GJA3

Summary

GJA3 (gap junction protein alpha 3, HGNC:4277) is a protein-coding gene on chromosome 13q12.11, encoding Gap junction alpha-3 protein (Q9Y6H8). Structural component of lens fiber gap junctions. It is a selective cancer dependency (DepMap: 18.5% of cell lines).

The protein encoded by this gene is a connexin and is a component of lens fiber gap junctions. Defects in this gene are a cause of zonular pulverulent cataract type 3 (CZP3).

Source: NCBI Gene 2700 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 14 multiple types (Definitive, GenCC) — +3 more curated relationships
• GWAS associations: 3
• Clinical variants (ClinVar): 290 total — 4 pathogenic, 27 likely-pathogenic
• Phenotypes (HPO): 2
• Cancer dependency (DepMap): dependent in 18.5% of screened cell lines
• MANE Select transcript: NM_021954

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4277
Approved symbol	GJA3
Name	gap junction protein alpha 3
Location	13q12.11
Locus type	gene with protein product
Status	Approved
Aliases	CX46
Ensembl gene	ENSG00000121743
Ensembl biotype	protein_coding
OMIM	121015
Entrez	2700

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000241125, ENST00000890229, ENST00000890230, ENST00000890231, ENST00000953338, ENST00000953339

RefSeq mRNA: 1 — MANE Select: NM_021954 NM_021954

CCDS: CCDS9289

Canonical transcript exons

ENST00000241125 — 2 exons

Exon	Start	End
ENSE00000825111	20138255	20143305
ENSE00001541425	20160890	20161052

Expression profiles

Bgee: expression breadth broad, 75 present calls, max score 90.75.

FANTOM5 (CAGE): breadth broad, TPM avg 0.4429 / max 29.6745, expressed in 222 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
136328	0.4429	222

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left ventricle myocardium	UBERON:0006566	90.75	gold quality
heart right ventricle	UBERON:0002080	89.98	gold quality
myocardium	UBERON:0002349	84.13	silver quality
tendon of biceps brachii	UBERON:0008188	81.27	silver quality
cardiac ventricle	UBERON:0002082	77.65	gold quality
heart left ventricle	UBERON:0002084	77.49	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.41	gold quality
heart	UBERON:0000948	73.53	gold quality
apex of heart	UBERON:0002098	71.53	gold quality
cardiac atrium	UBERON:0002081	68.32	gold quality
right atrium auricular region	UBERON:0006631	67.79	gold quality
secondary oocyte	CL:0000655	66.34	silver quality
right coronary artery	UBERON:0001625	66.13	gold quality
islet of Langerhans	UBERON:0000006	66.01	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	65.91	gold quality
gingival epithelium	UBERON:0001949	65.21	silver quality
gingiva	UBERON:0001828	62.97	silver quality
placenta	UBERON:0001987	62.46	gold quality
lower esophagus mucosa	UBERON:0035834	61.55	gold quality
left coronary artery	UBERON:0001626	61.40	gold quality
coronary artery	UBERON:0001621	60.62	gold quality
cerebellar vermis	UBERON:0004720	59.54	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	59.32	gold quality
parotid gland	UBERON:0001831	59.30	gold quality
germinal epithelium of ovary	UBERON:0001304	58.76	silver quality
Brodmann (1909) area 46	UBERON:0006483	57.29	gold quality
biceps brachii	UBERON:0001507	55.97	gold quality
decidua	UBERON:0002450	55.70	gold quality
esophagus squamous epithelium	UBERON:0006920	55.63	silver quality
nasal cavity epithelium	UBERON:0005384	55.52	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.84

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

143 targeting GJA3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6835-3P	99.93	70.49	2904

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 18.5% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• This finding is the first report of a mutation in the first transmembrane region of GJA3. (PMID:14627959)
• The present study has identified a fifth mutation in GJA3, rendering this connexin gene one of the most common non-crystallin genes associated with autosomal dominant cataracts in humans. (PMID:15208569)
• A novel CX46 missense mutation indetified in a large autosomal dominant congenital cataract Australian pedigree. (PMID:15286166)
• We conclude that connexin 46 mutations might account for as much as 3.3% of the hereditary congenital cataract in the Indian population. (PMID:16254549)
• This is the first report of a mutation in GJA3 causing autosomal dominant congenital cataract (ADCC) in this ethnic group. It is also the first reported cataract-causing mutation in the NH2-terminal region of the Cx46 protein. (PMID:16885921)
• The congenital “ant-egg” cataract phenotype is caused by a L11S mutation in connexin46 (Cx46) located in the signal peptide domain. (PMID:16971895)
• Particular form of Pelizaeus-Merzbacher disease involves mutation in connexin 46. (PMID:17492548)
• This is a novel mutation identified in the second transmembrane domain of the connexin 46. (PMID:17615540)
• Novel mutation (R33L) in the GJA3 associated with finely granular embryonal cataract. (PMID:17893674)
• Upregulation of connexin46 is associated with breast tumors. (PMID:20013805)
• Novel missense mutation identified in first extracellular loop of connexin 46; this expands mutation spectrum of GJA3 in association with congenital cataract. (PMID:20431721)
• Two new mutations, one in GJA3 and the other in CRYBB2, were identified co-segregating along with the respective cataract phenotype within the families that were not seen in healthy controls from India or Germany. (PMID:21031021)
• The genetic mutation in GJA3, GJA8, and LIM2 may slightly contribute to the development of age-related cataracts. (PMID:21386927)
• A novel mutation in the GJA3 (connexin46) gene is associated with autosomal dominant congenital nuclear cataract in a Chinese family. (PMID:21552498)
• Cx43 and Cx46 have novel functions in regulating each other’s expression and turnover in a reciprocal manner in addition to their conventional roles as gap junction proteins in lens cells. (PMID:21606502)
• A novel mutation in the connexin 46 (GJA3) gene associated with congenital cataract in a Chinese pedigree. (PMID:21647269)
• Cx46G2D of GJA3 is a novel mutation that was identified in a Chinese family with autosomal dominant nuclear pulverulent and posterior polar congenital cataracts. (PMID:21681855)
• A recurrent missense mutation in GJA3 is associated with autosomal dominant cataract linked to chromosome 13q in a 5-generation Caucasian American family. (PMID:21897748)
• Novel missense mutation in the second extracellular loop of the GJA3 protein was detected, causing coral-like opacities in a Chinese family. (PMID:22312188)
• A novel mutation (p.F206I) in the fourth transmembrane domain of connexin 46 is associated with autosomal dominant congenital cataract in a three-generation Chinese family. (PMID:22550389)
• These data indicate that biophysical and structural studies are converging towards a view that the N-terminal half of the Cx protein contains the principal components of the pore and gating elements. (PMID:22825713)
• the negatively charged aspartic acid residue at the third position of the N-terminus of hCx46 could be involved in the determination of the degree of metabolite cell-to-cell coupling and is essential for the voltage sensitivity of the hCx46 hemichannels. (PMID:22843197)
• A c.427G>A transition in exon 2 of GJA3 co-segregated with the cataract in the family members and was not observed in 100 control patients. (PMID:22876138)
• Coexpression of mutant with wild-type Cx50 or Cx46 gives rise to hemichannels with distinct electrophysiological properties, suggesting that the mutant connexins form heteromeric channels with wild-type connexins. (PMID:23302783)
• Suggest that Cx46 and Cx26 expression in breast cancer may improve the assessment of pathological response and refine intermediate prognostic subgroups of residual tumour classifications used after neoadjuvant chemotherapy. (PMID:23374644)
• A 1361 insertion of a cytosine mutation in the C-terminus of GJA3 is found to be associated with autosomal dominant congenital coralliform cataract. (PMID:23592915)
• these results suggest that mutation of this highly conserved residue on the cytoplasmic loop domain of Cx46 enhances its interaction with the C-terminus, resulting in a reduction of gap junction channel function (PMID:24019978)
• The crystallin beta cluster on chromosome 22, GJA3, and BFSP1 play a major role in maintaining lens transparency. (PMID:24319337)
• A novel GJA3 mutation (p.N55D) has been found in a Chinese family with congenital cataracts. (PMID:24728566)
• a GJA3 mutation in a Chinese family with congenital nuclear cataract (PMID:24772942)
• 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)
• A novel missense mutation, c.428G>A (p.G143E), in the GJA3 gene, localized to the cytoplasmic loop, was suggested to be the genetic cause of congenital nuclear cataract, which further expands the gene mutation spectrum. (PMID:25635993)
• Glioblastoma cancer stem cells (CSCs) express Cx46, while Cx43 is predominantly expressed in non-CSCs. During differentiation, Cx46 is reduced, while Cx43 is increased, and targeting Cx46 compromises CSC maintenance (PMID:25959821)
• Taken together, in Jar cells, placental connexins 43 and 46 are regulated during periods of low oxygen in opposite manners (PMID:26018820)
• The cataract related mutation N188T in human connexin46 revealed a critical role for residue N188 in the docking process of gap junction channels. (PMID:26449341)
• A novel missense GJA3 mutation that correlated with congenital cataract phenotype in a five-generation Chinese family. (PMID:26683566)
• the role of the charged residues at the end of TM-1 in voltage sensing in Cx26, Cx46, and Cx50. (PMID:27143357)
• The study identified a missense mutation (c. 176C>T) in GJA3 gene associated with autosomal dominant congenital pulverulent cataract in a Chinese family. (PMID:27609163)
• The LB2003 cells, devoid of three key K(+) uptake transport mechanisms, cannot grow in low-[K(+)] medium, but expression of Cx26, Cx43, or Cx46 rescues their growth defect (growth complementation (PMID:27789753)
• in vivo results indicated that down-regulation of GJA3 in lens epithelial cells was associated with age-related cataract genesis. Data from this study established the association of GJA3 down regulation with lens epithelial cells apoptosis and age-related cataract genesis (PMID:28088522)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gja3	ENSDARG00000021889
mus_musculus	Gja3	ENSMUSG00000048582
rattus_norvegicus	Gja3	ENSRNOG00000008847

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), 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-3 protein — Q9Y6H8 (reviewed: Q9Y6H8)

Alternative names: Connexin-46

All UniProt accessions (1): Q9Y6H8

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of lens fiber 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 GJA8.

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

Disease relevance. Cataract 14, multiple types (CTRCT14) [MIM:601885] 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. CTRCT14 includes zonular pulverulent cataract, among others. 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. Usually sharply separated from a clear cortex outside them, they may have projections from their outer edges known as riders or spokes. 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_068773* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002262	Connexin46	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR034634	Connexin_C	Homologous_superfamily
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029

UniProt features (44 total): sequence variant 23, topological domain 5, transmembrane region 4, compositionally biased region 3, disulfide bond 3, region of interest 2, initiator methionine 1, chain 1, intramembrane region 1, mutagenesis site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y6H8-F1	69.53	0.31

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): 54–192, 61–186, 65–181

Mutagenesis-validated functional residues (1):

Position	Phenotype
76	abolishes formation of gap junctions. no significant effect on formation of functional hemichannels.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 97 (showing top): REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_CELL_SIGNALING, NF1_Q6_01, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, KINSEY_TARGETS_OF_EWSR1_FLII_FUSION_DN, WTGAAAT_UNKNOWN, GOBP_SENSORY_PERCEPTION, REACTOME_GAP_JUNCTION_ASSEMBLY, LEE_CALORIE_RESTRICTION_NEOCORTEX_UP, CUI_TCF21_TARGETS_2_DN, GOCC_CELL_CELL_JUNCTION, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_MEMBRANE_PROTEIN_COMPLEX, GOCC_ANCHORING_JUNCTION, GOCC_PLASMA_MEMBRANE_PROTEIN_COMPLEX

GO Biological Process (5): cell-cell signaling (GO:0007267), visual perception (GO:0007601), gap junction-mediated intercellular transport (GO:1990349), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (2): gap junction channel activity (GO:0005243), gap junction hemi-channel activity (GO:0055077)

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
wide pore channel activity	2
cell communication	1
signaling	1
sensory perception of light stimulus	1
intercellular transport	1
transport	1
gap junction channel activity	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

430 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJA3	GJA8	P48165	955
GJA3	BFSP2	Q13515	939
GJA3	CRYGD	P07320	931
GJA3	CRYBB2	P43320	930
GJA3	CRYGS	P22914	921
GJA3	CRYBB1	P53674	919
GJA3	GJA1	P17302	853
GJA3	PITX3	O75364	850
GJA3	MIP	P30301	821
GJA3	CRYBA1	P05813	813
GJA3	CRYAA	P02489	812
GJA3	BFSP1	Q12934	806
GJA3	CRYGC	P07315	795
GJA3	LIM2	P55344	793
GJA3	CRYBB3	P26998	774

IntAct

1 interactions, top by confidence:

A	B	Type	Score
GJA3	GJB3	psi-mi:“MI:0914”(association)	0.350

BioGRID (18): GJA3 (Affinity Capture-MS), GJA3 (Affinity Capture-Western), GJA3 (Reconstituted Complex), GJA3 (Affinity Capture-Western), MAP1LC3B (Affinity Capture-Western), GJA3 (Affinity Capture-RNA), GJC1 (Affinity Capture-MS), PRMT2 (Affinity Capture-MS), SNX25 (Affinity Capture-MS), GPRC5C (Affinity Capture-MS), GJB3 (Affinity Capture-MS), KLHL13 (Affinity Capture-MS), TMEM9 (Affinity Capture-MS), KLHL9 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GVT2, A2RRL7, A3KN25, A4IFL1, G1TZA0, O18968, O54851, O70610, P08033, P0DKX4, P28230, P28234, P28235, P29414, P33725, P35212, P36382, P41987, P56513, Q01231, Q03190, Q08755, Q08EA8, Q0VCR2, Q2TA35, Q3MHM8, Q58CU5, Q5HZE8, Q5M8E3, Q5RCC0, Q60HF7, Q64448, Q6WGK6, Q7TNI2, Q866T7, Q8BSD4, Q8CFA6, Q8N6S5, Q8R0I4

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.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	27
Uncertain significance	178
Likely benign	20
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
16979	NM_021954.4(GJA3):c.1137dup (p.Ser380fs)	Pathogenic
2028307	NM_021954.4(GJA3):c.609C>A (p.Phe203Leu)	Pathogenic
3064923	NM_021954.4(GJA3):c.175C>G (p.Pro59Ala)	Pathogenic
4277287	NM_021954.4(GJA3):c.140A>G (p.Asp47Gly)	Pathogenic
1184603	NM_021954.4(GJA3):c.148T>C (p.Ser50Pro)	Likely pathogenic
1298563	NM_021954.4(GJA3):c.1082_1088del (p.Pro361fs)	Likely pathogenic
1345145	NM_021954.4(GJA3):c.178G>A (p.Gly60Ser)	Likely pathogenic
1474368	NM_021954.4(GJA3):c.151G>C (p.Asp51His)	Likely pathogenic
1527965	NM_021954.4(GJA3):c.98G>T (p.Arg33Leu)	Likely pathogenic
16978	NM_021954.4(GJA3):c.188A>G (p.Asn63Ser)	Likely pathogenic
16980	NM_021954.4(GJA3):c.560C>T (p.Pro187Leu)	Likely pathogenic
16981	NM_021954.4(GJA3):c.227G>A (p.Arg76His)	Likely pathogenic
2055275	NM_021954.4(GJA3):c.196T>C (p.Tyr66His)	Likely pathogenic
217334	NM_021954.4(GJA3):c.260C>T (p.Thr87Met)	Likely pathogenic
2570856	NM_021954.4(GJA3):c.176C>A (p.Pro59Gln)	Likely pathogenic
3253655	NM_021954.4(GJA3):c.1A>G (p.Met1Val)	Likely pathogenic
3253669	NM_021954.4(GJA3):c.96C>A (p.Phe32Leu)	Likely pathogenic
3253680	NM_021954.4(GJA3):c.134G>C (p.Trp45Ser)	Likely pathogenic
3253683	NM_021954.4(GJA3):c.143A>G (p.Glu48Gly)	Likely pathogenic
3253692	NM_021954.4(GJA3):c.584C>T (p.Ser195Phe)	Likely pathogenic
3253695	NM_021954.4(GJA3):c.771dup (p.Ser258fs)	Likely pathogenic
3253697	NM_021954.4(GJA3):c.32T>C (p.Leu11Ser)	Likely pathogenic
3253698	NM_021954.4(GJA3):c.950dup (p.His318fs)	Likely pathogenic
3253699	NM_021954.4(GJA3):c.1143_1165del (p.Ser381fs)	Likely pathogenic
3253700	NM_021954.4(GJA3):c.1152dup (p.Ser385fs)	Likely pathogenic
3253702	NM_021954.4(GJA3):c.1197dup (p.Thr400fs)	Likely pathogenic
3253734	NM_021954.4(GJA3):c.113G>A (p.Gly38Glu)	Likely pathogenic
3345933	NM_021954.4(GJA3):c.65G>T (p.Gly22Val)	Likely pathogenic
4531449	NM_021954.4(GJA3):c.1168_1175delinsCAGCAGTCTGGCAGGGGAGCGCCCTGGCAG (p.Thr390fs)	Likely pathogenic
50941	NM_021954.4(GJA3):c.563A>C (p.Asn188Thr)	Likely pathogenic

SpliceAI

614 predictions. Top by Δscore:

Variant	Effect	Δscore
13:20160884:CCTTA:C	donor_loss	1.0000
13:20160885:CTTA:C	donor_loss	1.0000
13:20160886:TTACC:T	donor_loss	1.0000
13:20160887:TACCC:T	donor_loss	1.0000
13:20160888:AC:A	donor_gain	1.0000
13:20160888:ACC:A	donor_gain	1.0000
13:20160889:CC:C	donor_gain	1.0000
13:20160889:CCC:C	donor_gain	1.0000
13:20160889:CCCCG:C	donor_gain	1.0000
13:20160888:A:AC	donor_gain	0.9900
13:20160889:C:CC	donor_gain	0.9900
13:20143306:C:CA	acceptor_loss	0.9700
13:20143307:T:G	acceptor_loss	0.9700
13:20146627:T:TA	donor_gain	0.9700
13:20160922:T:A	donor_gain	0.9700
13:20143308:G:C	acceptor_loss	0.9600
13:20160883:GCCTT:G	donor_loss	0.9400
13:20143184:CAAGA:C	acceptor_gain	0.9300
13:20160572:TAA:T	donor_gain	0.9300
13:20160573:AAA:A	donor_gain	0.9300
13:20143301:CTAAC:C	acceptor_gain	0.9200
13:20139083:T:TC	acceptor_gain	0.9100
13:20143315:GAAAA:G	acceptor_loss	0.9100
13:20143304:ACCT:A	acceptor_gain	0.9000
13:20160888:ACCC:A	donor_gain	0.9000
13:20160889:CCCC:C	donor_gain	0.9000
13:20143306:C:CC	acceptor_gain	0.8700
13:20143310:AAGAG:A	acceptor_loss	0.8700
13:20143303:AACC:A	acceptor_gain	0.8600
13:20160574:A:C	donor_gain	0.8600

AlphaMissense

2820 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:20143128:C:G	C54S	1.000
13:20143129:A:T	C54S	1.000
13:20142689:C:A	K200N	0.999
13:20142689:C:G	K200N	0.999
13:20142693:T:A	E199V	0.999
13:20142702:C:A	R196M	0.999
13:20142702:C:G	R196T	0.999
13:20142710:G:C	F193L	0.999
13:20142710:G:T	F193L	0.999
13:20142711:A:C	F193C	0.999
13:20142712:A:G	F193L	0.999
13:20142713:G:C	C192W	0.999
13:20142714:C:A	C192F	0.999
13:20142714:C:G	C192S	0.999
13:20142714:C:T	C192Y	0.999
13:20142715:A:G	C192R	0.999
13:20142715:A:T	C192S	0.999
13:20142800:G:C	F163L	0.999
13:20142800:G:T	F163L	0.999
13:20142802:A:G	F163L	0.999
13:20143026:G:C	P88R	0.999
13:20143026:G:T	P88H	0.999
13:20143057:A:G	W78R	0.999
13:20143057:A:T	W78R	0.999
13:20143079:G:C	F70L	0.999
13:20143079:G:T	F70L	0.999
13:20143081:A:G	F70L	0.999
13:20143094:G:C	C65W	0.999
13:20143095:C:T	C65Y	0.999
13:20143107:C:G	C61S	0.999

dbSNP variants (sampled 300 via entrez): RS1000027134 (13:20145356 A>C), RS1000092680 (13:20151408 G>T), RS1000187616 (13:20141760 C>G), RS1000209315 (13:20142470 C>T), RS1000444557 (13:20151589 C>T), RS1000582855 (13:20146319 T>C), RS1000657746 (13:20140036 C>A,T), RS1000728774 (13:20141523 A>T), RS1000736399 (13:20142524 C>G,T), RS1000817628 (13:20140976 A>C), RS1000889352 (13:20157679 C>G,T), RS1000928623 (13:20140409 G>A,C), RS1000935227 (13:20140601 G>T), RS1001070729 (13:20163504 G>C), RS1001234644 (13:20162906 G>C)

Disease associations

OMIM: gene MIM:121015 | disease phenotypes: MIM:601885, MIM:601371, MIM:604168

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 14 multiple types	Definitive	Autosomal dominant
pulverulent cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant
early-onset posterior polar cataract	Supportive	Autosomal dominant

Mondo (6): cataract 14 multiple types (MONDO:0011162), early-onset non-syndromic cataract (MONDO:0011060), congenital cataracts-facial dysmorphism-neuropathy syndrome (MONDO:0011402), pulverulent cataract (MONDO:0011430), early-onset nuclear cataract (MONDO:0020376), early-onset posterior polar cataract (MONDO:0020378)

Orphanet (2): Early onset non-syndromic cataract (Orphanet:91492), Congenital cataracts-facial dysmorphism-neuropathy syndrome (Orphanet:48431)

HPO phenotypes

2 total (2 of 2 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0010920	Zonular cataract

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004729_1	Facial emotion recognition (happy faces)	3.000000e-06
GCST008157_47	Body fat mass	1.000000e-06
GCST009196_6	Pericalcarine cortex volume	8.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
C563333	Cataract, Age-Related Nuclear (supp.)
C565133	Cataract, Coppock-Like (supp.)
C566608	Cataract, Zonular Pulverulent 3 (supp.)
C565822	Congenital Cataracts, Facial Dysmorphism, And Neuropathy (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

34 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	9
trichostatin A	affects cotreatment, increases expression	4
entinostat	increases expression, affects cotreatment	2
(+)-JQ1 compound	increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
FR900359	decreases phosphorylation	1
methyleugenol	increases expression	1
propionaldehyde	increases expression	1
bisphenol A	decreases expression, increases methylation	1
terbufos	increases methylation	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Aldehydes	increases expression	1
Cisplatin	affects cotreatment, increases expression	1
Dactinomycin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Fonofos	increases methylation	1
Methotrexate	increases expression	1
N-Nitrosopyrrolidine	increases expression	1
Parathion	increases methylation	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01902940	Not specified	COMPLETED	Natural History in CCFDN and IBM Syndromes