PCDH19

Summary

PCDH19 (protocadherin 19, HGNC:14270) is a protein-coding gene on chromosome Xq22.1, encoding Protocadherin-19 (Q8TAB3). Calcium-dependent cell-adhesion protein. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is a member of the delta-2 protocadherin subclass of the cadherin superfamily. The encoded protein is thought to be a calcium-dependent cell-adhesion protein that is primarily expressed in the brain. Mutations in this gene on human chromosome X are associated with sporadic infantile epileptic encephalopathy and to a female-restricted form of epilepsy (EFMR; also known as PCDH19RE). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 57526 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +2 more curated relationships
• Clinical variants (ClinVar): 1,422 total — 307 pathogenic, 89 likely-pathogenic
• Phenotypes (HPO): 73
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001184880

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14270
Approved symbol	PCDH19
Name	protocadherin 19
Location	Xq22.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1313, EIEE9
Ensembl gene	ENSG00000165194
Ensembl biotype	protein_coding
OMIM	300460
Entrez	57526

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 nonsense_mediated_decay

ENST00000255531, ENST00000373034, ENST00000420881, ENST00000464981, ENST00000636150, ENST00000909758

RefSeq mRNA: 3 — MANE Select: NM_001184880 NM_001105243, NM_001184880, NM_020766

CCDS: CCDS43976, CCDS48141, CCDS55462

Canonical transcript exons

ENST00000373034 — 6 exons

Exon	Start	End
ENSE00000401058	100402524	100402851
ENSE00000673367	100341903	100342075
ENSE00000673380	100350646	100350704
ENSE00001174648	100406451	100410273
ENSE00001459377	100291644	100296875
ENSE00001459378	100403524	100403664

Expression profiles

Bgee: expression breadth ubiquitous, 175 present calls, max score 88.85.

FANTOM5 (CAGE): breadth broad, TPM avg 8.0970 / max 376.3208, expressed in 718 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199917	7.8909	705
199918	0.1044	50
199916	0.1016	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	88.85	gold quality
entorhinal cortex	UBERON:0002728	88.70	gold quality
middle temporal gyrus	UBERON:0002771	88.54	gold quality
superior frontal gyrus	UBERON:0002661	86.51	gold quality
Brodmann (1909) area 46	UBERON:0006483	85.30	gold quality
Ammon’s horn	UBERON:0001954	85.25	gold quality
temporal lobe	UBERON:0001871	85.17	gold quality
Brodmann (1909) area 23	UBERON:0013554	85.15	gold quality
postcentral gyrus	UBERON:0002581	83.72	gold quality
amygdala	UBERON:0001876	83.27	gold quality
primary visual cortex	UBERON:0002436	83.04	gold quality
parietal lobe	UBERON:0001872	82.74	gold quality
cerebral cortex	UBERON:0000956	82.66	gold quality
hypothalamus	UBERON:0001898	82.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	82.32	gold quality
occipital lobe	UBERON:0002021	81.54	gold quality
neocortex	UBERON:0001950	81.42	gold quality
frontal cortex	UBERON:0001870	81.38	gold quality
anterior cingulate cortex	UBERON:0009835	81.35	gold quality
prefrontal cortex	UBERON:0000451	81.19	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.72	gold quality
Brodmann (1909) area 9	UBERON:0013540	78.87	gold quality
right frontal lobe	UBERON:0002810	78.53	gold quality
superior vestibular nucleus	UBERON:0007227	78.44	silver quality
mammary duct	UBERON:0001765	76.41	silver quality
epithelium of mammary gland	UBERON:0003244	76.25	silver quality
forebrain	UBERON:0001890	75.66	gold quality
medulla oblongata	UBERON:0001896	73.54	silver quality
trigeminal ganglion	UBERON:0001675	73.33	silver quality
embryo	UBERON:0000922	73.20	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.60

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NR2F1

miRNA regulators (miRDB)

273 targeting PCDH19, 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-3646	100.00	73.56	5283
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4283	100.00	66.42	2097
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Using a sample of male subjects diagnosed with autism spectrum disorders, markers were tested covering the entire X chromosome using a family-based association study. Association was revealed at DXS8043 (P=0.0101). (PMID:16261168)
• X-linked protocadherin 19 mutations cause female-limited epilepsy and cognitive impairment (PMID:18469813)
• Mutation of PCDH19 plays a major role in epileptic encephalopathies, mainly affects females. (PMID:19214208)
• This study indicted that PCDH19 is emerging as a major gene for infantile-onset familial or sporadic epilepsy in female patients with or without mental retardation. (PMID:20713952)
• Article shows importance of testing PCDH19 in females with early onset epilepsy, intellectual impairment, and autistic features, regardless of family history. (PMID:20830798)
• mutations in PCDH19 are a relatively frequent cause of epilepsy in females. (PMID:21053371)
• missense and frameshift mutations and spectrum of resulting epilepsy phenotypes in female patients (PMID:21480887)
• Cognitive impairment in patients with PCDH19 mutations and a Dravet-like phenotype varies in severity, and no sufficient evidence exists that any correlation exists between type of mutation and severity of cognitive impairment and epilepsy [review] (PMID:21504426)
• findings show that gonadal mosaicism of a PCDH19 mutation in a parent is an important molecular mechanism associated with the inheritance of epilepsy and mental retardation in females (PMID:21519002)
• case report of missense heterozygous c.1129G>C (p.Asp377His) mutation and acute-onset epilepsy triggered by fever (PMID:21777234)
• PCDH19 mutation is a relatively frequent cause of epilepsy in Japanese females. (PMID:22050978)
• Deletions at PCDH19 cause female-restricted epilepsy with mental retardation. (PMID:22091964)
• This study presented that PCDH19 mutation cause of genetic epilepsy in females. (PMID:22504056)
• SCN1A and PCDH19 mutations in Chinese children with Dravet syndrome (PMID:22848613)
• This study demonistrated that most patients with PCDH19 mutations exhibit a distinctive electroclinical pattern of focal seizures with affective symptoms, suggesting an epileptogenic dysfunction involving the frontotemporal limbic system. (PMID:22946748)
• this study describes a PCDH19 mutation segregating from an asymptomatic mother to an epilepsy with mental retardation patient. (PMID:22949144)
• Mutations in PCDH19 and other genes with rare copy number variations are not responsible for febrile infection-related epilepsy syndrome (FIRES). (PMID:23066759)
• Mutations of PCDH19 have also been reported in female patients with clinical findings compatible with Dravet syndrome [review] (PMID:23093055)
• Phenotypic spectrum associated with PCDH19 mutations in Dravet-like and epilepsy and mental retardation limited to females patients and in males with autism spectrum disorders. (PMID:23334464)
• This study highlighted the significance of PCDH19 deletion, a unique pattern of initial seizure clusters, and the efficacy of antiepileptic drugs (PMID:23712037)
• PCDH19-related epilepsy could be considered a well-defined epileptic syndrome, affecting only females, included in the group of epilepsies with febrile and afebrile seizures [review] (PMID:25204757)
• The present findings confirm that PCDH19 is a major causative gene for infantile onset familial or sporadic epilepsy in female patients with or without mental retardation. (PMID:25218114)
• analysis of four novel mutations in the PCDH19 gene found in isolated cases of girls with infantile onset epilepsy (PMID:25227595)
• girls with a de novo mutation in PCDH19 presented a delay of expressive language acquisition and lower scores at follow-up testing completed at older ages (PMID:25499160)
• This case report is suggestive of a good response of PCDH19-related Epilepsy to stiripentol (PMID:25510386)
• Epileptic encephalopathy related to mutations in the PCDH19 genes. (PMID:25818041)
• This study proposes corticosteroid treatment as an efficacious adjunctive treatment for the acute symptoms of PCDH19-Generalized Convulsive Epilepsy and suggests BBB involvement in this disease. (PMID:25891919)
• steroids and in particular neurosteroids (e.g. allopregnanolone) play an important role in PCDH19-FE and represent a realistic therapeutic target. (PMID:26123493)
• PCDH19 has a role in instructing the apico-basal polarity of the progenitor cells, thus regulating the development of a properly organized human brain (PMID:26450854)
• Two mosaic PCDH19 point mutations are described in male patients with PCDH19-related epilepsy. (PMID:26765483)
• The study demonistrated that most effective drugs in patients with PCDH19 mutations were bromide and clobazam. (PMID:26820223)
• mild tonic, fluttering and mild clonic phases were most characteristic of seizures of PCDH19-related epilepsy (PMID:26898795)
• This is the second male with somatic mosaicism for PCDH19 deficiency, providing further support for cellular interference as the pathogenic mechanism for this condition, which leads to this unusual mode of inheritance in which females are more severely affected than males. (PMID:27016041)
• Our results show a large spectrum of intellectual disability and a very high rate of Autism spectrum disorder in patients with epilepsy and PCDH-19 mutations (PMID:27179713)
• Results summarized the clinical spectrum of female epilepsy patients with protocadherin 19 (PCDH19) mutations in a Chinese population. (PMID:27527380)
• We report the fifth confirmed male with somatic mosaicism of a novel pathogenic variant c.2147+2 T>C located in the splice site of Intron 1 of the PCDH19 gene, which continues to support that cellular interference is responsible for the pathogenic mechanism (PMID:28462982)
• These findings point to multiple defects in peripheral steroidogenesis associated with and potentially relevant to PCDH19-FE. Some of these defects could be addressed by stimulating adrenocortical activity. (PMID:28471529)
• reaffirm the similarity between male and female PCDH19-related phenotypes, now also in a later phase of the disorder (PMID:28669061)
• Our results highlight the role of PCDH19 in determining cell adhesion affinities during cortical development (PMID:29301106)
• we have added to the characterization of PCDH19-related epilepsy. In addition to epilepsy, affected individuals display a complex neuropsychiatric syndrome in which the behavioral and sleep dysregulation are prominent. (PMID:29377098)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pcdh19	ENSDARG00000034344
mus_musculus	Pcdh19	ENSMUSG00000051323
rattus_norvegicus	Pcdh19	ENSRNOG00000003929

Paralogs (61): PCDHB4 (ENSG00000081818), PCDHA6 (ENSG00000081842), PCDHGA2 (ENSG00000081853), PCDHB2 (ENSG00000112852), PCDHB3 (ENSG00000113205), PCDHB5 (ENSG00000113209), PCDHB6 (ENSG00000113211), PCDHB7 (ENSG00000113212), PCDHB15 (ENSG00000113248), PCDH12 (ENSG00000113555), PCDH17 (ENSG00000118946), PCDHB8 (ENSG00000120322), PCDHB10 (ENSG00000120324), PCDHB14 (ENSG00000120327), PCDHB12 (ENSG00000120328), PCDH8 (ENSG00000136099), PCDH10 (ENSG00000138650), PCDH15 (ENSG00000150275), CDH16 (ENSG00000166589), PCDHB1 (ENSG00000171815), PCDHB9 (ENSG00000177839), PCDHB13 (ENSG00000187372), CDHR4 (ENSG00000187492), PCDH18 (ENSG00000189184), PCDHB11 (ENSG00000197479), PCDHGA1 (ENSG00000204956), PCDHA9 (ENSG00000204961), PCDHA8 (ENSG00000204962), PCDHA7 (ENSG00000204963), PCDHA5 (ENSG00000204965), PCDHA4 (ENSG00000204967), PCDHA2 (ENSG00000204969), PCDHA1 (ENSG00000204970), PCDHA13 (ENSG00000239389), PCDHGC3 (ENSG00000240184), PCDHGC5 (ENSG00000240764), PCDHGC4 (ENSG00000242419), PCDHAC2 (ENSG00000243232), PCDHAC1 (ENSG00000248383), PCDHA11 (ENSG00000249158)

Protein

Protein identifiers

Protocadherin-19 — Q8TAB3 (reviewed: Q8TAB3)

All UniProt accessions (3): A0A1B0GVC8, A0A1Y8EN23, Q8TAB3

UniProt curated annotations — full annotation on UniProt →

Function. Calcium-dependent cell-adhesion protein.

Subunit / interactions. Homodimer; antiparallel.

Subcellular location. Cell membrane.

Tissue specificity. Moderately expressed in all regions of the brain examined, with lowest levels found in the cerebellum. Moderate expression is also found in ovary, and low expression in all other tissues tested. Also detected in primary skin fibroblast.

Disease relevance. Developmental and epileptic encephalopathy 9 (DEE9) [MIM:300088] A condition characterized by seizure with onset in infancy or early childhood, cognitive impairment, and delayed development of variable severity in some patients. Additional features include autistic signs and psychosis. The disorder is sex-limited, with the phenotype being restricted to females. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8TAB3-1	1	yes
Q8TAB3-2	2
Q8TAB3-3	3

RefSeq proteins (3): NP_001098713, NP_001171809, NP_065817 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002126	Cadherin-like_dom	Domain
IPR013164	Cadherin_N	Domain
IPR015919	Cadherin-like_sf	Homologous_superfamily
IPR020894	Cadherin_CS	Conserved_site
IPR050174	Protocadherin/Cadherin-CA	Family

Pfam: PF00028, PF08266

UniProt features (191 total): binding site 78, sequence variant 45, strand 30, domain 6, helix 6, turn 6, glycosylation site 6, compositionally biased region 3, splice variant 2, region of interest 2, topological domain 2, signal peptide 1, chain 1, disulfide bond 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6VFU	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TAB3-F1	68.50	0.45

Functional residue map

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

Ligand- & substrate-binding residues (78): 31; 31; 32; 88; 90; 90; 121; 123; 124; 124; 125; 140 …

Disulfide bonds (1): 93–99

Glycosylation sites (6): 261, 420, 485, 546, 570, 676

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9830364	Formation of the nephric duct

MSigDB gene sets: 283 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_UP, GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE37336_LY6C_POS_VS_NEG_NAIVE_CD4_TCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_UP, ACTACCT_MIR196A_MIR196B, TTTGTAG_MIR520D, ATACCTC_MIR202, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_CELL_CELL_ADHESION, GTGCCTT_MIR506, CTAGGAA_MIR384, CATTTCA_MIR203, ATTACAT_MIR3803P, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_DN

GO Biological Process (2): cell adhesion (GO:0007155), homophilic cell-cell adhesion (GO:0007156)

GO Molecular Function (3): calcium ion binding (GO:0005509), cell adhesion molecule binding (GO:0050839), metal ion binding (GO:0046872)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Kidney development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	1
cell-cell adhesion	1
metal ion binding	1
protein binding	1
cation binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1086 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PCDH19	SCN1A	P35498	936
PCDH19	CDH2	P19022	896
PCDH19	CDKL5	O76039	893
PCDH19	STXBP1	P61764	872
PCDH19	KCNQ2	O43526	869
PCDH19	SLC25A22	Q9H936	847
PCDH19	SCN2A	Q99250	844
PCDH19	ARX	Q96QS3	818
PCDH19	PNKP	Q96T60	796
PCDH19	ARHGEF9	O43307	781
PCDH19	SPTAN1	Q13813	761
PCDH19	PLCB1	Q9NQ66	704
PCDH19	GABRG2	P18507	676
PCDH19	MECP2	P51608	668
PCDH19	SCN1B	Q07699	663

IntAct

9 interactions, top by confidence:

A	B	Type	Score
BRK1	CYFIP1	psi-mi:“MI:0914”(association)	0.640
IPPK	TMEM223	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM120B	psi-mi:“MI:0914”(association)	0.530
PCDHGB1	FAM171A2	psi-mi:“MI:0914”(association)	0.530
PCDH19	SPTAN1	psi-mi:“MI:0915”(physical association)	0.400
SPSB4	CCDC85C	psi-mi:“MI:0914”(association)	0.350
RYK	TNFRSF10B	psi-mi:“MI:0914”(association)	0.350
PCDH12	PCDH17	psi-mi:“MI:0914”(association)	0.350

BioGRID (35): PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Proximity Label-MS), PCDH19 (Proximity Label-MS), PCDH19 (Proximity Label-MS), PCDH19 (Proximity Label-MS), PCDH19 (Proximity Label-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Proximity Label-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS), PCDH19 (Affinity Capture-MS)

ESM2 similar proteins: A7MB46, F8W3X3, O14917, O35902, O54800, O97799, P05622, P16234, P20786, P26618, P26619, P32926, P35546, P55286, P55289, P79749, P97291, Q05030, Q08DJ5, Q13634, Q14126, Q28889, Q5RJH3, Q68SP4, Q6KEQ9, Q6W3B0, Q6WXV7, Q6WYY1, Q6X862, Q71M42, Q7TMD7, Q7TSF0, Q7YRU7, Q80TF3, Q86SJ6, Q8AXC6, Q8AXC7, Q8BIZ0, Q8N6Y1, Q8TAB3

Diamond homologs: A7MB46, D3ZE55, F8W3X3, O14917, O55134, O60330, O88689, O95206, Q5DRA2, Q5DRA3, Q5DRA4, Q5DRA5, Q5DRA6, Q5DRA7, Q5DRA8, Q5DRA9, Q5DRB0, Q5DRB1, Q5DRB2, Q5DRB3, Q5DRB4, Q5DRB5, Q5DRB6, Q5DRB7, Q5DRB8, Q5DRB9, Q5DRC0, Q5DRC1, Q5DRC2, Q5DRC6, Q5DRD3, Q5DRD6, Q5DRE0, Q5DRE1, Q5DRE3, Q5DRE4, Q5DRE5, Q5DRE6, Q5DRE7, Q5DRE8

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
NR2F1	“up-regulates quantity by expression”	PCDH19	“transcriptional regulation”
PCDH19	“up-regulates quantity by stabilization”	GABA-A	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA1	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA2	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA5	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA4	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA6	binding
PCDH19	“up-regulates quantity by stabilization”	GABRA3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1422 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	307
Likely pathogenic	89
Uncertain significance	568
Likely benign	302
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1002551	NM_001184880.2(PCDH19):c.688G>A (p.Asp230Asn)	Pathogenic
1021031	NM_001184880.2(PCDH19):c.445C>T (p.Pro149Ser)	Pathogenic
1023566	NM_001184880.2(PCDH19):c.1682C>T (p.Pro561Leu)	Pathogenic
1027675	NM_001184880.2(PCDH19):c.1081_1094del (p.Ser361fs)	Pathogenic
1045922	NM_001184880.2(PCDH19):c.1240G>A (p.Glu414Lys)	Pathogenic
1059075	NM_001184880.2(PCDH19):c.1297C>A (p.Leu433Met)	Pathogenic
1067709	NM_001184880.2(PCDH19):c.3G>A (p.Met1Ile)	Pathogenic
1068161	NM_001184880.2(PCDH19):c.696T>G (p.Asn232Lys)	Pathogenic
1069328	NM_001184880.2(PCDH19):c.1671del (p.Asn557fs)	Pathogenic
1069939	NM_001184880.2(PCDH19):c.1985_1995del (p.Leu662fs)	Pathogenic
1070780	NM_001184880.2(PCDH19):c.1425_1426del (p.Ser476fs)	Pathogenic
1070981	NM_001184880.2(PCDH19):c.291dup (p.Lys98fs)	Pathogenic
1071350	NM_001184880.2(PCDH19):c.1416_1420del (p.Leu473fs)	Pathogenic
1071427	NM_001184880.2(PCDH19):c.1681C>T (p.Pro561Ser)	Pathogenic
1071428	NM_001184880.2(PCDH19):c.1022A>G (p.Asp341Gly)	Pathogenic
1071429	NM_001184880.2(PCDH19):c.746A>G (p.Glu249Gly)	Pathogenic
1071820	NM_001184880.2(PCDH19):c.2662dup (p.His888fs)	Pathogenic
1072832	NM_001184880.2(PCDH19):c.714del (p.Phe238fs)	Pathogenic
1072976	NC_000023.10:g.(?99596891)(99597083_?)del	Pathogenic
1073149	NM_001184880.2(PCDH19):c.833del (p.Tyr278fs)	Pathogenic
1073565	NM_001184880.2(PCDH19):c.2764C>T (p.Gln922Ter)	Pathogenic
1073814	NM_001184880.2(PCDH19):c.1339A>G (p.Asn447Asp)	Pathogenic
1073896	NM_001184880.2(PCDH19):c.2619del (p.Glu874fs)	Pathogenic
1074349	NM_001184880.2(PCDH19):c.1189C>T (p.Gln397Ter)	Pathogenic
1075007	NM_001184880.2(PCDH19):c.807_810dup (p.Gly271fs)	Pathogenic
1075577	NM_001184880.2(PCDH19):c.2147+1G>T	Pathogenic
1076844	NM_001184880.2(PCDH19):c.577G>T (p.Glu193Ter)	Pathogenic
11016	NM_001184880.2(PCDH19):c.1322T>A (p.Val441Glu)	Pathogenic
11017	NM_001184880.2(PCDH19):c.253C>T (p.Gln85Ter)	Pathogenic
11018	NM_001184880.2(PCDH19):c.2012C>G (p.Ser671Ter)	Pathogenic

SpliceAI

1839 predictions. Top by Δscore:

Variant	Effect	Δscore
X:100296263:T:TA	donor_gain	1.0000
X:100310865:T:TA	donor_gain	1.0000
X:100341897:CCTTA:C	donor_loss	1.0000
X:100341898:CTT:C	donor_loss	1.0000
X:100341899:TTA:T	donor_loss	1.0000
X:100341900:TA:T	donor_loss	1.0000
X:100341901:ACCAT:A	donor_loss	1.0000
X:100341902:C:A	donor_loss	1.0000
X:100350642:ATACC:A	donor_loss	1.0000
X:100350643:TA:T	donor_loss	1.0000
X:100350644:A:AG	donor_loss	1.0000
X:100350645:C:A	donor_loss	1.0000
X:100350645:CCT:C	donor_gain	1.0000
X:100350701:CAGT:C	acceptor_gain	1.0000
X:100350702:AGTCT:A	acceptor_loss	1.0000
X:100350703:GT:G	acceptor_gain	1.0000
X:100350704:TCTGC:T	acceptor_loss	1.0000
X:100350705:C:CA	acceptor_loss	1.0000
X:100350705:C:CC	acceptor_gain	1.0000
X:100350710:A:AC	acceptor_gain	1.0000
X:100369985:T:TA	donor_gain	1.0000
X:100402513:G:C	donor_gain	1.0000
X:100402518:ACTC:A	donor_loss	1.0000
X:100402519:CTCA:C	donor_loss	1.0000
X:100402520:TCACC:T	donor_loss	1.0000
X:100402521:CAC:C	donor_loss	1.0000
X:100402522:A:AC	donor_gain	1.0000
X:100402523:C:CC	donor_gain	1.0000
X:100402523:CCT:C	donor_gain	1.0000
X:100402847:CAATT:C	acceptor_gain	1.0000

AlphaMissense

7563 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:100406925:T:G	D558A	1.000
X:100406927:G:C	N557K	1.000
X:100406927:G:T	N557K	1.000
X:100406988:T:G	D537A	1.000
X:100406989:C:G	D537H	1.000
X:100406994:G:T	A535D	1.000
X:100407060:C:A	G513V	1.000
X:100407060:C:T	G513D	1.000
X:100407081:A:T	V506D	1.000
X:100407130:A:C	Y490D	1.000
X:100407168:G:T	A477D	1.000
X:100407207:T:A	E464V	1.000
X:100407240:A:C	F453C	1.000
X:100407240:A:G	F453S	1.000
X:100407246:G:T	P451Q	1.000
X:100407247:G:A	P451S	1.000
X:100407255:T:G	D448A	1.000
X:100407257:A:C	N447K	1.000
X:100407257:A:T	N447K	1.000
X:100407264:T:A	D445V	1.000
X:100407265:C:G	D445H	1.000
X:100407330:A:T	I423N	1.000
X:100407336:A:G	L421P	1.000
X:100407360:C:G	R413P	1.000
X:100407361:G:T	R413S	1.000
X:100407384:A:T	I405N	1.000
X:100407417:A:G	F394S	1.000
X:100407597:A:T	V334D	1.000
X:100407603:A:T	V332D	1.000
X:100407639:T:G	D320A	1.000

dbSNP variants (sampled 300 via entrez): RS1000008214 (X:100371992 A>G), RS1000107957 (X:100381058 A>G), RS1000183309 (X:100374920 C>A,T), RS1000227554 (X:100362689 C>T), RS1000280042 (X:100362410 A>G), RS1000289266 (X:100316436 G>A), RS1000303215 (X:100343712 G>A), RS1000333555 (X:100337241 G>A), RS1000344330 (X:100385849 G>A), RS1000373214 (X:100301727 T>A,C), RS1000418335 (X:100353414 C>T), RS1000430285 (X:100302427 T>C), RS1000431471 (X:100361557 G>T), RS1000505849 (X:100371727 C>T), RS1000525255 (X:100371830 T>C,G)

Disease associations

OMIM: gene MIM:300460 | disease phenotypes: MIM:300088, MIM:308350, MIM:605899, MIM:117100

GenCC curated gene-disease

Disease	Classification	Inheritance
developmental and epileptic encephalopathy, 9	Definitive	X-linked
X-linked complex neurodevelopmental disorder	Definitive	X-linked
Dravet syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (10): developmental and epileptic encephalopathy, 9 (MONDO:0010246), developmental and epileptic encephalopathy, 1 (MONDO:0010632), glycine encephalopathy (MONDO:0011612), strabismus (MONDO:0003432), epilepsy (MONDO:0005027), autism spectrum disorder (MONDO:0005258), intellectual disability (MONDO:0001071), self-limited epilepsy with centrotemporal spikes (MONDO:0007295), X-linked complex neurodevelopmental disorder (MONDO:0100148), (MONDO:0011794)

Orphanet (6): Female restricted epilepsy with intellectual disability (Orphanet:101039), X-linked intellectual disability-epilepsy syndrome (Orphanet:2076), Glycine encephalopathy (Orphanet:407), Self-limited epilepsy with centrotemporal spikes (Orphanet:1945), NON RARE IN EUROPE: Autism (Orphanet:106), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

73 total (30 of 73 shown, HPO-id order):

HPO	Term
HP:0000466	Limited neck range of motion
HP:0000708	Atypical behavior
HP:0000709	Psychosis
HP:0000718	Aggressive behavior
HP:0000722	Compulsive behaviors
HP:0000729	Autistic behavior
HP:0000736	Short attention span
HP:0000739	Anxiety
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000980	Pallor
HP:0001249	Intellectual disability
HP:0001256	Mild intellectual disability
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001300	Parkinsonism
HP:0001327	Photosensitive myoclonic seizure
HP:0001336	Myoclonus
HP:0001417	X-linked inheritance
HP:0001763	Pes planus
HP:0002063	Rigidity
HP:0002067	Bradykinesia
HP:0002069	Bilateral tonic-clonic seizure
HP:0002119	Ventriculomegaly
HP:0002121	Generalized non-motor (absence) seizure
HP:0002123	Generalized myoclonic seizure
HP:0002133	Status epilepticus
HP:0002187	Profound intellectual disability
HP:0002283	Global brain atrophy
HP:0002307	Drooling

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D004827	Epilepsy	C10.228.140.490
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D013285	Strabismus	C10.292.562.887; C11.590.810
C564715	Epilepsy, Female-Restricted, with Mental Retardation (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	8
trichostatin A	affects cotreatment, increases expression, decreases expression	4
methylmercuric chloride	increases expression	2
Benzo(a)pyrene	affects methylation, decreases methylation, increases mutagenesis	2
N(4)-hydroxycytidine	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
4-chloro-1,2-diaminobenzene	affects response to substance	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
bisphenol S	decreases methylation	1
Decitabine	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Arsenic Trioxide	decreases expression	1
Arsenicals	decreases expression	1
Calcium	affects binding	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	decreases expression	1
Nickel	decreases expression	1
Niclosamide	decreases expression	1
Silicon Dioxide	increases expression	1
Thiram	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1
Aflatoxin B1	decreases methylation	1
Antirheumatic Agents	increases expression	1

Cellosaurus cell lines

12 cell lines: 12 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C9RV	HPS1655	Induced pluripotent stem cell	Female
CVCL_C9RW	HPS1656	Induced pluripotent stem cell	Female
CVCL_C9RX	HPS1657	Induced pluripotent stem cell	Female
CVCL_C9RY	HPS1658	Induced pluripotent stem cell	Female
CVCL_C9RZ	HPS1659	Induced pluripotent stem cell	Female
CVCL_C9S0	HPS1660	Induced pluripotent stem cell	Female
CVCL_C9WY	HPS2313	Induced pluripotent stem cell	Female
CVCL_C9WZ	HPS2314	Induced pluripotent stem cell	Female
CVCL_C9X0	HPS2315	Induced pluripotent stem cell	Female
CVCL_C9X1	HPS2316	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00461656	PHASE4	COMPLETED	Povidone-iodine Antisepsis for Strabismus Surgery
NCT01901588	PHASE4	COMPLETED	Efficacy of Single-Shot Dexmedetomidine Versus Placebo in Preventing Pediatric Emergence Delirium in Strabismus Surgery
NCT02379546	PHASE4	COMPLETED	The Effect of Anaesthesia Depth on Oculo-cardiac Reflex
NCT03349515	PHASE4	COMPLETED	The Effect of Povidone-iodine Ophthalmic Surgical Prep Solution on Respiration in Children Undergoing Strabismus Surgery With General Anesthesia.
NCT04549844	PHASE4	UNKNOWN	Peribulbar Block for Prevention of Oculocardiac Reflex
NCT06035757	PHASE4	RECRUITING	The Occurrence of Emergence Agitation in Pediatric Strabismus Surgery
NCT06560268	PHASE4	NOT_YET_RECRUITING	Low Flow Anesthesia in Children Undergoing Strabismus Surgery
NCT00004637	PHASE4	COMPLETED	Double-Blind, Placebo-Controlled Trial of Vitamin E as Add-on Therapy for Children With Epilepsy
NCT00043914	PHASE4	COMPLETED	Measurement Of Serum Levels Of Two Antiepileptic Drugs During Conversion In Patients With Epilepsy
NCT00132223	PHASE4	UNKNOWN	Effects on the Diagnostic Accuracy of Magnetic Imaging Angiographies of the Supra-Aortic Vessels by Three Different Magnetic Resonance Contrast Agents in Patients
NCT00133081	PHASE4	UNKNOWN	Study to Improve the Treatment of Epilepsy (SITE)
NCT00137709	PHASE4	UNKNOWN	Hormone Profiles in Adults With Newly Diagnosed Epilepsy
NCT00154076	PHASE4	COMPLETED	A Multicenter Comparative Trial of Zonisamide and Topiramate as Initial Monotherapy in Untreated Epilepsies
NCT00165828	PHASE4	TERMINATED	Efficacy and Safety of an add-on Treatment With Zonisamide in Adults With Focal Epileptic Seizures With or Without Secondary Generalization
NCT00181116	PHASE4	COMPLETED	Levetiracetam for Benign Rolandic Epilepsy
NCT00207935	PHASE4	COMPLETED	Use of Sustained Release Antiepileptic Medication (Depakote® ER) for Pediatric Epilepsy in a Mental Retardation/Developmental Disorder Population
NCT00215592	PHASE4	COMPLETED	Open Label, Zonegran (Zonisamide) In Partial Onset Seizures
NCT00266604	PHASE4	COMPLETED	A Study to Evaluate the Dosing, Effectiveness and Safety of Topiramate for the Treatment of Epilepsy
NCT00288639	PHASE4	COMPLETED	Lyrica (Pregabalin) Administered as an Add-on Therapy for Partial Seizures (LEADER).
NCT00312676	PHASE4	UNKNOWN	Compare Tolerability of an Overnight Switch to Gradual Switch Between Two Different Forms of Depakote
NCT00323947	PHASE4	COMPLETED	Methylphenidate for Treating Attention Deficit Hyperactivity Disorder in Children With Both ADHD and Epilepsy
NCT00385411	PHASE4	COMPLETED	Study of Valproate in Young Patients Suffering From Epilepsy
NCT00522418	PHASE4	TERMINATED	Study Comparing Best Medical Practice With or Without VNS Therapy in Pharmacoresistant Partial Epilepsy Patients
NCT00537940	PHASE4	COMPLETED	Comparative Study Of Pregabalin And Gabapentin As Adjunctive Therapy In Subjects With Partial Seizures
NCT00552526	PHASE4	UNKNOWN	Ketogenic Diet vs.Antiepileptic Drug Treatment in Drug Resistant Epilepsy
NCT00564915	PHASE4	COMPLETED	RCT of the Efficacy of the Ketogenic Diet in the Treatment of Epilepsy
NCT00571155	PHASE4	COMPLETED	Trial of Levetiracetam in Patients With Primary Brain Tumors and Symptomatic Seizures Who Undergo Surgery
NCT00572195	PHASE4	COMPLETED	RNS® System LTT Study
NCT00610532	PHASE4	TERMINATED	Evaluating the Transporter Protein Inhibitor Probenecid In Patients With Epilepsy
NCT00630357	PHASE4	COMPLETED	Trial to Evaluate the Safety and Efficacy of Keppra After Conversion to Mono-therapy in Subjects With Partial Epilepsy
NCT00630630	PHASE4	COMPLETED	Study on Safety and Efficacy of Levetiracetam in the Adjunctive Treatment of Female Subjects With C1 Catamenial Epilepsy
NCT00630968	PHASE4	COMPLETED	S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00631150	PHASE4	COMPLETED	A Phase IV-Pharmacovigilance Study of Keppra Greece - S.K.A.T.E.: Safety of Keppra as Adjunctive Therapy in Epilepsy
NCT00659958	PHASE4	COMPLETED	ZAGAL Study: Evaluating Effectiveness and Tolerability of Zonisamide as Adjunctive Therapy in Patients With Partial Onset Seizures Treated With Two Antiepileptic Drugs
NCT00713622	PHASE4	COMPLETED	Comparing The Effect On Cognition Of Adjunctive Therapy With Zonisamide Versus Sodium Valproate
NCT00807989	PHASE4	COMPLETED	The Efficacy and Safety of Low Dose Combination of LTG and VPA Compared to CBZ Monotherapy
NCT00832884	PHASE4	COMPLETED	The Safety of Intravenous Lacosamide
NCT00869622	PHASE4	COMPLETED	Antiepileptic Drugs and Osteoporotic Prevention Trial
NCT00896987	PHASE4	COMPLETED	Lamotrigine Cognitive Function Study in Adult Untreated Epilepsies
NCT00952081	PHASE4	COMPLETED	A Pilot Study to Evaluate Efficacy and Safety of Clevidipine in Neurosurgical Patients