GJA8

Summary

GJA8 (gap junction protein alpha 8, HGNC:4281) is a protein-coding gene on chromosome 1q21.2, encoding Gap junction alpha-8 protein (P48165). Structural component of eye lens gap junctions.

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.

Source: NCBI Gene 2703 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 1 multiple types (Definitive, GenCC) — +5 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 304 total — 16 pathogenic, 30 likely-pathogenic
• Phenotypes (HPO): 108
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4281
Approved symbol	GJA8
Name	gap junction protein alpha 8
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	CX50
Ensembl gene	ENSG00000121634
Ensembl biotype	protein_coding
OMIM	600897
Entrez	2703

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000369235

RefSeq mRNA: 1 — MANE Select: NM_005267 NM_005267

CCDS: CCDS30834

Canonical transcript exons

ENST00000369235 — 2 exons

Exon	Start	End
ENSE00001449272	147907945	147909269
ENSE00003902687	147902795	147902861

Expression profiles

Bgee: expression breadth broad, 17 present calls, max score 85.67.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0560 / max 40.8275, expressed in 12 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4988	0.0406	9
4989	0.0092	3
201686	0.0062	3

Top tissues by expression

251 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	85.67	silver quality
frontal pole	UBERON:0002795	83.24	silver quality
paraflocculus	UBERON:0005351	82.03	gold quality
middle frontal gyrus	UBERON:0002702	80.07	gold quality
sperm	CL:0000019	78.21	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	77.87	gold quality
endometrium epithelium	UBERON:0004811	77.41	gold quality
cerebellar vermis	UBERON:0004720	77.37	gold quality
cardia of stomach	UBERON:0001162	76.61	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	76.28	gold quality
trachea	UBERON:0003126	75.03	gold quality
quadriceps femoris	UBERON:0001377	74.85	gold quality
pons	UBERON:0000988	74.65	gold quality
body of tongue	UBERON:0011876	74.55	gold quality
vastus lateralis	UBERON:0001379	74.28	gold quality
dorsal plus ventral thalamus	UBERON:0001897	74.17	gold quality
subthalamic nucleus	UBERON:0001906	74.13	gold quality
saphenous vein	UBERON:0007318	74.11	gold quality
gingival epithelium	UBERON:0001949	74.10	gold quality
lateral globus pallidus	UBERON:0002476	73.86	gold quality
myocardium	UBERON:0002349	73.75	gold quality
substantia nigra pars reticulata	UBERON:0001966	73.64	gold quality
vena cava	UBERON:0004087	73.60	gold quality
tongue	UBERON:0001723	73.58	gold quality
pharyngeal mucosa	UBERON:0000355	73.23	gold quality
pylorus	UBERON:0001166	73.06	gold quality
superior surface of tongue	UBERON:0007371	72.94	gold quality
inferior vagus X ganglion	UBERON:0005363	72.91	gold quality
ventral tegmental area	UBERON:0002691	72.80	gold quality
nipple	UBERON:0002030	72.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.13

Regulation

Is transcription factor: no

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• the C-terminus of human Cx50 is involved in pHi sensitivity, but has little influence over single-channel conductance, voltage dependence, or gating kinetics. (PMID:11944087)
• Study confirmed that GJA8 plays a vital role in the maintenance of human lens transparency and its mutation could be the genetic defect causing autosomal dominant congenital cataract . (PMID:15696487)
• The pulverulent cataract described in this family is associated with a novel GJA8 mutation and has a different clinical phenotype from previously described GJA8 mutants. (PMID:16397066)
• This is the first report of mutations in GJA8 (connexin50) to be associated with autosomal dominant cataract and microcornea. (PMID:16604058)
• Resultsdemonstrated that Cx50 hemichannels gating control can be cooperated by CaM and Ca2+. (PMID:16740131)
• Matched case-control and family study indicate that Cx50 may play a role in the genetic susceptibility to schizophrenia. (PMID:17412882)
• a cross-talk between CFTR and a variety of gap junction channels. Cytoskeletal scaffolding proteins and/or other intermediate cytoplasmic proteins are likely to play a role in CFTR-connexins interaction. (PMID:17546509)
• Mutation of the gap junction protein alpha 8 (GJA8) gene causes autosomal recessive cataract. (PMID:17601931)
• Five novel mutations in CRYAA, CRYGD, and GJA8 genes were detected in congenital cataract in association with microcornea (PMID:17724170)
• Pulverulent cataracts present in members of a family are associated with a novel mutation, Cx50D47N, that acts as a loss-of-function mutation. The consequent decrease in lens intercellular communication may contribute to cataract formation. (PMID:18006672)
• A novel disease-causing mutation (D47Y) of GJA8 gene in a Chinese family with ADCC is reported. (PMID:18247306)
• This is a novel mutation identified in the first transmembrane domain (M1) of GJA8. (PMID:18334946)
• A novel GJA8 gene mutation was found to be associated with hereditary cataract in a Chinese congenital cataract family. (PMID:18334966)
• The ins776G mutation most likely causes a recessive triangular cataract with variable expressivity of a weak phenotype in heterozygotes. (PMID:18483562)
• A p.P88Q mutation in GJA8 associated with Y-sutural cataract in a family of Indian origin, is reported. (PMID:18587493)
• The biochemical results indirectly suggest a potential novel mechanism by which connexin mutants could lead to cataracts. (PMID:19684000)
• Direct sequencing of the PCR product produced from lens cDNA showed that the proband was heterozygous for a G>T transition at position 741 of the GJA8 gene, encoding the exchange of methionine for isoleucine at position 247 of CX50. (PMID:19756179)
• A novel mutation in GJA8 was detected in a Chinese family with autosomal dominant congenital nuclear cataract, providing clear evidence of a relationship between the genotype and the corresponding cataract phenotype. (PMID:20019893)
• the gap junction protein-alpha 8 polymorphisms may have a role in age-related cataracts (PMID:20582632)
• This study has identified a novel missense mutation located in the carboxyl terminus of GJA8 (S258F) associated with autosomal dominant nuclear cataract. (PMID:20597646)
• This report is the first to relate p.R198W mutation in GJA8 with congenital cataract-microcornea syndrome. (PMID:20806042)
• The D47N mutation of Cx50 causes the hereditary nuclear cataract in this family in an autosomal dominant mode of inheritance with incomplete penetrance. (PMID:21174522)
• The G46V and W45S mutations of connexin 50 are in adjacent amino acids. W45S inhibits gap junctional channel function while G46V reduces cell viability by forming open hemichannels. (PMID:21228318)
• Autophagy is involoved in the degradation of CX43 and CX50. (PMID:21378309)
• The genetic mutation in GJA3, GJA8, and LIM2 may slightly contribute to the development of age-related cataracts. (PMID:21386927)
• Two novel nonsynonymous variations and four reported variations in CRYAB, CRYGC, CRYGD, and GJA8, were observed. (PMID:21423869)
• Mutations in GJA8 and CRYAA were identified in three Chinese families with cataract and microcornea. (PMID:21686328)
• A missense D47N mutation in GJA8 is associated with autosomal dominant congenital cataract in a Chinese family. (PMID:21921990)
• A PDZ-binding motif and ZO-1 protein are necessary for Cx50 intercellular channel formation (PMID:21965293)
• a novel G>A mutation of GJA8 in a three-generation Chinese pedigree was associated with perinuclear opacities of the lens involving the nucleus (PMID:23555834)
• A novel connexin 50 gene (GJA8) mutation, resulting in the amino substitution p. D47H in a Chinese family with nuclear and zonular pulverulent congenital cataracts, is reported. (PMID:23592913)
• Data indicate that after inhibition of new protein synthesis with cycloheximide, CX50fs disappeared much more rapidly than CX50, suggesting increased degradation of the mutant. (PMID:23720739)
• The results provide a molecular basis for the formation of various cataract phenotypes in human patients with Cx50 mutations. (PMID:24005045)
• Exome sequencing in developmental eye disease leads to identification of causal variants in GJA8, CRYGC, PAX6 and CYP1B1. (PMID:24281366)
• Tthe molecular consequences of the p.P88T mutation in GJA8 include changes in connexin 50 protein localization patterns. (PMID:24535056)
• structural bases of the varied functional consequences of Cx50 missense mutations, were determined. (PMID:25003127)
• A recurrent missense mutation c.773C>T (p.S258F) in exon 2 of the gap junction protein alpha 8 gene (GJA8) was identified in the proband with nuclear cataract. (PMID:25301372)
• We have used trio-based exome sequencing to uncover a recurrent missense mutation in CRYGD and two novel missense mutations in GJA8 associated with autosomal dominant cataract in three nuclear families. (PMID:25403472)
• GJA8 mutation (p.V44A) is associated with autosomal dominant congenital cataract. (PMID:25517998)
• This study identified three mutations in three Chinese families with hereditary cataracts. Of the three mutations, two were novel (c.125 A > C in GJA3 and c.268 C > T in GJA3), one was previously reported (c.218 C > T in GJA8). (PMID:25549162)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gja8b	ENSDARG00000015076
danio_rerio	gja8a	ENSDARG00000069451
mus_musculus	Gja8	ENSMUSG00000049908
rattus_norvegicus	Gja8	ENSRNOG00000046703

Paralogs (20): GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), GJC3 (ENSG00000176402), GJD4 (ENSG00000177291), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB3 (ENSG00000188910), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction alpha-8 protein — P48165 (reviewed: P48165)

Alternative names: Connexin-50, Lens fiber protein MP70

All UniProt accessions (2): P48165, X5D7G1

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of eye lens gap junctions. Gap junctions are dodecameric channels that connect the cytoplasm of adjoining cells. They are formed by the docking of two hexameric hemichannels, one from each cell membrane. Small molecules and ions diffuse from one cell to a neighboring cell via the central pore.

Subunit / interactions. A hemichannel or connexon is composed of a hexamer of connexins. A functional gap junction is formed by the apposition of two hemichannels. Forms heteromeric channels with GJA3.

Subcellular location. Cell membrane. Cell junction. Gap junction.

Tissue specificity. Eye lens.

Disease relevance. Cataract 1, multiple types (CTRCT1) [MIM:116200] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT1 includes congenital, zonular pulverulent, nuclear progressive, nuclear pulverulent, nuclear total, total, and posterior subcapsular types of cataract. Zonular or lamellar cataracts are opacities, broad or narrow, usually consisting of powdery white dots affecting only certain layers or zones between the cortex and nucleus of an otherwise clear lens. The opacity may be so dense as to render the entire central region of the lens completely opaque, or so translucent that vision is hardly if at all impeded. Zonular cataracts generally do not involve the embryonic nucleus, though sometimes they involve the fetal nucleus. Usually sharply separated from a clear cortex outside them, they may have projections from their outer edges known as riders or spokes. In some cases cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the connexin family. Alpha-type (group II) subfamily.

RefSeq proteins (1): NP_005258* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002266	Connexin50_C	Domain
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029, PF03509

UniProt features (41 total): sequence variant 19, topological domain 5, transmembrane region 4, compositionally biased region 4, disulfide bond 3, region of interest 2, initiator methionine 1, chain 1, intramembrane region 1, sequence conflict 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P48165-F1	65.85	0.32

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 54–194, 61–188, 65–183

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 287 (showing top): REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_CELL_SIGNALING, REACTOME_GAP_JUNCTION_ASSEMBLY, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOCC_CELL_CELL_JUNCTION, GOBP_TRANSMEMBRANE_TRANSPORT, GOBP_LENS_DEVELOPMENT_IN_CAMERA_TYPE_EYE, SHEN_SMARCA2_TARGETS_DN, chr1q21, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_ANCHORING_JUNCTION, GOCC_PLASMA_MEMBRANE_PROTEIN_COMPLEX, GOCC_GAP_JUNCTION, GOMF_PASSIVE_TRANSMEMBRANE_TRANSPORTER_ACTIVITY, GOMF_WIDE_PORE_CHANNEL_ACTIVITY

GO Biological Process (6): lens development in camera-type eye (GO:0002088), cell-cell signaling (GO:0007267), gap junction-mediated intercellular transport (GO:1990349), cell communication (GO:0007154), camera-type eye development (GO:0043010), transmembrane transport (GO:0055085)

GO Molecular Function (2): gap junction channel activity (GO:0005243), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), connexin complex (GO:0005922), gap junction (GO:0005921), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gap junction trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
camera-type eye development	1
anatomical structure development	1
cell communication	1
signaling	1
intercellular transport	1
eye development	1
transport	1
wide pore channel activity	1
binding	1
membrane	1
cell periphery	1
gap junction	1
plasma membrane protein complex	1
cell-cell junction	1
cellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

628 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJA8	MIP	P30301	957
GJA8	GJA3	Q9Y6H8	955
GJA8	BFSP2	Q13515	946
GJA8	CRYGD	P07320	937
GJA8	CRYBB2	P43320	937
GJA8	CRYGS	P22914	923
GJA8	CRYBB1	P53674	922
GJA8	LIM2	P55344	860
GJA8	PITX3	O75364	855
GJA8	CRYAA	P02489	827
GJA8	CRYBA1	P05813	812
GJA8	BFSP1	Q12934	812
GJA8	CRYGC	P07315	797
GJA8	TJP1	Q07157	792
GJA8	CRYBB3	P26998	784

IntAct

362 interactions, top by confidence:

A	B	Type	Score
YIF1A	GJA8	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC39A7	GJA8	psi-mi:“MI:0915”(physical association)	0.560
RUSF1	GJA8	psi-mi:“MI:0915”(physical association)	0.560
YIPF6	GJA8	psi-mi:“MI:0915”(physical association)	0.560
LEPROTL1	GJA8	psi-mi:“MI:0915”(physical association)	0.560
PLN	GJA8	psi-mi:“MI:0915”(physical association)	0.560
LHFPL5	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMBIM6	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SCARF1	GJA8	psi-mi:“MI:0915”(physical association)	0.560
PRAF2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
APOL3	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMEM86B	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC30A3	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC66A2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMEM100	GJA8	psi-mi:“MI:0915”(physical association)	0.560
GIMAP5	GJA8	psi-mi:“MI:0915”(physical association)	0.560
CD53	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMEM243	GJA8	psi-mi:“MI:0915”(physical association)	0.560
PNLIPRP1	GJA8	psi-mi:“MI:0915”(physical association)	0.560
TMEM107	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SEC23A	GJA8	psi-mi:“MI:0915”(physical association)	0.560
ORMDL2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
MFSD11	GJA8	psi-mi:“MI:0915”(physical association)	0.560
CXCL16	GJA8	psi-mi:“MI:0915”(physical association)	0.560
SLC39A2	GJA8	psi-mi:“MI:0915”(physical association)	0.560
GPR61	GJA8	psi-mi:“MI:0915”(physical association)	0.560
APOD	GJA8	psi-mi:“MI:0915”(physical association)	0.560
CLDN19	GJA8	psi-mi:“MI:0915”(physical association)	0.560
S1PR5	GJA8	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (159): GJA8 (Proximity Label-MS), GJA8 (Affinity Capture-Western), GJA8 (Reconstituted Complex), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid), GJA8 (Two-hybrid)

ESM2 similar proteins: A0A8I5ZN27, A6X8Z5, E1AZ71, F1N8V3, O35668, O54963, O70318, P20689, P48165, P51954, P54256, P54257, P55917, P62025, P70278, Q01538, Q13029, Q13127, Q14028, Q16799, Q28139, Q28181, Q2M1Z3, Q3SYS4, Q3UH66, Q4KMM3, Q4V8B0, Q5DW34, Q5IS59, Q5TCY1, Q62100, Q63HN8, Q640N3, Q64548, Q6IR42, Q6PCN3, Q7Z6I6, Q811Q2, Q8BYM7, Q8C5W0

Diamond homologs: A2VE67, A4GG66, A4GVD1, A4IFL1, A6XKM2, O18968, O54851, O57474, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08050, P08983, P14154, P16863, P16864, P17302, P18246, P18860, P18861, P21994, P23242, P25305, P28228, P28229, P28230, P28231, P28232, P28233, P28234, P28235, P28236, P29033, P29414, P29415, P33725

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
R-HSA-425366	5	15.6×	1e-03
SLC-mediated transmembrane transport	8	8.2×	1e-03
Transport of small molecules	11	4.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

304 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	30
Uncertain significance	170
Likely benign	33
Benign	13

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1484682	NM_005267.5(GJA8):c.143A>G (p.Glu48Gly)	Pathogenic
153061	GRCh38/hg38 1q21.1-21.2(chr1:143515074-149076087)x1	Pathogenic
1704073	NM_005267.5(GJA8):c.130G>A (p.Val44Met)	Pathogenic
2030122	NM_005267.5(GJA8):c.94T>G (p.Phe32Val)	Pathogenic
2103996	NM_005267.5(GJA8):c.137G>A (p.Gly46Glu)	Pathogenic
2425333	NC_000001.10:g.(?146714354)(147381384_?)del	Pathogenic
3236402	NM_005267.5(GJA8):c.196T>G (p.Tyr66Asp)	Pathogenic
4768435	NM_005267.5(GJA8):c.136G>C (p.Gly46Arg)	Pathogenic
574353	NM_005267.5(GJA8):c.153C>G (p.Asp51Glu)	Pathogenic
655801	NM_005267.5(GJA8):c.196T>C (p.Tyr66His)	Pathogenic
833373	NC_000001.10:g.(?147380063)(147381404_?)del	Pathogenic
842078	NM_005267.5(GJA8):c.176C>T (p.Pro59Leu)	Pathogenic
850845	NM_005267.5(GJA8):c.197A>C (p.Tyr66Ser)	Pathogenic
861618	NM_005267.5(GJA8):c.602A>G (p.Glu201Gly)	Pathogenic
8727	NM_005267.5(GJA8):c.139G>A (p.Asp47Asn)	Pathogenic
938578	NM_005267.5(GJA8):c.197A>G (p.Tyr66Cys)	Pathogenic
1328353	NM_005267.5(GJA8):c.227G>A (p.Arg76His)	Likely pathogenic
154954	GRCh38/hg38 1q21.2(chr1:147773472-148355961)x3	Likely pathogenic
1684591	NM_005267.5(GJA8):c.263C>A (p.Pro88Gln)	Likely pathogenic
1710337	NM_005267.5(GJA8):c.175C>T (p.Pro59Ser)	Likely pathogenic
217331	NM_005267.5(GJA8):c.89dup (p.Ile31fs)	Likely pathogenic
2444115	NM_005267.5(GJA8):c.116C>A (p.Thr39Lys)	Likely pathogenic
2574629	NM_005267.5(GJA8):c.101T>C (p.Ile34Thr)	Likely pathogenic
2672348	NM_005267.5(GJA8):c.208T>G (p.Phe70Val)	Likely pathogenic
2782760	NM_005267.5(GJA8):c.263C>G (p.Pro88Arg)	Likely pathogenic
2845763	NM_005267.5(GJA8):c.64G>T (p.Gly22Cys)	Likely pathogenic
3253656	NM_005267.5(GJA8):c.235G>C (p.Val79Leu)	Likely pathogenic
3253662	NM_005267.5(GJA8):c.430_444del (p.Glu144_Leu148del)	Likely pathogenic
3253668	NM_005267.5(GJA8):c.607dup (p.Thr203fs)	Likely pathogenic
3253670	NM_005267.5(GJA8):c.766dup (p.Ala256fs)	Likely pathogenic

SpliceAI

91 predictions. Top by Δscore:

Variant	Effect	Δscore
1:147908668:GGCCT:G	donor_gain	0.4700
1:147908669:GCCTG:G	donor_gain	0.4700
1:147908670:C:T	donor_gain	0.4500
1:147908617:TGATG:T	donor_gain	0.4300
1:147908618:GATGG:G	donor_gain	0.4300
1:147908619:ATGGA:A	donor_gain	0.4300
1:147908690:G:GT	donor_gain	0.4300
1:147908690:G:T	donor_gain	0.4300
1:147908766:G:GT	donor_gain	0.4300
1:147908926:CTCAG:C	donor_loss	0.4300
1:147908927:TCAGG:T	donor_loss	0.4300
1:147908928:CAGGT:C	donor_loss	0.4300
1:147908929:AGGT:A	donor_loss	0.4300
1:147908930:GG:G	donor_loss	0.4300
1:147908931:G:C	donor_loss	0.4300
1:147908932:T:A	donor_loss	0.4300
1:147909009:G:GT	donor_gain	0.4200
1:147908748:GGC:G	donor_gain	0.4100
1:147908925:GCTCA:G	donor_loss	0.3900
1:147908875:G:GT	donor_gain	0.3700
1:147908656:C:A	donor_gain	0.3600
1:147909040:A:T	donor_gain	0.3600
1:147909047:G:GA	donor_gain	0.3600
1:147909174:G:C	acceptor_gain	0.3600
1:147909046:T:TA	donor_gain	0.3500
1:147909066:A:T	donor_gain	0.3500
1:147908934:G:GC	donor_loss	0.3400
1:147909127:TGTCA:T	donor_gain	0.3400
1:147908528:G:GA	donor_gain	0.3300
1:147909048:GCC:G	donor_gain	0.3300

AlphaMissense

2821 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:147908115:T:A	C54S	1.000
1:147908116:G:C	C54S	1.000
1:147908088:T:A	W45R	0.999
1:147908088:T:C	W45R	0.999
1:147908090:G:C	W45C	0.999
1:147908090:G:T	W45C	0.999
1:147908115:T:C	C54R	0.999
1:147908116:G:A	C54Y	0.999
1:147908116:G:T	C54F	0.999
1:147908117:C:G	C54W	0.999
1:147908120:C:A	N55K	0.999
1:147908120:C:G	N55K	0.999
1:147908136:T:A	C61S	0.999
1:147908137:G:A	C61Y	0.999
1:147908137:G:C	C61S	0.999
1:147908148:T:A	C65S	0.999
1:147908148:T:C	C65R	0.999
1:147908149:G:A	C65Y	0.999
1:147908149:G:C	C65S	0.999
1:147908150:C:G	C65W	0.999
1:147908163:T:C	F70L	0.999
1:147908165:T:A	F70L	0.999
1:147908165:T:G	F70L	0.999
1:147908535:T:A	C194S	0.999
1:147908535:T:C	C194R	0.999
1:147908536:G:A	C194Y	0.999
1:147908536:G:C	C194S	0.999
1:147908537:C:G	C194W	0.999
1:147908538:T:C	F195L	0.999
1:147908540:C:A	F195L	0.999

dbSNP variants (sampled 300 via entrez): RS1000211598 (1:147913994 A>G), RS1000758400 (1:147907980 A>G), RS1001010280 (1:147901636 C>T), RS1001342500 (1:147901980 G>A), RS1001814903 (1:147902210 C>T), RS1001892240 (1:147907347 T>C), RS1002503433 (1:147913628 A>G), RS1003096196 (1:147911900 G>A,C), RS1003541721 (1:147912158 T>C,G), RS1004477827 (1:147914904 A>G), RS1004698720 (1:147901796 A>G), RS1004770892 (1:147901949 G>A), RS1005483091 (1:147913352 C>G,T), RS1006485012 (1:147911552 G>A), RS1006613290 (1:147912270 A>G)

Disease associations

OMIM: gene MIM:600897 | disease phenotypes: MIM:116200, MIM:612474, MIM:107250

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 1 multiple types	Definitive	Autosomal dominant
cataract - microcornea syndrome	Supportive	Autosomal dominant
pulverulent cataract	Supportive	Autosomal dominant
early-onset sutural cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (9): cataract 1 multiple types (MONDO:0007285), microphthalmia (MONDO:0021129), chromosome 1q21.1 deletion syndrome (MONDO:0012914), anterior segment dysgenesis (MONDO:0019503), cataract - microcornea syndrome (MONDO:0015300), pulverulent cataract (MONDO:0011430), early-onset sutural cataract (MONDO:0020372), early-onset nuclear cataract (MONDO:0020376), total early-onset cataract (MONDO:0021548)

Orphanet (3): Cataract-microcornea syndrome (Orphanet:1377), 1q21.1 microdeletion syndrome (Orphanet:250989), Anterior segment developmental anomaly (Orphanet:88632)

HPO phenotypes

108 total (30 of 108 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000269	Prominent occiput
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares
HP:0000470	Short neck
HP:0000482	Microcornea
HP:0000486	Strabismus

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST010548_1	Retinopathy x type 2 diabetes interaction	1.000000e-11
GCST012048_2	Triglyceride levels	3.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004530	triglyceride measurement

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D008850	Microphthalmos	C11.250.566; C16.131.384.666
C538287	Cataract microcornea syndrome (supp.)
C563333	Cataract, Age-Related Nuclear (supp.)
C565133	Cataract, Coppock-Like (supp.)
C566158	Cataract, Zonular Pulverulent 1 (supp.)
C567291	Chromosome 1q21.1 Deletion Syndrome, 1.35-Mb (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Connexins and Pannexins

CTD chemical–gene interactions

12 total (human), top 12 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	2
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Air Pollutants	increases abundance, increases expression	1
Arsenic	affects methylation	1
Catechin	affects cotreatment, increases expression	1
Silicon Dioxide	affects expression	1
Tetracycline	decreases expression	1
Aflatoxin B1	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	increases expression, increases abundance	1

Clinical trials (associated diseases)

7 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT03748732	Not specified	UNKNOWN	Extensive Circumferential Partial Thickness Sclerectomy in Nanophthalmic Eyes
NCT04759560	Not specified	UNKNOWN	Biometric Characteristics of the Eye With Microcornea/Microphthalmia and Congenital Cataract Before And After Cataract Extraction
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children
NCT05641103	Not specified	COMPLETED	PREDIGA 2: Spanish Acronym of Educational and Diagnostic Project for Gaucher and ASMD