UNC13A

Summary

UNC13A (unc-13 homolog A, HGNC:23150) is a protein-coding gene on chromosome 19p13.11, encoding Protein unc-13 homolog A (Q9UPW8). Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.

This gene encodes a member of the UNC13 family. UNC13 proteins bind to phorbol esters and diacylglycerol and play important roles in neurotransmitter release at synapses. Single nucleotide polymorphisms in this gene may be associated with sporadic amyotrophic lateral sclerosis.

Source: NCBI Gene 23025 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 13
• Clinical variants (ClinVar): 420 total — 8 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 47
• MANE Select transcript: NM_001080421

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:23150
Approved symbol	UNC13A
Name	unc-13 homolog A
Location	19p13.11
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1032, Munc13-1
Ensembl gene	ENSG00000130477
Ensembl biotype	protein_coding
OMIM	609894
Entrez	23025

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 retained_intron

ENST00000517497, ENST00000519716, ENST00000523229, ENST00000550896, ENST00000551649, ENST00000552293, ENST00000601528

RefSeq mRNA: 4 — MANE Select: NM_001080421 NM_001080421, NM_001387021, NM_001387022, NM_001387023

CCDS: CCDS46013, CCDS92557

Canonical transcript exons

ENST00000519716 — 44 exons

Exon	Start	End
ENSE00000895065	17624829	17624952
ENSE00000895168	17645674	17645843
ENSE00000952238	17626633	17626785
ENSE00000952247	17627863	17627940
ENSE00001056183	17621832	17621870
ENSE00001056184	17620693	17620722
ENSE00001184927	17629240	17629323
ENSE00001184931	17630145	17630288
ENSE00001184936	17630654	17630750
ENSE00001184944	17632782	17632908
ENSE00001184954	17636024	17636157
ENSE00001184958	17639083	17639217
ENSE00001184964	17639436	17639525
ENSE00001184969	17639840	17639908
ENSE00001184972	17640511	17640661
ENSE00001184976	17641393	17641556
ENSE00001482197	17647265	17647492
ENSE00001482200	17648912	17648983
ENSE00001482202	17649509	17649587
ENSE00001482204	17652631	17652677
ENSE00001482205	17655274	17655382
ENSE00001482208	17655883	17656398
ENSE00001482209	17658062	17658269
ENSE00001482210	17663532	17663567
ENSE00001482214	17666650	17666704
ENSE00001482218	17668117	17668190
ENSE00001482220	17669553	17669676
ENSE00001482222	17672378	17672495
ENSE00001482227	17676012	17676041
ENSE00001627908	17649339	17649344
ENSE00001641559	17623542	17623547
ENSE00001672515	17618906	17618962
ENSE00001713942	17645970	17646111
ENSE00001719895	17642845	17642960
ENSE00001726620	17633108	17633193
ENSE00001742598	17674657	17674756
ENSE00001757181	17648431	17648650
ENSE00002092344	17688178	17688354
ENSE00002107641	17601336	17606354
ENSE00003558630	17627509	17627597
ENSE00003568937	17618421	17618501
ENSE00003574637	17609940	17610099
ENSE00003588730	17617702	17617849
ENSE00003623606	17611763	17611855

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 94.95.

FANTOM5 (CAGE): breadth broad, TPM avg 7.2600 / max 262.4185, expressed in 422 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
179880	6.7785	372
179881	0.2093	79
179879	0.1346	73
179876	0.0692	28
179878	0.0685	37

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	94.95	gold quality
cerebellar hemisphere	UBERON:0002245	94.63	gold quality
cerebellar cortex	UBERON:0002129	94.54	gold quality
type B pancreatic cell	CL:0000169	94.04	silver quality
olfactory bulb	UBERON:0002264	93.43	silver quality
cerebellum	UBERON:0002037	93.17	gold quality
right frontal lobe	UBERON:0002810	92.68	gold quality
prefrontal cortex	UBERON:0000451	92.67	gold quality
superior frontal gyrus	UBERON:0002661	91.17	gold quality
middle temporal gyrus	UBERON:0002771	91.11	gold quality
frontal cortex	UBERON:0001870	90.95	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	90.88	gold quality
Brodmann (1909) area 9	UBERON:0013540	90.82	gold quality
pituitary gland	UBERON:0000007	90.72	gold quality
postcentral gyrus	UBERON:0002581	90.30	gold quality
parietal lobe	UBERON:0001872	90.29	gold quality
neocortex	UBERON:0001950	89.92	gold quality
cerebral cortex	UBERON:0000956	89.11	gold quality
adenohypophysis	UBERON:0002196	89.01	gold quality
entorhinal cortex	UBERON:0002728	88.91	gold quality
occipital lobe	UBERON:0002021	88.87	gold quality
islet of Langerhans	UBERON:0000006	88.61	gold quality
primary visual cortex	UBERON:0002436	88.61	gold quality
cingulate cortex	UBERON:0003027	88.19	gold quality
telencephalon	UBERON:0001893	87.87	gold quality
anterior cingulate cortex	UBERON:0009835	87.86	gold quality
nucleus accumbens	UBERON:0001882	87.82	gold quality
cortical plate	UBERON:0005343	87.66	gold quality
brain	UBERON:0000955	87.56	gold quality
forebrain	UBERON:0001890	87.55	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.68
E-MTAB-4850	no	0.30

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): RIMS1, RIMS2

miRNA regulators (miRDB)

164 targeting UNC13A, 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-6873-3P	100.00	71.42	2626
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-507	99.97	70.11	1915
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-557	99.96	70.01	1640
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-6845-3P	99.94	66.88	1439

Literature-anchored findings (GeneRIF, showing 19)

• rs12608932 Single Nucleotide Polymorphism is located at 19p13.3 and maps to a haplotype block within the boundaries of UNC13A, which regulates the release of neurotransmitters such as glutamate at neuromuscular synapses. (PMID:19734901)
• Results do not provide evidence of an association between a variant in the UNC13A gene and susceptibility to sporadic Amyotrophic lateral sclerosis in a French homogeneous population. (PMID:20385924)
• Our results further corroborate the role of UNC13A in amyotrophic lateral sclerosis pathogenesis. (PMID:22118904)
• Here, we report that, like Rab3A, RIM and Munc13 are present in human sperm and that they play a functional role in acrosomal exocytosis before the acrosomal calcium efflux (PMID:22248876)
• This study demonistrated that UNC13A influences survival in Italian amyotrophic lateral sclerosis patients. (PMID:22921269)
• CAPS1 binds to the full-length of cytoplasmic syntaxin-1 with preference to its “open” conformation, whereas Munc13-1 binds to the first 80 N-terminal residues of syntaxin-1. (PMID:23801330)
• Munc13-1, on account of its role in both insulin and neurotransmitter exocytosis and through its binding properties, may be an important factor contributing to the development or progression of diabetic neuropathy. (PMID:23830992)
• UNC13A provides a novel link between amyotrophic lateral sclerosis and frontotemporal dementia and identifies changes in neurotransmitter release and synaptic function as a converging mechanism in the pathogenesis of ALS and FTD-TDP. (PMID:24931836)
• UNC13A rs12608932 is a risk factor for ALS and a modifying factor for survival and disease progression rate in a Spanish cohort. (PMID:26162714)
• This study demonstrated that the population specific rare variants of UNC13A may modulate survival in ALS in United kingdom. (PMID:27584932)
• Synaptic UNC13A protein variant causes increased neurotransmission and dyskinetic movement disorder (PMID:28192369)
• Its polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis. (PMID:30368160)
• rs12608932(C) is associated with increased ALS susceptibility, especially in Caucasian and European subjects, and that the CC genotype of rs12608932 is associated with reduced ALS patient survival. (PMID:31201598)
• The Distinct Traits of the UNC13A Polymorphism in Amyotrophic Lateral Sclerosis. (PMID:32627229)
• Probing the Diacylglycerol Binding Site of Presynaptic Munc13-1. (PMID:33818064)
• TDP-43 represses cryptic exon inclusion in the FTD-ALS gene UNC13A. (PMID:35197626)
• TDP-43 loss and ALS-risk SNPs drive mis-splicing and depletion of UNC13A. (PMID:35197628)
• Interaction of the C9orf72-Amyotrophic Lateral Sclerosis-Related Proline-Arginine Dipeptide Repeat Protein with the RNA-Binding Protein NOVA1 Causes Decreased Expression of UNC13A Due to Enhanced Inclusion of Cryptic Exons, Which Is Reversed by Betulin Treatment. (PMID:37887320)
• Cryptic splicing of stathmin-2 and UNC13A mRNAs is a pathological hallmark of TDP-43-associated Alzheimer’s disease. (PMID:38175301)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	unc13a	ENSDARG00000061829
mus_musculus	Unc13a	ENSMUSG00000034799
rattus_norvegicus	Unc13a	ENSRNOG00000018452

Paralogs (2): UNC13C (ENSG00000137766), UNC13B (ENSG00000198722)

Protein

Protein identifiers

Protein unc-13 homolog A — Q9UPW8 (reviewed: Q9UPW8)

Alternative names: Munc13-1

All UniProt accessions (4): Q9UPW8, F8VZH8, F8W059, F8W0P6

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway. Involved in neurotransmitter release by acting in synaptic vesicle priming prior to vesicle fusion and participates in the activity-dependent refilling of readily releasable vesicle pool (RRP). Essential for synaptic vesicle maturation in most excitatory/glutamatergic but not inhibitory/GABA-mediated synapses. Facilitates neuronal dense core vesicles fusion as well as controls the location and efficiency of their synaptic release. Also involved in secretory granule priming in insulin secretion. Plays a role in dendrite formation by melanocytes.

Subunit / interactions. Interacts with the N-termini of STX1A and/or STX1B1 and DOC2A. Interacts with BSN. Interacts with RIMS1 which recruits UNC13A to the active zone. Forms homodimers via its first C2 domain. Also interacts via this domain with the zinc finger domain of RIMS2. Part of a complex consisting of ERC2, RIMS1 and UNC13A. Also part of a complex consisting of UNC13A, RIMS2 and RAB3A. Interacts with FBXO45 (via SRY domain); leading to the degradation of UNC13A by the proteasome.

Subcellular location. Cytoplasm. Cell membrane. Presynaptic cell membrane. Presynaptic active zone.

Tissue specificity. Expressed in pancreatic islet cells. Expressed in melanocytes.

Domain organisation. The C2 domains are not involved in calcium-dependent phospholipid binding. The C-terminal region containing both MHD domains and the third C2 domain is required for synaptic vesicle priming activity.

Similarity. Belongs to the unc-13 family.

RefSeq proteins (4): NP_001073890, NP_001373950, NP_001373951, NP_001373952 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000008	C2_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR010439	MUN_dom	Domain
IPR014770	Munc13_1	Domain
IPR014772	Munc13_dom-2	Domain
IPR027080	Unc-13	Family
IPR035892	C2_domain_sf	Homologous_superfamily
IPR037302	Unc-13_C2B	Domain
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF00168, PF06292

UniProt features (36 total): binding site 14, compositionally biased region 7, domain 5, modified residue 4, chain 1, sequence variant 1, sequence conflict 1, zinc finger region 1, region of interest 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UPW8-F1	73.58	0.36

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 (14): 567; 570; 584; 587; 595; 603; 692; 692; 698; 744; 744; 746 …

Post-translational modifications (4): 240, 242, 245, 256

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 268 (showing top): GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_VESICLE_LOCALIZATION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, MODULE_418, ASTON_MAJOR_DEPRESSIVE_DISORDER_DN, GOBP_GROWTH, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_MEMBRANE_DOCKING, GOBP_EXOCYTOSIS, GOBP_VESICLE_DOCKING_INVOLVED_IN_EXOCYTOSIS

GO Biological Process (11): neurotransmitter secretion (GO:0007269), obsolete synaptic vesicle docking (GO:0016081), synaptic vesicle priming (GO:0016082), cell differentiation (GO:0030154), synaptic transmission, glutamatergic (GO:0035249), regulation of synaptic transmission, glutamatergic (GO:0051966), dense core granule priming (GO:0061789), neuronal dense core vesicle exocytosis (GO:0099011), positive regulation of dendrite extension (GO:1903861), exocytosis (GO:0006887), chemical synaptic transmission (GO:0007268)

GO Molecular Function (7): calcium ion binding (GO:0005509), calmodulin binding (GO:0005516), phospholipid binding (GO:0005543), zinc ion binding (GO:0008270), syntaxin-1 binding (GO:0017075), diacylglycerol binding (GO:0019992), metal ion binding (GO:0046872)

GO Cellular Component (11): plasma membrane (GO:0005886), synaptic vesicle membrane (GO:0030672), neuromuscular junction (GO:0031594), presynaptic membrane (GO:0042734), neuron projection (GO:0043005), terminal bouton (GO:0043195), presynaptic active zone (GO:0048786), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
presynapse	4
cellular anatomical structure	4
chemical synaptic transmission	2
protein-containing complex assembly	2
exocytic process	2
dense core granule exocytosis	2
lipid binding	2
neurotransmitter transport	1
establishment of localization in cell	1
signal release from synapse	1
synaptic vesicle exocytosis	1
cellular developmental process	1
synaptic transmission, glutamatergic	1
modulation of chemical synaptic transmission	1
positive regulation of cell growth	1
positive regulation of developmental growth	1
dendrite extension	1
regulation of dendrite extension	1
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
anterograde trans-synaptic signaling	1
metal ion binding	1
protein binding	1
transition metal ion binding	1
syntaxin binding	1
cation binding	1
membrane	1
cell periphery	1
synaptic vesicle	1
exocytic vesicle membrane	1
synapse	1
synaptic membrane	1
plasma membrane bounded cell projection	1
axon terminus	1
intracellular anatomical structure	1
cell junction	1

Protein interactions and networks

STRING

1592 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
UNC13A	RIMS1	Q86UR5	960
UNC13A	CALM1	P02593	909
UNC13A	CALML3	P27482	906
UNC13A	CALML5	Q9NZT1	906
UNC13A	CALML6	Q8TD86	900
UNC13A	CALML4	Q96GE6	900
UNC13A	FBXO45	P0C2W1	858
UNC13A	RAB3A	P20336	853
UNC13A	SYT1	P21579	848
UNC13A	RIMS2	Q9UQ26	811
UNC13A	STX1A	Q16623	793
UNC13A	VAMP2	P19065	771
UNC13A	STXBP1	P61764	766
UNC13A	ERC1	Q8IUD2	760
UNC13A	SNAP25	P13795	751

IntAct

9 interactions, top by confidence:

A	B	Type	Score
DIRAS1	UNC13B	psi-mi:“MI:0914”(association)	0.500
EPB41L3	UNC13A	psi-mi:“MI:0915”(physical association)	0.370
NS1		psi-mi:“MI:0914”(association)	0.350
NS1	ESYT2	psi-mi:“MI:0914”(association)	0.350
RIMS1	KIF2A	psi-mi:“MI:0914”(association)	0.350
RIMS1	PSMD12	psi-mi:“MI:0914”(association)	0.350
DNPEP	UNC13A	psi-mi:“MI:0915”(physical association)	0.000
FMR1	UNC13A	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): UNC13A (Affinity Capture-RNA), UNC13A (Affinity Capture-RNA), UBXN10 (Reconstituted Complex), UNC13A (Affinity Capture-Western), UNC13A (Affinity Capture-Western), UNC13A (Affinity Capture-MS), UNC13A (Affinity Capture-MS), UNC13A (Affinity Capture-MS), TMED5 (Cross-Linking-MS (XL-MS)), UNC13A (Co-fractionation), UNC13A (Co-fractionation), UNC13A (Co-fractionation), UNC13A (Co-fractionation), UNC13A (Co-fractionation), UNC13A (Affinity Capture-MS)

ESM2 similar proteins: A0A4X1TB62, A4VCH4, G3V7Q0, O14795, O35841, O43237, O70585, P23116, P48553, Q0P5J8, Q14152, Q15542, Q1JU68, Q3TLI0, Q3UHE1, Q4R5P6, Q5R660, Q5R7S4, Q5R7U7, Q5RE09, Q5RE70, Q5VSL9, Q5XI83, Q658Y4, Q68E01, Q6IQ26, Q6PAL8, Q6PDL0, Q6TEP1, Q6WKZ8, Q7SYD9, Q7TPD0, Q8BIK4, Q8BWQ6, Q8C079, Q8C092, Q8C9H6, Q8CBY8, Q8IWV8, Q8K400

Diamond homologs: A0A075F932, A0FGR8, A0FGR9, A1ZBD6, A8KBH6, D4ABL6, K8FE10, O00443, O00750, O08835, O35681, O43581, P13677, P21521, P21579, P21707, P24506, P24507, P27715, P29101, P34693, P40748, P40749, P41823, P41885, P46096, P46097, P47191, P47708, P47709, P48018, P50232, P70169, P70610, P97610, Q06846, Q14183, Q14184, Q15811, Q3TZZ7

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
UNC13A	“up-regulates activity”	SNARE_complex	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	3
Uncertain significance	247
Likely benign	108
Benign	28

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
3775364	NM_001080421.3(UNC13A):c.1903_1951del (p.Arg634_Glu635insTer)	Pathogenic
4681175	UNC13A, 1-BP DEL, 1188C	Pathogenic
4681176	NM_001080421.3(UNC13A):c.154G>A (p.Glu52Lys)	Pathogenic
4681177	NM_001080421.3(UNC13A):c.605G>A (p.Arg202His)	Pathogenic
4681178	NM_001080421.2:c.338_339insAAAGGACC	Pathogenic
4681189	NM_001080421.3(UNC13A):c.2422G>T (p.Gly808Cys)	Pathogenic
4681190	NM_001080421.3(UNC13A):c.2423G>A (p.Gly808Asp)	Pathogenic
4681191	NM_001080421.3(UNC13A):c.1760_1761delinsTT (p.Cys587Phe)	Pathogenic
1709996	NM_001080421.3(UNC13A):c.1668C>A (p.Phe556Leu)	Likely pathogenic
545226	NC_000019.10:g.(?17607118)(17624457_?)del	Likely pathogenic
996014	NM_001080421.3(UNC13A):c.2441C>T (p.Pro814Leu)	Likely pathogenic

SpliceAI

6816 predictions. Top by Δscore:

Variant	Effect	Δscore
19:17606079:T:TA	donor_gain	1.0000
19:17606350:GCGTG:G	acceptor_gain	1.0000
19:17606351:CGTG:C	acceptor_gain	1.0000
19:17606351:CGTGC:C	acceptor_gain	1.0000
19:17606353:TG:T	acceptor_gain	1.0000
19:17606355:C:CC	acceptor_gain	1.0000
19:17606359:G:C	acceptor_gain	1.0000
19:17609935:CTCA:C	donor_loss	1.0000
19:17609936:TCACA:T	donor_loss	1.0000
19:17609937:CAC:C	donor_loss	1.0000
19:17609938:A:AC	donor_gain	1.0000
19:17609939:C:CC	donor_gain	1.0000
19:17609939:CA:C	donor_gain	1.0000
19:17609939:CAA:C	donor_gain	1.0000
19:17609972:G:C	donor_gain	1.0000
19:17610095:CACCA:C	acceptor_gain	1.0000
19:17610096:ACCA:A	acceptor_gain	1.0000
19:17610097:CCA:C	acceptor_gain	1.0000
19:17610097:CCAC:C	acceptor_gain	1.0000
19:17610098:CA:C	acceptor_gain	1.0000
19:17610098:CAC:C	acceptor_gain	1.0000
19:17610100:C:A	acceptor_loss	1.0000
19:17610100:C:CC	acceptor_gain	1.0000
19:17610103:T:TC	acceptor_gain	1.0000
19:17617700:AC:A	donor_gain	1.0000
19:17617701:CC:C	donor_gain	1.0000
19:17617845:TATTG:T	acceptor_gain	1.0000
19:17617846:ATTG:A	acceptor_gain	1.0000
19:17617847:TTG:T	acceptor_gain	1.0000
19:17617848:TG:T	acceptor_gain	1.0000

AlphaMissense

11379 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:17606102:C:A	K1688N	1.000
19:17606102:C:G	K1688N	1.000
19:17606114:G:C	F1684L	1.000
19:17606114:G:T	F1684L	1.000
19:17606115:A:G	F1684S	1.000
19:17606116:A:G	F1684L	1.000
19:17606124:G:T	A1681D	1.000
19:17606151:A:G	L1672P	1.000
19:17606154:A:G	I1671T	1.000
19:17606154:A:T	I1671N	1.000
19:17606173:C:G	G1665R	1.000
19:17606202:A:T	L1655H	1.000
19:17606265:C:T	G1634E	1.000
19:17606266:C:A	G1634W	1.000
19:17606266:C:G	G1634R	1.000
19:17606266:C:T	G1634R	1.000
19:17606286:G:T	A1627E	1.000
19:17606288:G:C	F1626L	1.000
19:17606288:G:T	F1626L	1.000
19:17606289:A:C	F1626C	1.000
19:17606289:A:G	F1626S	1.000
19:17606290:A:C	F1626V	1.000
19:17606290:A:G	F1626L	1.000
19:17606290:A:T	F1626I	1.000
19:17606291:G:C	C1625W	1.000
19:17606295:T:C	Y1624C	1.000
19:17606296:A:C	Y1624D	1.000
19:17606296:A:G	Y1624H	1.000
19:17606298:T:A	D1623V	1.000
19:17606298:T:C	D1623G	1.000

dbSNP variants (sampled 300 via entrez): RS1000042318 (19:17670309 C>T), RS1000097149 (19:17612517 C>T), RS1000178437 (19:17673902 T>C), RS1000272409 (19:17680398 G>A), RS1000273719 (19:17640514 A>G,T), RS1000290500 (19:17674184 G>A), RS1000293061 (19:17635601 A>T), RS1000311931 (19:17601817 T>C,G), RS1000379868 (19:17669432 C>A,T), RS1000384970 (19:17628621 C>T), RS1000410881 (19:17669272 CAAGG>C), RS1000448182 (19:17617874 G>T), RS1000475392 (19:17634608 G>A), RS1000514323 (19:17672914 T>C), RS1000573040 (19:17679549 G>A)

Disease associations

OMIM: gene MIM:609894 | disease phenotypes: MIM:105400, MIM:621455, MIM:621456, MIM:621457, MIM:209850

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Strong	Autosomal dominant
congenital nervous system disorder	Limited	Unknown
congenital myasthenic syndrome	Limited	Autosomal recessive

Mondo (11): amyotrophic lateral sclerosis type 1 (MONDO:0007103), amyotrophic lateral sclerosis (MONDO:0004976), neurodevelopmental disorder (MONDO:0700092), neurodevelopmental disorder with hypotonia, epilepsy, and absent speech (MONDO:0980940), cerebellar ataxia (MONDO:0000437), microcephaly (MONDO:0001149), neurodevelopmental disorder with speech delay, movement abnormalities, and seizures (MONDO:0980941), intellectual developmental disorder with seizures and dysmorphic facies (MONDO:0980942), autism (MONDO:0005260), congenital nervous system disorder (MONDO:0002320), congenital myasthenic syndrome (MONDO:0018940)

Orphanet (2): Amyotrophic lateral sclerosis (Orphanet:803), Rare ataxia (Orphanet:102002)

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000217	Xerostomia
HP:0000708	Atypical behavior
HP:0000712	Emotional lability
HP:0000716	Depression
HP:0000739	Anxiety
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001308	Tongue fasciculations
HP:0001347	Hyperreflexia
HP:0001618	Dysphonia
HP:0001824	Weight loss
HP:0002015	Dysphagia
HP:0002094	Dyspnea
HP:0002145	Frontotemporal dementia
HP:0002180	Neurodegeneration
HP:0002307	Drooling
HP:0002313	Spastic paraparesis
HP:0002360	Sleep disturbance
HP:0002380	Fasciculations
HP:0002463	Language impairment
HP:0002878	Respiratory failure
HP:0003202	Skeletal muscle atrophy
HP:0003324	Generalized muscle weakness
HP:0003376	Steppage gait
HP:0003394	Muscle spasm
HP:0003470	Paralysis
HP:0003484	Upper limb muscle weakness
HP:0003487	Babinski sign
HP:0003693	Distal amyotrophy
HP:0004326	Cachexia

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000481_8	Amyotrophic lateral sclerosis	3.000000e-14
GCST001664_15	Amyotrophic lateral sclerosis	5.000000e-08
GCST001762_77	Obesity-related traits	8.000000e-06
GCST002283_1	Amyotrophic lateral sclerosis (sporadic)	6.000000e-06
GCST002508_1	Frontotemporal dementia	7.000000e-06
GCST002509_2	Amyotrophic lateral sclerosis	2.000000e-08
GCST004692_6	Amyotrophic lateral sclerosis	2.000000e-08
GCST004792_2	Amyotrophic lateral sclerosis in C9orf72 mutation positive individuals	4.000000e-07
GCST004901_1	Amyotrophic lateral sclerosis (sporadic)	3.000000e-10
GCST005647_4	Amyotrophic lateral sclerosis	4.000000e-15
GCST008169_3	Benign prostatic hyperplasia	5.000000e-07
GCST008169_9	Benign prostatic hyperplasia	6.000000e-07
GCST008576_1	IgG levels	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005189	respiratory quotient

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D001321	Autistic Disorder	F03.625.164.113.500
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D020294	Myasthenic Syndromes, Congenital	C10.668.758.800; C16.320.590
D065886	Neurodevelopmental Disorders	F03.625
C531617	Amyotrophic lateral sclerosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs12608932	UNC13A		0.00	0

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Silicon Dioxide	affects expression, increases expression	2
Esketamine	increases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects expression, affects response to substance	1
sodium arsenite	affects splicing, decreases reaction, decreases expression	1
benzo(e)pyrene	affects methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	affects methylation	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	decreases expression	1
Methapyrilene	affects methylation	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1
Okadaic Acid	increases expression	1
Sirolimus	affects splicing, decreases reaction	1

Clinical trials (associated diseases)

513 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,
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
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
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease