GJC2

Summary

GJC2 (gap junction protein gamma 2, HGNC:17494) is a protein-coding gene on chromosome 1q42.13, encoding Gap junction gamma-2 protein (Q5T442). One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

This gene encodes a gap junction protein. Gap junction proteins are members of a large family of homologous connexins and comprise 4 transmembrane, 2 extracellular, and 3 cytoplasmic domains. This gene plays a key role in central myelination and is involved in peripheral myelination in humans. Defects in this gene are the cause of autosomal recessive Pelizaeus-Merzbacher-like disease-1.

Source: NCBI Gene 57165 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hypomyelinating leukodystrophy 2 (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 431 total — 33 pathogenic, 36 likely-pathogenic
• Phenotypes (HPO): 75
• MANE Select transcript: NM_020435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17494
Approved symbol	GJC2
Name	gap junction protein gamma 2
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Aliases	CX47, CX46.6, SPG44
Ensembl gene	ENSG00000198835
Ensembl biotype	protein_coding
OMIM	608803
Entrez	57165

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000366714, ENST00000886860, ENST00000963922

RefSeq mRNA: 1 — MANE Select: NM_020435 NM_020435

CCDS: CCDS1569

Canonical transcript exons

ENST00000366714 — 2 exons

Exon	Start	End
ENSE00001442465	228157740	228159826
ENSE00001442466	228149930	228150007

Expression profiles

Bgee: expression breadth ubiquitous, 181 present calls, max score 93.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.5429 / max 67.2219, expressed in 78 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8930	0.3856	72
8931	0.0866	37
8929	0.0476	32
201982	0.0231	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
C1 segment of cervical spinal cord	UBERON:0006469	93.65	gold quality
spinal cord	UBERON:0002240	92.70	gold quality
inferior vagus X ganglion	UBERON:0005363	90.88	gold quality
subthalamic nucleus	UBERON:0001906	89.20	gold quality
type B pancreatic cell	CL:0000169	88.09	gold quality
olfactory bulb	UBERON:0002264	87.63	gold quality
ventral tegmental area	UBERON:0002691	86.82	silver quality
dorsal plus ventral thalamus	UBERON:0001897	86.57	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.21	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	86.06	gold quality
pons	UBERON:0000988	85.27	gold quality
medulla oblongata	UBERON:0001896	85.04	gold quality
Brodmann (1909) area 10	UBERON:0013541	85.04	silver quality
lateral nuclear group of thalamus	UBERON:0002736	84.87	silver quality
substantia nigra pars compacta	UBERON:0001965	84.81	silver quality
vena cava	UBERON:0004087	84.42	gold quality
midbrain	UBERON:0001891	84.36	gold quality
substantia nigra pars reticulata	UBERON:0001966	84.07	silver quality
substantia nigra	UBERON:0002038	84.04	gold quality
pharyngeal mucosa	UBERON:0000355	83.96	gold quality
cardia of stomach	UBERON:0001162	83.84	gold quality
superior vestibular nucleus	UBERON:0007227	83.63	gold quality
triceps brachii	UBERON:0001509	82.44	gold quality
gluteal muscle	UBERON:0002000	81.70	gold quality
tongue squamous epithelium	UBERON:0006919	81.50	gold quality
cervix squamous epithelium	UBERON:0006922	81.48	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	81.37	gold quality
cerebellar vermis	UBERON:0004720	81.37	gold quality
nipple	UBERON:0002030	81.12	gold quality
saphenous vein	UBERON:0007318	81.00	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.50

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SOX10

miRNA regulators (miRDB)

22 targeting GJC2, 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-4267	99.96	66.53	2368
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-149-5P	99.25	67.16	1315
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-3150B-3P	98.81	67.21	1728
HSA-MIR-4656	98.79	66.22	1306
HSA-MIR-4680-3P	98.64	68.60	2093
HSA-MIR-4290	98.51	65.17	907
HSA-MIR-3928-5P	98.50	67.48	980
HSA-MIR-6806-3P	98.50	67.31	980
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-3189-5P	97.55	66.71	655
HSA-MIR-1225-3P	97.29	64.60	876
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-3162-5P	95.67	67.53	794
HSA-MIR-328-3P	92.82	64.37	521

Literature-anchored findings (GeneRIF, showing 27)

• Patients from one family carrying a homozygous frameshift mutation in GJA12 presenting with nystagmus and brain demyelinating disease. (PMID:16969684)
• GJA12 mutations are the initiaial genetic test in patients with consanguineous parents with Pelizaeus-Merzbacher-like disease. (PMID:17031678)
• study shows the Cx47 mutants associated with Pelizaeus-Merzbacher-like disease likely disrupt the gap junction coupling between astrocytes and oligodendrocytes (PMID:17344063)
• The clinical phenotype of patients with a GJA12 mutation was evaluated and is overall comparable to the clinical features seen in mild forms of PLP1-related disorder but with better cognition and earlier signs of axonal degeneration. (PMID:18094336)
• GJA12 alterations are a rare cause of Pelizaeus-Merzbacher-like disease even after extending the screening for copy number variation and for mutations in the non-coding region of GJA12. (PMID:18521858)
• GJA12/GJC2 mutations can result in a milder phenotype than previously appreciated, but whether I33M retains a function of Cx47 not directly related to forming functional gap junction channels is not known. (PMID:19056803)
• GJA12 gene mutations reported from two Chinese Pelizaeus-Merzbacher-like disease patients (PMID:19423250)
• She carried no GJA12 mutations. These facts suggested that this disease is a novel, autosomal recessive hypomyelinating leukodystrophy. (PMID:20120347)
• The identification of GJC2 mutations as a cause of primary lymphedema (PMID:20537300)
• Mutations within the GJC2 gene are associated with primary lymphoedema. (PMID:21266381)
• We report the identification of the GJC2 promoter mutation (c.-167A>G) in nine patients from three unrelated Pakistani families with Pelizaeus-Merzbacher-like disease. Linkage analysis was consistent with a likely founder effect of this mutation (PMID:21959080)
• This study identified novel chromosomal rearrangements proximal and distal to, and exclusive of the PLP1 gene, showed equal frequencies of PLP1 and GJA12/GJC2 mutations (PMID:22283455)
• Cx47 mutations were identified in individuals having secondary lymphedema following breast cancer treatment; these novel mutations are dysfunctional and provide evidence that altered gap junction function leads to lymphedema (PMID:22351697)
• the extremely severe clinical Pelizaeus-Merzbacher-like disease form likely correlates with the predicted impairment of gap junction channel assembly resulting from the detrimental effect of the new p.Glu260Lys mutant allele on Cx47 protein (PMID:22669416)
• founder mutation c.-167A>G localized in the GJC2 protein promoter region in patients with Pelizaeus Merzbacher disease and Pelizaeus Merzbacher like disease (PMID:23142375)
• Most of the Pelizaeus-Merzbacher-like disease (PMLD)-linked Cx47 mutants disrupt Cx47/Cx47 and Cx47/Cx43 GJ function in the glial network, which may play a role in leading to PMLD symptoms (PMID:23544880)
• we provide evidence that a mutation in GJA1 leads not only to ODD as already described in the literature, but can also lead to lymphoedema as an associated feature. (PMID:23550541)
• a novel homozygous mutation in GJC2 was identified in a 21-year-old female patient with Pelizaeus-Merzbacher-like disease (PMID:23684670)
• GJC2 promoter region mutation screening should be included in the evaluation of patients with unexplained hypomyelinating leukodystrophies. (PMID:24374284)
• Identi fi cation of GJC2 gene mutations in Chinese patients with Pelizaeus-Merzbacher-like disease. (PMID:27057822)
• Different mutations in the Cx47 lead to discrepant activation of unfolded protein response (UPR) pathway, which encouraged apoptotic cell death at different levels. Inappropriate activation of UPR may play important roles in the pathophysiology of Pelizaeus-Merzbacher-Like Disease. (PMID:28712094)
• The expression of the transcription factors Foxc2 and Nfatc1 and the gap junction proteins Gjc2, Gja1, and Gja4 were temporospatially regulated during this process. (PMID:28724617)
• Connexin 43-connexin 47 channels are important for astrocyte/ oligodendrocyte cross-talk in myelination and demyelination. (Review) (PMID:30541963)
• Resequencing of VEGFR3 pathway genes implicate GJC2 and FLT4 in the formation of primary congenital chylothorax. (PMID:34994518)
• Activation of the unfolded protein response by Connexin47 mutations associated with Pelizaeus-Merzbacher-like disease. (PMID:35276347)
• Lack of embryonic homozygous or adult heterozygous lymphatic phenotypes for a Sos1 mutation and lack of lymphatic embryonic phenotypes for a homozygous Cx47 mutation in mice. (PMID:36446400)
• Mechanisms of Diseases Associated with Mutation in GJC2/Connexin 47. (PMID:37189458)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gjc2	ENSDARG00000073896
mus_musculus	Gjc2	ENSMUSG00000043448
rattus_norvegicus	Gjc2	ENSRNOG00000038328

Paralogs (20): GJA8 (ENSG00000121634), 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), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction gamma-2 protein — Q5T442 (reviewed: Q5T442)

Alternative names: Connexin-46.6, Connexin-47, Gap junction alpha-12 protein

All UniProt accessions (2): Q5T442, A0A654IBV7

UniProt curated annotations — full annotation on UniProt →

Function. One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell. May play a role in myelination in central and peripheral nervous systems.

Subunit / interactions. A connexon is composed of a hexamer of connexins. Interacts with TJP1.

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

Tissue specificity. Expressed in central nervous system, in sciatic nerve and sural nerve. Also detected in skeletal muscles.

Disease relevance. Leukodystrophy, hypomyelinating, 2 (HLD2) [MIM:608804] An autosomal recessive hypomyelinating leukodystrophy with symptoms of Pelizaeus-Merzbacher disease. Clinically characterized by nystagmus, impaired motor development, ataxia, choreoathetotic movements, dysarthria, and progressive spasticity. The disease is caused by variants affecting the gene represented in this entry. Spastic paraplegia 44, autosomal recessive (SPG44) [MIM:613206] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The disease is caused by variants affecting the gene represented in this entry. Lymphatic malformation 3 (LMPHM3) [MIM:613480] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Patients with lymphedema may suffer from recurrent local infections. LMPHM3 is an autosomal dominant form with variable severity and reduced penetrance. Affected individuals manifest lymphedema of the lower limbs and some patients have lymphedema of the hands. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the connexin family. Gamma-type subfamily.

RefSeq proteins (1): NP_065168* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00029

UniProt features (28 total): sequence variant 10, topological domain 5, transmembrane region 4, compositionally biased region 3, region of interest 2, sequence conflict 2, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5T442-F1	68.50	0.28

Functional residue map

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

Post-translational modifications (1): 371

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 229 (showing top): MODULE_255, MODULE_317, REACTOME_MEMBRANE_TRAFFICKING, CAGCTG_AP4_Q5, GOBP_CELL_CELL_SIGNALING, SOX9_B1, GOBP_CELL_COMMUNICATION_BY_ELECTRICAL_COUPLING, MODULE_99, REACTOME_GAP_JUNCTION_ASSEMBLY, GOBP_RESPONSE_TO_TOXIC_SUBSTANCE, GOCC_CELL_CELL_JUNCTION, GOBP_TRANSMEMBRANE_TRANSPORT, GOCC_MYELIN_SHEATH, GOCC_MEMBRANE_PROTEIN_COMPLEX, MODULE_69

GO Biological Process (5): cell-cell signaling (GO:0007267), response to toxic substance (GO:0009636), cell communication by electrical coupling (GO:0010644), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (2): gap junction channel activity (GO:0005243), gap junction channel activity involved in cell communication by electrical coupling (GO:1903763)

GO Cellular Component (6): gap junction (GO:0005921), connexin complex (GO:0005922), myelin sheath (GO:0043209), plasma membrane (GO:0005886), 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
cell communication	2
cellular process	2
cellular anatomical structure	2
signaling	1
response to chemical	1
transport	1
wide pore channel activity	1
gap junction channel activity	1
cell communication by electrical coupling	1
cell-cell junction	1
gap junction	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
cell junction	1

Protein interactions and networks

STRING

622 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJC2	HYCC1	Q9BYI3	899
GJC2	PNPLA6	Q8IY17	859
GJC2	AP5Z1	O43299	839
GJC2	SPG21	Q9NZD8	820
GJC2	SPG7	Q9UQ90	786
GJC2	FOXC2	Q99958	780
GJC2	SPG11	Q96JI7	779
GJC2	SPART	Q8N0X7	760
GJC2	AIMP1	Q12904	725
GJC2	GJB2	P29033	689
GJC2	GJA1	P17302	665
GJC2	GJE1	A6NN92	661
GJC2	FLT4	P35916	658
GJC2	PLP1	P04400	655
GJC2	GJB6	O95452	653

IntAct

8 interactions, top by confidence:

A	B	Type	Score
GJC2	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
GJC2	F2RL1	psi-mi:“MI:0915”(physical association)	0.370
GJC2	GPR35	psi-mi:“MI:0915”(physical association)	0.370
GJC2	LTB4R2	psi-mi:“MI:0915”(physical association)	0.370
GJC2	CHRM2	psi-mi:“MI:0915”(physical association)	0.370
GJC2	PTGER4	psi-mi:“MI:0915”(physical association)	0.370
ALB	CDC45	psi-mi:“MI:0914”(association)	0.350

BioGRID (8): GJC2 (Two-hybrid), GJC2 (Two-hybrid), GJC2 (Two-hybrid), GJC2 (Two-hybrid), GJC2 (Two-hybrid), GJC2 (Two-hybrid), GJC2 (Negative Genetic), GJC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A0U1RQ45, A0A0U1RQS6, A0A2R8YCJ5, A2A699, A2AEV7, A6NGB7, A6NJG2, A6NKF7, A6NKL6, A6NL88, A8MVW0, A9JSM3, B2RU40, B8ZZ34, C9JH25, D4A9R4, J3QNX5, P0CG09, P98077, Q0VD38, Q14761, Q17QH7, Q29RK8, Q2KJ18, Q2M3V2, Q3SX20, Q5BJT1, Q5HZJ5, Q5RKR3, Q5T442, Q64697, Q69YZ2, Q6PB97, Q6PCT2, Q6UXK2, Q6ZMQ8, Q6ZVH7, Q6ZW31, Q80XF7, Q8BLS7

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

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	36
Uncertain significance	241
Likely benign	77
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1027507	NM_020435.4(GJC2):c.219_220del (p.Leu74fs)	Pathogenic
1363305	NM_020435.4(GJC2):c.1141_1151del (p.Ser381fs)	Pathogenic
1453719	NM_020435.4(GJC2):c.914_933dup (p.Ala312fs)	Pathogenic
1525995	NM_020435.4(GJC2):c.472_481dup (p.Ala161fs)	Pathogenic
1694548	NM_020435.4(GJC2):c.392dup (p.His132fs)	Pathogenic
2002110	NM_020435.4(GJC2):c.369_370del (p.Arg125fs)	Pathogenic
2071	NM_020435.4(GJC2):c.857T>C (p.Met286Thr)	Pathogenic
2073	NM_020435.4(GJC2):c.989del (p.Pro330fs)	Pathogenic
2074	NM_020435.4(GJC2):c.718C>T (p.Arg240Ter)	Pathogenic
2075	NM_020435.4(GJC2):c.814T>G (p.Tyr272Asp)	Pathogenic
2076	NM_020435.4(GJC2):c.914_947del (p.Pro305fs)	Pathogenic
2077	NM_020435.4(GJC2):c.695_696insG (p.Tyr232Ter)	Pathogenic
2078	NM_020435.4(GJC2):c.108C>G (p.Ile36Met)	Pathogenic
2079	NM_020435.4(GJC2):c.143C>T (p.Ser48Leu)	Pathogenic
2080	NM_020435.4(GJC2):c.778C>T (p.Arg260Cys)	Pathogenic
2101617	NM_020435.4(GJC2):c.224C>A (p.Ser75Ter)	Pathogenic
2202995	NM_020435.4(GJC2):c.-20+1G>C	Pathogenic
2726006	NM_020435.4(GJC2):c.69_82dup (p.Leu28fs)	Pathogenic
3336782	NM_020435.4(GJC2):c.790A>T (p.Lys264Ter)	Pathogenic
3337147	NM_020435.4(GJC2):c.706G>A (p.Gly236Ser)	Pathogenic
3338029	NM_020435.4(GJC2):c.282C>G (p.Tyr94Ter)	Pathogenic
3340090	NM_020435.4(GJC2):c.404G>A (p.Trp135Ter)	Pathogenic
3362644	NM_020435.4(GJC2):c.401del (p.Gly134fs)	Pathogenic
3645858	NM_020435.4(GJC2):c.562del (p.Ala188fs)	Pathogenic
3674179	NM_020435.4(GJC2):c.145del (p.Asp49fs)	Pathogenic
3896190	NM_020435.4(GJC2):c.523G>T (p.Glu175Ter)	Pathogenic
4725482	NM_020435.4(GJC2):c.400_437del (p.Gly134fs)	Pathogenic
4848031	NM_020435.4(GJC2):c.914_947dup (p.Pro317fs)	Pathogenic
520879	NM_020435.4(GJC2):c.80G>A (p.Trp27Ter)	Pathogenic
60683	NM_020435.4(GJC2):c.787G>A (p.Glu263Lys)	Pathogenic

SpliceAI

218 predictions. Top by Δscore:

Variant	Effect	Δscore
1:228157738:A:AG	acceptor_gain	0.9900
1:228157739:G:GG	acceptor_gain	0.9900
1:228149964:TGG:T	donor_gain	0.9800
1:228157734:CCACA:C	acceptor_loss	0.9800
1:228157735:CACAG:C	acceptor_loss	0.9800
1:228157737:CAGGA:C	acceptor_loss	0.9800
1:228157738:A:T	acceptor_loss	0.9800
1:228157738:AG:A	acceptor_gain	0.9800
1:228157739:G:A	acceptor_loss	0.9800
1:228157739:GG:G	acceptor_gain	0.9800
1:228149965:G:GA	donor_gain	0.9700
1:228150005:AAG:A	donor_loss	0.9600
1:228150006:AG:A	donor_loss	0.9600
1:228150007:GG:G	donor_loss	0.9600
1:228150008:GTA:G	donor_loss	0.9600
1:228150009:T:A	donor_loss	0.9600
1:228157739:GGACC:G	acceptor_gain	0.9600
1:228150004:GAAG:G	donor_gain	0.9200
1:228157739:GGA:G	acceptor_gain	0.9200
1:228149970:GGCTC:G	donor_gain	0.9000
1:228149979:G:GT	donor_gain	0.9000
1:228157739:GGAC:G	acceptor_gain	0.9000
1:228156580:G:A	acceptor_gain	0.8900
1:228150009:TAGGG:T	donor_gain	0.8100
1:228150008:G:GG	donor_gain	0.7700
1:228150007:GGT:G	donor_gain	0.7500
1:228151170:G:GT	donor_gain	0.7400
1:228149966:GAAGG:G	donor_gain	0.7300
1:228155159:G:T	donor_gain	0.7200
1:228157730:C:A	acceptor_loss	0.7200

AlphaMissense

2796 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:228157918:T:C	F54L	1.000
1:228157919:T:C	F54S	1.000
1:228157919:T:G	F54C	1.000
1:228157920:C:A	F54L	1.000
1:228157920:C:G	F54L	1.000
1:228157925:G:A	C56Y	1.000
1:228157958:G:A	C67Y	1.000
1:228157959:C:G	C67W	1.000
1:228158526:C:G	C256W	1.000
1:228157828:G:C	G24R	0.999
1:228157837:T:A	W27R	0.999
1:228157837:T:C	W27R	0.999
1:228157924:T:A	C56S	0.999
1:228157924:T:C	C56R	0.999
1:228157925:G:C	C56S	0.999
1:228157925:G:T	C56F	0.999
1:228157926:C:G	C56W	0.999
1:228157929:C:A	N57K	0.999
1:228157929:C:G	N57K	0.999
1:228157945:T:A	C63S	0.999
1:228157945:T:C	C63R	0.999
1:228157946:G:A	C63Y	0.999
1:228157946:G:C	C63S	0.999
1:228157946:G:T	C63F	0.999
1:228157947:C:G	C63W	0.999
1:228157957:T:A	C67S	0.999
1:228157957:T:C	C67R	0.999
1:228157958:G:C	C67S	0.999
1:228157958:G:T	C67F	0.999
1:228157969:T:C	F71L	0.999

dbSNP variants (sampled 300 via entrez): RS1000192269 (1:228159370 T>G), RS1000241127 (1:228152716 G>T), RS1000248340 (1:228160000 G>C), RS1000543924 (1:228151301 C>G), RS1000547808 (1:228149365 C>T), RS1000573675 (1:228151614 G>A), RS1000949473 (1:228155888 GC>G), RS1001001925 (1:228156156 G>C,T), RS1001090685 (1:228156804 A>C), RS1001521316 (1:228158827 G>A), RS1001769935 (1:228152223 C>T), RS1001845435 (1:228156247 T>C), RS1001987806 (1:228156701 G>A,T), RS1002073985 (1:228150748 C>T), RS1002138603 (1:228152046 C>T)

Disease associations

OMIM: gene MIM:608803 | disease phenotypes: MIM:608804, MIM:108600, MIM:303350, MIM:613206, MIM:613480, MIM:607086, MIM:312080

GenCC curated gene-disease

Disease	Classification	Inheritance
hypomyelinating leukodystrophy 2	Definitive	Autosomal recessive
hereditary spastic paraplegia 44	Strong	Autosomal recessive
lymphatic malformation 3	Strong	Autosomal dominant
lymphatic malformation	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hypomyelinating leukodystrophy 2	Definitive	AR

Mondo (12): hypomyelinating leukodystrophy 2 (MONDO:0012125), spastic ataxia (MONDO:0017845), hereditary spastic paraplegia (MONDO:0019064), congenital nervous system disorder (MONDO:0002320), hereditary spastic paraplegia 44 (MONDO:0013179), lymphatic malformation 3 (MONDO:0013278), breast ductal adenocarcinoma (MONDO:0005590), familial thoracic aortic aneurysm and aortic dissection (MONDO:0019625), intellectual disability (MONDO:0001071), dystonic disorder (MONDO:0003441), Pelizaeus-Merzbacher spectrum disorder (MONDO:0010714), lymphatic malformation (MONDO:0019313)

Orphanet (9): Pelizaeus-Merzbacher-like disease (Orphanet:280270), Pelizaeus-Merzbacher-like disease due to GJC2 mutation (Orphanet:280282), Spastic ataxia (Orphanet:316226), Hereditary spastic paraplegia (Orphanet:685), Autosomal recessive spastic paraplegia type 44 (Orphanet:320401), Milroy disease (Orphanet:79452), Familial thoracic aortic aneurysm and aortic dissection (Orphanet:91387), Pelizaeus-Merzbacher disease (Orphanet:702), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

75 total (30 of 75 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000282	Facial edema
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000514	Slow saccadic eye movements
HP:0000545	Myopia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0001004	Lymphedema
HP:0001250	Seizure
HP:0001251	Ataxia
HP:0001258	Spastic paraplegia
HP:0001260	Dysarthria
HP:0001263	Global developmental delay
HP:0001266	Choreoathetosis
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001332	Dystonia
HP:0001347	Hyperreflexia
HP:0001581	Recurrent skin infections
HP:0001583	Rotary nystagmus
HP:0001761	Pes cavus
HP:0001785	Ankle swelling
HP:0002019	Constipation
HP:0002059	Cerebral atrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (8)

Descriptor	Name	Tree numbers
D018270	Carcinoma, Ductal, Breast	C04.557.470.200.025.232.500; C04.557.470.615.132.500; C04.588.180.390; C17.800.090.500.390
D020821	Dystonic Disorders	C10.228.662.300
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D020371	Pelizaeus-Merzbacher Disease	C10.228.140.163.100.362.775; C10.228.140.695.625.775; C10.314.400.775; C16.320.322.906; C16.320.565.189.362.775; C18.452.132.100.362.775; C18.452.648.189.362.775
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820
C563855	Leukodystrophy, Hypomyelinating, 2 (supp.)
C564815	Spastic Ataxia (supp.)
C567707	Spastic Paraplegia 44, Autosomal Recessive (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

19 total (human), top 19 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, decreases expression	2
Tobacco Smoke Pollution	decreases expression	2
aristolochic acid I	increases expression	1
dicrotophos	decreases expression	1
bisphenol A	decreases expression	1
ethyl-p-hydroxybenzoate	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Atrazine	increases expression	1
Plant Oils	increases expression	1
Smoke	decreases expression	1
Thiram	increases expression	1
Urethane	decreases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1
Acrylamide	increases expression	1
Particulate Matter	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT07285005	PHASE3	NOT_YET_RECRUITING	A Study to Investigate Efficacy and Safety of KP-001 Compared With Placebo in Patients Aged ≥2 Years With Common VM, Common LM, or KTS/CLOVES Syndrome
NCT03414970	PHASE3	ACTIVE_NOT_RECRUITING	Hypofractionated Radiation Therapy After Mastectomy in Preventing Recurrence in Patients With Stage IIa-IIIa Breast Cancer
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT02335242	PHASE2	COMPLETED	Sildenafil for the Treatment of Lymphatic Malformations
NCT03243019	PHASE2	RECRUITING	Efficacy of Rapamycin in the Treatment of Cervico-facial Lymphatic Malformations
NCT03427619	PHASE2	COMPLETED	OK432 (Picibanil) in the Treatment of Lymphatic Malformations
NCT03972592	PHASE2	COMPLETED	Topical Sirolimus in Cutaneous Lymphatic Malformations
NCT04861064	PHASE2	RECRUITING	Weekly Sirolimus Therapy
NCT05871970	PHASE2	RECRUITING	Safety and Efficacy Study of Intracystic TARA-002 for the Treatment of Lymphatic Malformations in Participants 6 Months to Less Than 18 Years of Age
NCT05983159	PHASE2	RECRUITING	A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations
NCT06437158	PHASE2	RECRUITING	Use of Bleomycin in the Sclerotherapy of Lymphatic Malformations for Pediatric Patients
NCT06789913	PHASE2	RECRUITING	A Phase 2 Study of Mutant-selective PI3Kα Inhibitor, RLY-2608, in Adults and Children With PIK3CA Related Overgrowth Spectrum and Malformations Driven by PIK3CA Mutation
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00461344	PHASE2	TERMINATED	Docetaxel + Doxorubicin as Neoadjuvant Chemotherapy in Patients With Breast Cancer
NCT07499999	PHASE2	NOT_YET_RECRUITING	Randomized Double-Blind Phase II Trial of Baby Exemestane Versus Baby Tamoxifen in Post-Menopausal Women at High Risk for Breast Cancer
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm