RPH3A

Summary

RPH3A (rabphilin 3A, HGNC:17056) is a protein-coding gene on chromosome 12q24.13, encoding Rabphilin-3A (Q9Y2J0). Plays an essential role in docking and fusion steps of regulated exocytosis.

The protein encoded by this gene is thought to be an effector for RAB3A, which is a small G protein that acts in the late stages of neurotransmitter exocytosis. The encoded protein may be involved in neurotransmitter release and synaptic vesicle traffic.

Source: NCBI Gene 22895 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 19
• Clinical variants (ClinVar): 118 total — 1 pathogenic
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001143854

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17056
Approved symbol	RPH3A
Name	rabphilin 3A
Location	12q24.13
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0985, rabphilin, exophilin-1
Ensembl gene	ENSG00000089169
Ensembl biotype	protein_coding
OMIM	612159
Entrez	22895

Gene structure

Transcript identifiers

Ensembl transcripts: 30 — 22 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000389385, ENST00000415485, ENST00000543106, ENST00000546426, ENST00000546687, ENST00000546703, ENST00000547099, ENST00000547222, ENST00000547686, ENST00000547728, ENST00000547840, ENST00000548197, ENST00000548866, ENST00000549324, ENST00000549736, ENST00000549769, ENST00000549913, ENST00000550901, ENST00000551052, ENST00000551198, ENST00000551593, ENST00000551748, ENST00000552352, ENST00000552667, ENST00000552679, ENST00000552755, ENST00000553114, ENST00000942157, ENST00000942158, ENST00000942159

RefSeq mRNA: 6 — MANE Select: NM_001143854 NM_001143854, NM_001347952, NM_001347953, NM_001347954, NM_001347955, NM_014954

CCDS: CCDS31904, CCDS44979

Canonical transcript exons

ENST00000389385 — 22 exons

Exon	Start	End
ENSE00001512449	112792143	112792263
ENSE00002366702	112791748	112792012
ENSE00003460585	112875679	112875741
ENSE00003466802	112828301	112828389
ENSE00003472924	112866757	112866840
ENSE00003480164	112881772	112881846
ENSE00003480453	112890024	112890080
ENSE00003535358	112879119	112879198
ENSE00003536499	112887797	112887923
ENSE00003553301	112836491	112836502
ENSE00003569110	112896650	112898881
ENSE00003581256	112876642	112876866
ENSE00003601537	112875084	112875170
ENSE00003613092	112890849	112891003
ENSE00003613731	112847696	112847842
ENSE00003633528	112869759	112869797
ENSE00003640715	112869893	112870039
ENSE00003642022	112883293	112883402
ENSE00003666931	112894578	112894659
ENSE00003670321	112895777	112895873
ENSE00003676637	112868430	112868595
ENSE00003786825	112865414	112865543

Expression profiles

Bgee: expression breadth ubiquitous, 194 present calls, max score 97.42.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 4.6017 / max 602.8518, expressed in 122 samples.

FANTOM5 promoters (13 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128088	1.7598	100
128092	0.6179	89
128090	0.5330	81
128091	0.2677	62
128082	0.2306	71
128087	0.2049	65
128083	0.1969	73
128089	0.1802	56
128084	0.1757	62
128093	0.1749	64

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.42	gold quality
prefrontal cortex	UBERON:0000451	97.14	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.81	gold quality
cerebellar hemisphere	UBERON:0002245	96.66	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	96.64	gold quality
cerebellar cortex	UBERON:0002129	96.60	gold quality
frontal cortex	UBERON:0001870	96.44	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.02	gold quality
orbitofrontal cortex	UBERON:0004167	95.94	gold quality
frontal pole	UBERON:0002795	95.91	gold quality
cerebellum	UBERON:0002037	95.89	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.88	gold quality
superior frontal gyrus	UBERON:0002661	95.83	gold quality
cingulate cortex	UBERON:0003027	95.59	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.57	gold quality
anterior cingulate cortex	UBERON:0009835	95.53	gold quality
neocortex	UBERON:0001950	95.16	gold quality
parietal lobe	UBERON:0001872	95.02	gold quality
primary visual cortex	UBERON:0002436	95.00	gold quality
postcentral gyrus	UBERON:0002581	94.96	gold quality
occipital lobe	UBERON:0002021	94.87	gold quality
cerebral cortex	UBERON:0000956	93.08	gold quality
telencephalon	UBERON:0001893	91.77	gold quality
nucleus accumbens	UBERON:0001882	91.47	gold quality
caudate nucleus	UBERON:0001873	91.21	gold quality
entorhinal cortex	UBERON:0002728	90.55	gold quality
temporal lobe	UBERON:0001871	90.06	gold quality
amygdala	UBERON:0001876	89.64	gold quality
middle temporal gyrus	UBERON:0002771	89.23	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.45

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

112 targeting RPH3A, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-6857-5P	99.87	65.32	985
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-548AJ-5P	99.78	71.12	3085
HSA-MIR-548F-5P	99.78	71.02	3093

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 11)

• Rabphilin-3A and Rab3A are present in normal mouse, rat, and human kidneys, with an exclusively glomerular expression and a comma-like pattern of positivity along the glomerular capillary wall, suggestive for podocyte staining. (PMID:12937130)
• Since rab3a participates in the docking and fusion of synaptic vesicles, and rabsa binding to alpha-synuclein is increased in Lewy body disease (LBD), it can be suggested that exocytosis of neurotransmitters may be impaired in LBD. (PMID:15207266)
• We found a reduction in rabphilin 3a, a protein involved in vesicle docking and recycling, in Huntington disease[HD] brains of grade III and IV. A deficient pre-synaptic transmitter release may underlie some symptoms of HD. (PMID:17877635)
• rabphilin 3A loss correlated with dementia severity, cholinergic deafferentation, and increased beta-amyloid concentrations (PMID:24200817)
• Structural insights into the Ca2+ and PI(4,5)P2 binding modes of the C2 domains of rabphilin 3A and synaptotagmin 1. (PMID:24302762)
• Rabphilin-3A is a major autoantigen in Lymphocytic infundibulo-neurohypophysitis (LINH). Autoantibodies to rabphilin-3A may serve as biomarker for the diagnosis of LINH and be useful for the differential diagnosis of Central diabetes insipidus. (PMID:25919460)
• Findings indicate that Rph3A activity is linked to the aberrant synaptic localization of GluN2A-expressing NMDARs characterizing levodopa-induced dyskinesias; suggest that Rph3A/GluN2A complex could represent an innovative therapeutic target for those pathological conditions where NMDAR composition is significantly altered. (PMID:28823933)
• Rab27/Rabphilin3a/GRAB/Rab3 constitutes a signaling module in sperm exocytosis. (PMID:30599141)
• Protein and fat intake interacts with the haplotype of PTPN11_rs11066325, RPH3A_rs886477, and OAS3_rs2072134 to modulate serum HDL concentrations in middle-aged people. (PMID:31006500)
• Small GTPase ARF6 Is a Coincidence-Detection Code for RPH3A Polarization in Neutrophil Polarization. (PMID:31924649)
• Missense variants in RPH3A cause defects in excitatory synaptic function and are associated with a clinically variable neurodevelopmental disorder. (PMID:37403762)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rph3aa	ENSDARG00000063436
danio_rerio	rph3ab	ENSDARG00000105490
mus_musculus	Rph3a	ENSMUSG00000029608
rattus_norvegicus	Rph3a	ENSRNOG00000001368

Paralogs (31): SYT7 (ENSG00000011347), SYT13 (ENSG00000019505), SYT1 (ENSG00000067715), SYTL4 (ENSG00000102362), SYT17 (ENSG00000103528), SYT10 (ENSG00000110975), SYT5 (ENSG00000129990), SYT11 (ENSG00000132718), SYT4 (ENSG00000132872), SYT6 (ENSG00000134207), SYTL2 (ENSG00000137501), SYT16 (ENSG00000139973), SYTL1 (ENSG00000142765), SYT14 (ENSG00000143469), SYT2 (ENSG00000143858), SYTL5 (ENSG00000147041), SYT8 (ENSG00000149043), DOC2A (ENSG00000149927), SYTL3 (ENSG00000164674), TC2N (ENSG00000165929), SYT9 (ENSG00000170743), SYT12 (ENSG00000173227), RPH3AL (ENSG00000181031), C2CD4C (ENSG00000183186), C2CD4A (ENSG00000198535), SYT15 (ENSG00000204176), C2CD4B (ENSG00000205502), SYT3 (ENSG00000213023), C2CD4D (ENSG00000225556), DOC2B (ENSG00000272636), SYT15B (ENSG00000277758)

Protein

Protein identifiers

Rabphilin-3A — Q9Y2J0 (reviewed: Q9Y2J0)

Alternative names: Exophilin-1

All UniProt accessions (16): Q9Y2J0, F8VNP7, F8VNU2, F8VNW3, F8VP47, F8VR41, F8VRJ1, F8VTR7, F8VV58, F8VVK8, F8VZS2, F8W045, F8W116, F8W131, F8W1A3, F8W1K7

UniProt curated annotations — full annotation on UniProt →

Function. Plays an essential role in docking and fusion steps of regulated exocytosis. At the presynaptic level, RPH3A is recruited by RAB3A to the synaptic vesicle membrane in a GTP-dependent manner where it modulates synaptic vesicle trafficking and calcium-triggered neurotransmitter release. In the post-synaptic compartment, forms a ternary complex with GRIN2A and DLG4 and regulates NMDA receptor stability. Also plays a role in the exocytosis of arginine vasopressin hormone.

Subunit / interactions. Interacts with RAB3B, RAB3C, RAB3D, RAB8A, RAB27A and RAB27B. Interacts with RAB3A; this interaction recruits RPH3A to synaptic vesicules. Interacts (via C2B domain) with SNAP25. Interacts with deubiquitinating enzyme CAND1; this interaction results in the deubiquitination of RPH3A. Interacts with GRIN2A and DLG4; this ternary complex regulates NMDA receptor composition at postsynaptic membranes. Interacts with SNCA.

Subcellular location. Cytoplasmic vesicle. Secretory vesicle. Synaptic vesicle membrane. Cell projection. Dendritic spine. Postsynaptic cell membrane. Membrane.

Post-translational modifications. Ubiquitinated. Deubiquitinated by CAND1 to prevent its degradation.

Domain organisation. Binds calcium via the C2 domains. The calcium-bound C2 domains mediate interactions with phospholipid bilayers.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y2J0-1	1	yes
Q9Y2J0-2	2

RefSeq proteins (6): NP_001137326, NP_001334881, NP_001334882, NP_001334883, NP_001334884, NP_055769 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR001565	Synaptotagmin	Domain
IPR010911	Rab_BD	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR028698	FYVE_RPH3A	Domain
IPR035892	C2_domain_sf	Homologous_superfamily
IPR041282	FYVE_2	Domain
IPR043566	Rabphilin/DOC2/Noc2	Family
IPR047022	Rabphilin_Doc2_C2A	Domain

Pfam: PF00168, PF02318

UniProt features (45 total): binding site 28, compositionally biased region 5, modified residue 4, domain 3, region of interest 2, chain 1, zinc finger region 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y2J0-F1	69.79	0.39

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 (28): 98; 101; 115; 118; 123; 126; 140; 143; 422; 423; 423; 429 …

Post-translational modifications (4): 226, 272, 692, 693

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 198 (showing top): GOBP_REGULATION_OF_VESICLE_FUSION, GOBP_POSITIVE_REGULATION_OF_CALCIUM_ION_DEPENDENT_EXOCYTOSIS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_EXOCYTOSIS, JOHANSSON_GLIOMAGENESIS_BY_PDGFB_DN, GOBP_NEUROTRANSMITTER_TRANSPORT, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, GOMF_GTPASE_BINDING, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT

GO Biological Process (6): intracellular protein transport (GO:0006886), synaptic vesicle priming (GO:0016082), positive regulation of calcium ion-dependent exocytosis (GO:0045956), spontaneous neurotransmitter secretion (GO:0061669), calcium-dependent activation of synaptic vesicle fusion (GO:0099502), protein transport (GO:0015031)

GO Molecular Function (13): calcium ion binding (GO:0005509), calcium-dependent phospholipid binding (GO:0005544), phosphatidylinositol-4,5-bisphosphate binding (GO:0005546), zinc ion binding (GO:0008270), selenium binding (GO:0008430), small GTPase binding (GO:0031267), phosphate ion binding (GO:0042301), protein-containing complex binding (GO:0044877), inositol 1,4,5 trisphosphate binding (GO:0070679), phosphatidylinositol phosphate binding (GO:1901981), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (15): synaptic vesicle (GO:0008021), extrinsic component of membrane (GO:0019898), secretory granule (GO:0030141), synaptic vesicle membrane (GO:0030672), protein-containing complex (GO:0032991), neuron projection (GO:0043005), dendritic spine (GO:0043197), synapse (GO:0045202), postsynaptic membrane (GO:0045211), extrinsic component of synaptic vesicle membrane (GO:0098850), plasma membrane (GO:0005886), membrane (GO:0016020), transport vesicle membrane (GO:0030658), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	3
cellular anatomical structure	3
intracellular protein localization	2
synaptic vesicle exocytosis	2
phospholipid binding	2
anion binding	2
membrane	2
postsynapse	2
protein transport	1
intracellular transport	1
protein-containing complex assembly	1
exocytic process	1
calcium-ion regulated exocytosis	1
regulation of calcium ion-dependent exocytosis	1
positive regulation of regulated secretory pathway	1
neurotransmitter secretion	1
spontaneous synaptic transmission	1
positive regulation of synaptic vesicle fusion to presynaptic active zone membrane	1
transport	1
establishment of protein localization	1
metal ion binding	1
phosphatidylinositol phosphate binding	1
phosphatidylinositol bisphosphate binding	1
transition metal ion binding	1
small molecule binding	1
GTPase binding	1
alcohol binding	1
cation binding	1
exocytic vesicle	1
presynapse	1
endomembrane system	1
secretory vesicle	1
synaptic vesicle	1
exocytic vesicle membrane	1
cellular_component	1
plasma membrane bounded cell projection	1
dendrite	1
neuron spine	1
cell junction	1
synaptic membrane	1

Protein interactions and networks

STRING

1338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RPH3A	RAB3A	P20336	999
RPH3A	RAB27A	P51159	915
RPH3A	MLPH	Q9BV36	812
RPH3A	MYO5A	Q9Y4I1	793
RPH3A	RAB3C	Q96E17	765
RPH3A	SNAP25	P13795	746
RPH3A	RAB3B	P20337	732
RPH3A	WTIP	A6NIX2	728
RPH3A	RAB27B	O00194	726
RPH3A	GRIN2A	Q12879	695
RPH3A	LIMD1	Q9UGP4	680
RPH3A	STX1A	Q16623	636
RPH3A	STXBP1	P61764	632
RPH3A	RAB8A	P24407	629
RPH3A	UNC13B	O14795	610

IntAct

11 interactions, top by confidence:

A	B	Type	Score
PALS1	LIN7A	psi-mi:“MI:0914”(association)	0.870
TP63	TP73	psi-mi:“MI:0914”(association)	0.770
RPH3A	CASK	psi-mi:“MI:0915”(physical association)	0.580
CASK	RPH3A	psi-mi:“MI:0915”(physical association)	0.580
RAB3A	RPH3A	psi-mi:“MI:0915”(physical association)	0.370
PRNP	WDR91	psi-mi:“MI:0914”(association)	0.350
SYDE1	POLR2D	psi-mi:“MI:0914”(association)	0.350
ALOX15B	TAF5L	psi-mi:“MI:0914”(association)	0.350
RPH3A	RAB27A	psi-mi:“MI:0914”(association)	0.350
CFAP298	RPH3A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (47): RPH3A (Affinity Capture-MS), RPH3A (Affinity Capture-MS), DOC2B (Affinity Capture-MS), RAB8B (Affinity Capture-MS), RPH3A (Affinity Capture-MS), RAB27A (Affinity Capture-MS), RPH3A (Affinity Capture-MS), RAB8A (Affinity Capture-MS), UBE3A (Affinity Capture-MS), RPH3A (Reconstituted Complex), CAND1 (Affinity Capture-MS), CAND1 (Affinity Capture-Western), RPH3A (Affinity Capture-Western), SNAP25 (Affinity Capture-Western), RPH3A (Two-hybrid)

ESM2 similar proteins: A0A075F932, A1ZBD6, K8FE10, O08835, P05130, P13677, P13678, P21521, P21579, P21707, P23678, P24505, P24506, P24507, P29101, P34693, P34722, P35991, P40749, P41823, P46096, P46097, P47191, P48018, P50232, P51813, P70169, P70610, P70611, P97610, Q06187, Q06846, Q14184, Q16975, Q5M7N9, Q5R4J5, Q60HC0, Q69ZN7, Q7TNF0, Q7ZWU7

Diamond homologs: A0A075F932, A0FGR8, A4IJ05, K8FE10, O00445, O00750, O08625, O08835, O35681, O43581, P04409, P05128, P05129, P05130, P05696, P10102, P10829, P13677, P17252, P20444, P21521, P21579, P21707, P24505, P24506, P24507, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P47861, P48018, P50232

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	105
Likely benign	5
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
801393	NM_001143854.2(RPH3A):c.763G>C (p.Gly255Arg)	Pathogenic

SpliceAI

2846 predictions. Top by Δscore:

Variant	Effect	Δscore
12:112828390:G:GG	donor_gain	1.0000
12:112847694:A:AG	acceptor_gain	1.0000
12:112847695:G:GG	acceptor_gain	1.0000
12:112847840:CGGG:C	donor_loss	1.0000
12:112847841:GGGT:G	donor_loss	1.0000
12:112847842:GGTGA:G	donor_loss	1.0000
12:112847843:G:C	donor_loss	1.0000
12:112847844:T:A	donor_loss	1.0000
12:112865521:T:TA	donor_gain	1.0000
12:112865522:A:AA	donor_gain	1.0000
12:112865523:G:GG	donor_gain	1.0000
12:112865531:GGACT:G	donor_gain	1.0000
12:112865532:GACTG:G	donor_gain	1.0000
12:112865540:GAAG:G	donor_gain	1.0000
12:112865541:AAGG:A	donor_loss	1.0000
12:112865543:GG:G	donor_loss	1.0000
12:112865544:GTATC:G	donor_loss	1.0000
12:112866265:T:TG	donor_gain	1.0000
12:112866755:A:AG	acceptor_gain	1.0000
12:112866756:G:GA	acceptor_gain	1.0000
12:112866756:GA:G	acceptor_gain	1.0000
12:112866756:GAAC:G	acceptor_gain	1.0000
12:112866836:GGGAG:G	donor_gain	1.0000
12:112866837:GGAG:G	donor_gain	1.0000
12:112866837:GGAGG:G	donor_gain	1.0000
12:112866838:GAGG:G	donor_gain	1.0000
12:112866838:GAGGT:G	donor_loss	1.0000
12:112866840:GGT:G	donor_loss	1.0000
12:112866841:G:A	donor_loss	1.0000
12:112866842:T:G	donor_loss	1.0000

AlphaMissense

4555 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:112847785:T:A	I58N	1.000
12:112847803:G:C	R64P	1.000
12:112847805:G:C	A65P	1.000
12:112865475:T:A	C98S	1.000
12:112865475:T:C	C98R	1.000
12:112865476:G:A	C98Y	1.000
12:112865476:G:C	C98S	1.000
12:112865477:C:G	C98W	1.000
12:112865484:T:C	C101R	1.000
12:112865485:G:A	C101Y	1.000
12:112865526:T:A	C115S	1.000
12:112865526:T:C	C115R	1.000
12:112865527:G:A	C115Y	1.000
12:112865527:G:C	C115S	1.000
12:112865528:T:G	C115W	1.000
12:112865535:T:C	C118R	1.000
12:112865536:G:A	C118Y	1.000
12:112866763:T:C	C123R	1.000
12:112866764:G:A	C123Y	1.000
12:112866765:C:G	C123W	1.000
12:112866772:T:A	C126S	1.000
12:112866772:T:C	C126R	1.000
12:112866773:G:C	C126S	1.000
12:112866814:T:A	C140S	1.000
12:112866814:T:C	C140R	1.000
12:112866815:G:A	C140Y	1.000
12:112866815:G:C	C140S	1.000
12:112866815:G:T	C140F	1.000
12:112866816:C:G	C140W	1.000
12:112866823:T:A	C143S	1.000

dbSNP variants (sampled 300 via entrez): RS1000011430 (12:112618225 C>G), RS1000018780 (12:112753044 G>A), RS1000043941 (12:112849121 G>A), RS1000054145 (12:112760661 A>G), RS1000066546 (12:112717866 G>T), RS1000069533 (12:112802913 G>A,T), RS1000075988 (12:112842878 A>G), RS1000081411 (12:112775867 T>C), RS1000108909 (12:112884901 A>G), RS1000113392 (12:112629080 A>G), RS1000123697 (12:112718155 A>G), RS1000148744 (12:112823903 A>G), RS1000149722 (12:112582732 G>A), RS1000165770 (12:112628850 G>A,C), RS1000176888 (12:112784403 C>T)

Disease associations

OMIM: gene MIM:612159 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
complex neurodevelopmental disorder	Moderate	Autosomal dominant
congenital myasthenic syndrome	Limited	Autosomal recessive

Mondo (3): congenital myasthenic syndrome (MONDO:0018940), complex neurodevelopmental disorder (MONDO:0100038), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

19 associations (top):

Study	Trait	p-value
GCST001337_38	Platelet count	1.000000e-08
GCST005441_8	Alcohol consumption (max-drinks)	2.000000e-12
GCST005951_2	Body mass index	9.000000e-09
GCST006004_4	Low density lipoprotein cholesterol levels	8.000000e-09
GCST006030_11	Chloride levels	3.000000e-09
GCST006666_15	Lipid traits (pleiotropy) (HIPO component 1)	4.000000e-09
GCST007840_1	Low HDL-cholesterol levels	3.000000e-13
GCST007840_2	Low HDL-cholesterol levels	2.000000e-07
GCST008971_121	Urate levels	9.000000e-07
GCST008972_120	Urate levels	8.000000e-06
GCST008972_24	Urate levels	3.000000e-11
GCST010204_177	Low density lipoprotein cholesterol levels	5.000000e-13
GCST010243_11	Apolipoprotein B levels	1.000000e-13
GCST010245_156	LDL cholesterol levels	2.000000e-18
GCST010479_30	Coronary artery disease	7.000000e-09
GCST010512_32	Serum uric acid levels	4.000000e-08
GCST010512_33	Serum uric acid levels	4.000000e-08
GCST012370_7	Epilepsy	1.000000e-08
GCST90016667_23	Spleen volume	8.000000e-15

EFO canonical traits (9, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004340	body mass index
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004530	triglyceride measurement
EFO:0004574	total cholesterol measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004531	urate measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004761	uric acid measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Aflatoxin B1	decreases methylation, increases methylation	2
triphenyl phosphate	affects expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
bisphenol S	decreases methylation	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Ethanol	affects response to substance	1
Benzo(a)pyrene	affects methylation	1
Copper	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Lead	affects expression	1
Malathion	decreases expression	1
Phthalic Acids	increases methylation	1
Tretinoin	decreases expression	1
Acrylamide	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01203592	PHASE1	COMPLETED	Efficacy of Albuterol in the Treatment of Congenital Myasthenic Syndromes
NCT06436742	PHASE1	RECRUITING	A Phase 1b Study to Investigate Safety and Tolerability of ARGX-119 in Adult Participants With DOK7-Congenital Myasthenic Syndromes (CMS)
NCT07226726	PHASE1	RECRUITING	Patients With Congenital Myasthenic Syndrome Will be Treated With Mesenchymal Stem Cell Exosome Solution
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT00872950	Not specified	APPROVED_FOR_MARKETING	3,4-Diaminopyridine Use in Lambert-Eaton Myasthenic Syndrome(LEMS) and Congenital Myasthenic Syndromes (CMS)
NCT01403402	Not specified	RECRUITING	Congenital Muscle Disease Study of Patient and Family Reported Medical Information
NCT01474980	Not specified	COMPLETED	Pregnancy Outcomes in Congenital Myasthenie Syndrome
NCT02012933	Not specified	NO_LONGER_AVAILABLE	3,4-Diaminopyridine for Lambert-Eaton Myasthenic Syndrome (LEMS) and Congenital Myasthenia (CM)
NCT02189720	Not specified	APPROVED_FOR_MARKETING	Expanded Access Study Amifampridine Phosphate in Lambert-Eaton Myasthenic Syndrome (LEMS),Congenital Myasthenic Syndrome
NCT03062631	Not specified	NO_LONGER_AVAILABLE	Treatment Use of 3,4 Diaminopyridine in Congenital Myasthenia
NCT05408702	Not specified	COMPLETED	Exercise in Autoimmune Myasthenia Gravis and Myasthenic Syndromes
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06078553	Not specified	RECRUITING	A Natural History Study in Participants With Congenital Myasthenic Syndromes (CMS) Due to Mutations in DOK7, MUSK, AGRN, or LRP4
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays