.79top 25%

GOF

0.85top 5%

LOF

0.2483th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 87% of P/LP are missense

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.

Literature Evidence

DNMD simulation revealed that the introduction of the deletion destabilized the Cx50 gap junction channel, indicating the deletion as a dominant-negative mutation.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

1.PMID 26996484 ↗

ClinVar Variant Classifications

302 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic14

Likely Pathogenic40

VUS171

Likely Benign38

Benign13

Conflicting26

Pathogenic

Likely Pathogenic

171

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	13	1	0	14
Likely Pathogenic	5	34	1	0	40
VUS	9	156	3	3	171
Likely Benign	0	12	1	25	38
Benign	0	3	7	3	13
Conflicting	—				26
Total	14	218	13	31	302

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

View in ClinVar →

287 pathogenic / likely-pathogenic (of 302) ClinVar copy-number / structural variants overlap GJA8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →