GJA8

Chr 1AD

gap junction protein alpha 8

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

NCBI Gene: 2703ENSG00000121634UniProt: P48165

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]

Primary Disease Associations & Inheritance

Cataract 1, multiple typesMIM #116200
AD
593
ClinVar variants
337
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GJA8
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
337 Pathogenic / Likely Pathogenic· 179 VUS of 593 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.00LOEUF
pLI 0.002
Z-score 1.58
OE 0.51 (0.28–1.00)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.20Z-score
OE missense 1.03 (0.94–1.14)
270 obs / 261.0 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.51 (0.28–1.00)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.03 (0.94–1.14)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.18
0≤1.21.6
LoF obs/exp: 6 / 11.9Missense obs/exp: 270 / 261.0Syn Z: -1.57

ClinVar Variant Classifications

593 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic260
Likely Pathogenic77
VUS179
Likely Benign38
Benign13
Conflicting26
260
Pathogenic
77
Likely Pathogenic
179
VUS
38
Likely Benign
13
Benign
26
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
13
247
0
260
Likely Pathogenic
5
33
39
0
77
VUS
4
151
21
3
179
Likely Benign
0
12
1
25
38
Benign
0
3
7
3
13
Conflicting
—26
Total921231531593

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

View in ClinVar →

Protein Context — Lollipop Plot

GJA8 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

GJA8-related cataract

definitive
ADUndeterminedAltered Gene Product Structure
Dev. DisordersEye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Cataract 1, multiple types

MIM #116200

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GJA8
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GJA8-associated developmental eye disorders: a new multicentre study highlights mutational hotspots and genotype-phenotype correlations.
Merepa SS et al.·Eur J Hum Genet
2025
Different GJA8 missense variants reveal distinct pathogenic mechanisms in congenital cataract.
Li Z et al.·Life Sci
2025Functional
Modeling ocular lens disease in Xenopus.
Viet J et al.·Dev Dyn
2020Functional
Pathogenic genetic variants identified in Australian families with paediatric cataract.
Jones JL et al.·BMJ Open Ophthalmol
2022
Identification and functional analysis of two GJA8 variants in Chinese families with eye anomalies.
Zhou L et al.·Mol Genet Genomics
2022Functional
Mutation screening and genotype phenotype correlation of α-crystallin, γ-crystallin and GJA8 gene in congenital cataract.
Kumar M et al.·Mol Vis
2011
Association of variants in GJA8 with familial acorea-microphthalmia-cataract syndrome.
Dong S et al.·Eur J Hum Genet
2024
Gap junctions or hemichannel-dependent and independent roles of connexins in cataractogenesis and lens development.
Jiang JX·Curr Mol Med
2010Review
Microphthalmia and anterior segment dysgenesis due to a double gene variant in GJA8 and CRYGC.
Zhou L et al.·Eur J Ophthalmol
2024Case report
Clinical and genetic findings in patients with congenital cataract and heart diseases.
Li X et al.·Orphanet J Rare Dis
2021Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools