GNAL

Summary

GNAL (G protein subunit alpha L, HGNC:4388) is a protein-coding gene on chromosome 18p11.21, encoding Guanine nucleotide-binding protein G(olf) subunit alpha (P38405). Guanine nucleotide-binding protein (G protein) involved as transducer in olfactory signal transduction controlled by G protein-coupled receptors (GPCRs).

This gene encodes a stimulatory G protein alpha subunit which mediates odorant signaling in the olfactory epithelium. This protein couples dopamine type 1 receptors and adenosine A2A receptors and is widely expressed in the central nervous system. Mutations in this gene have been associated with dystonia 25 and this gene is located in a susceptibility region for bipolar disorder and schizophrenia. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 2774 — RefSeq curated summary.

At a glance

• Gene–disease (curated): dystonia 25 (Definitive, GenCC)
• GWAS associations: 8
• Clinical variants (ClinVar): 318 total — 16 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 11
• MANE Select transcript: NM_182978

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4388
Approved symbol	GNAL
Name	G protein subunit alpha L
Location	18p11.21
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000141404
Ensembl biotype	protein_coding
OMIM	139312
Entrez	2774

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 8 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000269162, ENST00000334049, ENST00000423027, ENST00000535121, ENST00000585590, ENST00000585642, ENST00000586926, ENST00000590228, ENST00000590972, ENST00000602628

RefSeq mRNA: 5 — MANE Select: NM_182978 NM_001142339, NM_001261443, NM_001261444, NM_001369387, NM_182978

CCDS: CCDS11851, CCDS11852, CCDS58614

Canonical transcript exons

ENST00000334049 — 12 exons

Exon	Start	End
ENSE00001163135	11752853	11752925
ENSE00001331183	11689264	11689939
ENSE00001914778	11880989	11885685
ENSE00003513184	11872268	11872398
ENSE00003522064	11862395	11862449
ENSE00003554091	11868543	11868663
ENSE00003590305	11867168	11867226
ENSE00003602908	11876621	11876688
ENSE00003619030	11753628	11753682
ENSE00003638958	11824918	11825015
ENSE00003649584	11864533	11864606
ENSE00003667272	11753826	11753945

Expression profiles

Bgee: expression breadth ubiquitous, 274 present calls, max score 98.25.

FANTOM5 (CAGE): breadth broad, TPM avg 7.4583 / max 466.4616, expressed in 735 samples.

FANTOM5 promoters (18 alternative TSS)

Promoter ID	TPM avg	Samples expressed
169433	1.7778	505
169461	1.0284	140
169442	1.0081	128
169440	0.7923	132
169432	0.5380	299
169434	0.4774	236
169441	0.4626	109
169444	0.4037	114
169431	0.3414	200
169437	0.1427	30

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	98.25	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.12	gold quality
middle temporal gyrus	UBERON:0002771	94.70	gold quality
nucleus accumbens	UBERON:0001882	94.49	gold quality
entorhinal cortex	UBERON:0002728	93.96	gold quality
substantia nigra pars compacta	UBERON:0001965	93.38	gold quality
pons	UBERON:0000988	92.74	gold quality
superior vestibular nucleus	UBERON:0007227	92.67	gold quality
putamen	UBERON:0001874	92.57	gold quality
cortical plate	UBERON:0005343	92.06	gold quality
caudate nucleus	UBERON:0001873	91.95	gold quality
seminal vesicle	UBERON:0000998	91.82	gold quality
substantia nigra pars reticulata	UBERON:0001966	91.58	gold quality
parietal lobe	UBERON:0001872	91.48	gold quality
postcentral gyrus	UBERON:0002581	91.25	gold quality
CA1 field of hippocampus	UBERON:0003881	91.08	gold quality
orbitofrontal cortex	UBERON:0004167	90.76	gold quality
endothelial cell	CL:0000115	90.65	gold quality
Brodmann (1909) area 46	UBERON:0006483	90.63	gold quality
ventral tegmental area	UBERON:0002691	90.15	gold quality
gluteal muscle	UBERON:0002000	90.14	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.05	gold quality
cauda epididymis	UBERON:0004360	90.03	gold quality
superior frontal gyrus	UBERON:0002661	89.99	gold quality
urethra	UBERON:0000057	89.96	gold quality
penis	UBERON:0000989	89.60	gold quality
epithelium of bronchus	UBERON:0002031	89.24	gold quality
temporal lobe	UBERON:0001871	89.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.14	gold quality
nasal cavity epithelium	UBERON:0005384	89.09	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.14

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EBF1, NEUROD1

miRNA regulators (miRDB)

142 targeting GNAL, 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-340-5P	100.00	72.50	4437
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-4283	100.00	66.42	2097
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6753-3P	99.93	66.57	637
HSA-MIR-7107-3P	99.93	66.73	627
HSA-MIR-6744-5P	99.93	66.82	748
HSA-MIR-4778-3P	99.93	70.40	1818

Literature-anchored findings (GeneRIF, showing 25)

• investigation of whether polymorphisms in the alpha subunit of the Golf gene (A–>G in intron 3, and T–>G in intron 10) are associated with major depression; additionally tested for a parent-of-origin effect in separated gender groups (PMID:11901355)
• promotes cellular invasion, survival and neuroendocrine differentiation in colon, kidney and prostate epithelial cells (PMID:12037684)
• No support for the hypothesis that the olfactory G-protein gene is a major susceptibility factor for bipolar disorders. (PMID:12782961)
• identified a transcriptional variant of the GNAL gene in chromosome 18p11.2 in susceptibility to bipolar disorder and schizophrenia (PMID:16044173)
• Galpha(olf) variant XLGalpha(olf) interacts with the human adenosine A2A receptor (PMID:16818375)
• We hypothesized that the G(s)-like subunit Galpha(olf), expressed in D1-rich areas of the brain, contributes to the genetic susceptibility of ADHD. We examined the inheritance pattern of 12 GNAL polymorphisms in 258 nuclear families. (PMID:17166517)
• This study provides important clues toward understanding physiological functions of XLGalpha(olf). (PMID:19245791)
• these findings provide important clues to understanding physiological functions of XLGalpha(olf). (PMID:22120635)
• Mutations in GNAL cause primary torsion dystonia. (PMID:23222958)
• Familial adult-onset primary dystonia can result from mutations in GNAL. (PMID:23449625)
• Mutations in GNAL gene can cause adult-onset primary dystonia in Chinese patients (PMID:23759320)
• The GNAL dystonia gene is central for striatal responses to dopamine (DA) and is a component of a molecular pathway already implicated in DOPA-responsive dystonia (DRD). (PMID:24144882)
• GNAL variants seem to be a rare cause of primary torsion dystonia in our mainly sporadic German sample. (PMID:24151159)
• Our own data suggest that GNAL mutations do not represent a common cause of dystonia in the U.K. population. (PMID:24222099)
• The findings of this study further support GNAL as causative gene in adult-onset isolated dystonia. (PMID:24408567)
• Primary dystonia in the Amish-Mennonites is genetically diverse and includes not only the THAP1 indel founder mutation but also different mutations in THAP1 and GNAL as well as the TOR1A GAG deletion. (PMID:24500857)
• GNAL mutations potentially increase ethnic susceptibility to movement disorders induced by dopamine antagonists. (PMID:24535567)
• This study identified a novel likely disease-causing GNAL mutation in a Serbian patient with cervical dystonia and a classical DYT25 phenotype. (PMID:24729450)
• identified two novel GNAL mutations: one heterozygous missense variant in GNAL exon 4, c.289A>G. (PMID:25382112)
• This study demonstrated that Mutations in GNAL may cause Dystonia. (PMID:25847575)
• Mutations in the GNAL gene may not be a common cause of isolated dystonia in the Chinese population. (PMID:26365774)
• We report a novel GNAL mutation in Italian family with adult-onset, dominantly-inherited dystonia (PMID:26725140)
• GNAL mutations are not a common cause of dystonia in the Brazilian population (PMID:26810727)
• GNAL mutation may represent one of the rare causative genetic factors of isolated laryngeal dystonia. (PMID:27093447)
• cases extend and support prior limited literature that suggested that cervical dystonia from GNAL mutations may significantly improve with GPi deep brain stimulation (PMID:30536916)

Cross-species orthologs

18 orthologs

Organism	Symbol	Gene ID
danio_rerio	gnal	ENSDARG00000045415
danio_rerio	gnal2	ENSDARG00000075850
danio_rerio		ENSDARG00000102797
mus_musculus	Gnal	ENSMUSG00000024524
rattus_norvegicus	Gnal	ENSRNOG00000010440
drosophila_melanogaster	Galphaf	FBGN0010223
drosophila_melanogaster	CG17760	FBGN0033756
drosophila_melanogaster	CG30054	FBGN0050054
caenorhabditis_elegans		WBGENE00001664
caenorhabditis_elegans		WBGENE00001665
caenorhabditis_elegans		WBGENE00001667
caenorhabditis_elegans		WBGENE00001668
caenorhabditis_elegans		WBGENE00001670
caenorhabditis_elegans		WBGENE00001671
caenorhabditis_elegans		WBGENE00001673
caenorhabditis_elegans		WBGENE00001675
caenorhabditis_elegans	gpa-14	WBGENE00001676
caenorhabditis_elegans	gsa-1	WBGENE00001745

Paralogs (15): GNA15 (ENSG00000060558), GNAI3 (ENSG00000065135), GNAO1 (ENSG00000087258), GNAS (ENSG00000087460), GNA11 (ENSG00000088256), GNAT1 (ENSG00000114349), GNAI2 (ENSG00000114353), GNA13 (ENSG00000120063), GNAI1 (ENSG00000127955), GNAZ (ENSG00000128266), GNAT2 (ENSG00000134183), GNA12 (ENSG00000146535), GNA14 (ENSG00000156049), GNAQ (ENSG00000156052), GNAT3 (ENSG00000214415)

Protein

Protein identifiers

Guanine nucleotide-binding protein G(olf) subunit alpha — P38405 (reviewed: P38405)

Alternative names: Adenylate cyclase-stimulating G alpha protein, olfactory type

All UniProt accessions (5): A8K1Y9, P38405, K7EMY6, K7EPE2, K7EQ80

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-binding protein (G protein) involved as transducer in olfactory signal transduction controlled by G protein-coupled receptors (GPCRs). Contains the guanine nucleotide binding site and alternates between an active, GTP-bound state and an inactive, GDP-bound state. Signaling by an activated GPCR promotes GDP release and GTP binding. The alpha subunit has a low GTPase activity that converts bound GTP to GDP, thereby terminating the signal. Both GDP release and GTP hydrolysis are modulated by numerous regulatory proteins. GNAL/G(olf) alpha specifically mediates olfactory signal transduction within the olfactory neuroepithelium and the basal ganglia following GPCRs activation. Acts by promoting the specific activation of adenylyl cyclase ADCY3, resulting in increased levels of the signaling molecule cAMP.

Subunit / interactions. G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site. Interacts with GAS2L2. Interacts (GDP-bound form) with RIC8B (via C-terminus); promoting GNAL folding and association with the plasma membrane.

Subcellular location. Cell membrane.

Tissue specificity. Detected in olfactory neuroepithelium, brain, testis, and to a lower extent in retina, lung alveoli, spleen. Trace amounts where seen in kidney, adrenal gland and liver. Found to be expressed in all the insulinomas examined.

Disease relevance. Dystonia 25 (DYT25) [MIM:615073] A form of dystonia, a disorder defined by the presence of sustained involuntary muscle contraction, often leading to abnormal postures. DYT25 is an autosomal dominant neurologic disorder characterized by adult onset of focal dystonia, usually involving the neck. The dystonia most often progresses to involve other regions, particularly the face and laryngeal muscles, and less commonly the trunk and limbs. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-alpha family. G(s) subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
P38405-1	1	yes
P38405-2	2
P38405-3	3

RefSeq proteins (5): NP_001135811, NP_001248372, NP_001248373, NP_001356316, NP_892023* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000367	Gprotein_alpha_S	Family
IPR001019	Gprotein_alpha_su	Family
IPR011025	GproteinA_insert	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00503

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (56 total): binding site 17, helix 9, strand 8, region of interest 6, sequence variant 4, modified residue 2, lipid moiety-binding region 2, splice variant 2, turn 2, initiator methionine 1, chain 1, domain 1, compositionally biased region 1

Structure

Experimental structures (PDB)

10 structures.

PDB	Method	Resolution (Å)
9LE0	ELECTRON MICROSCOPY	2.54
9LDW	ELECTRON MICROSCOPY	2.62
9LDV	ELECTRON MICROSCOPY	2.78
9LDX	ELECTRON MICROSCOPY	2.83
8KH4	ELECTRON MICROSCOPY	3.1
8KGK	ELECTRON MICROSCOPY	3.16
8EL8	ELECTRON MICROSCOPY	3.2
9LE1	ELECTRON MICROSCOPY	3.3
9LE2	ELECTRON MICROSCOPY	3.33
8IW1	ELECTRON MICROSCOPY	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P38405-F1	93.46	0.86

Antibody-complex structures (SAbDab): 3 — 8IW1, 8KGK, 8KH4

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 (17): 52; 53; 54; 55; 56; 56; 57; 185; 186; 191; 191; 210 …

Post-translational modifications (4): 178, 188, 2, 3

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-170660	Adenylate cyclase activating pathway
R-HSA-170670	Adenylate cyclase inhibitory pathway
R-HSA-381753	Olfactory Signaling Pathway

MSigDB gene sets: 233 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_RESPONSE_TO_AMINE, GOBP_SENSORY_PERCEPTION_OF_CHEMICAL_STIMULUS, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_RESPONSE_TO_ALKALOID, MODULE_289, GOBP_RESPONSE_TO_AMPHETAMINE, BILD_E2F3_ONCOGENIC_SIGNATURE, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_RESPONSE_TO_CAFFEINE, GOBP_CELLULAR_RESPONSE_TO_NITROGEN_COMPOUND, ZHOU_INFLAMMATORY_RESPONSE_LIVE_DN, GOBP_ADENYLATE_CYCLASE_ACTIVATING_DOPAMINE_RECEPTOR_SIGNALING_PATHWAY

GO Biological Process (8): response to amphetamine (GO:0001975), signal transduction (GO:0007165), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), adenylate cyclase-activating dopamine receptor signaling pathway (GO:0007191), sensory perception of chemical stimulus (GO:0007606), sensory perception of smell (GO:0007608), response to caffeine (GO:0031000), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (11): G protein-coupled receptor binding (GO:0001664), GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), G-protein beta/gamma-subunit complex binding (GO:0031683), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), adenylate cyclase regulator activity (GO:0010854), hydrolase activity (GO:0016787), guanyl nucleotide binding (GO:0019001)

GO Cellular Component (5): cytoplasm (GO:0005737), heterotrimeric G-protein complex (GO:0005834), plasma membrane (GO:0005886), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
G-protein mediated events	2
Activation of GABAB receptors	1
Sensory Perception	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
response to amine	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
adenylate cyclase-activating G protein-coupled receptor signaling pathway	1
G protein-coupled dopamine receptor signaling pathway	1
sensory perception	1
sensory perception of chemical stimulus	1
response to purine-containing compound	1
response to alkaloid	1
G protein-coupled receptor activity	1
signal transduction	1
signaling receptor binding	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
protein-containing complex binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
adenylate cyclase activity	1
cyclase regulator activity	1
catalytic activity	1
purine nucleotide binding	1
intracellular anatomical structure	1
extrinsic component of cytoplasmic side of plasma membrane	1
plasma membrane protein complex	1
GTPase complex	1
membrane	1
cell periphery	1
extracellular vesicle	1

Protein interactions and networks

STRING

2326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNAL	TMTC1	Q8IUR5	871
GNAL	IMPA2	O14732	844
GNAL	MPPE1	Q53F39	833
GNAL	THAP1	Q9NVV9	807
GNAL	ANO3	Q9BYT9	801
GNAL	DRD1	P21728	796
GNAL	RIC8B	Q9NVN3	781
GNAL	TOR1A	O14656	720
GNAL	CIZ1	Q9ULV3	720
GNAL	ADCY3	O60266	711
GNAL	CNGA2	Q16280	696
GNAL	GNG13	Q9P2W3	692
GNAL	RIC8A	Q9NPQ8	677
GNAL	SGCE	O43556	624
GNAL	TUBB4A	P04350	618

IntAct

20 interactions, top by confidence:

A	B	Type	Score
GNAS	CPT2	psi-mi:“MI:0914”(association)	0.530
MAGED2	GNAL	psi-mi:“MI:0914”(association)	0.530
SPATA2	CASK	psi-mi:“MI:0914”(association)	0.530
Haus1	GNAT3	psi-mi:“MI:0915”(physical association)	0.400
CD177	MYO1G	psi-mi:“MI:0914”(association)	0.350
FNDC5	CAPN15	psi-mi:“MI:0914”(association)	0.350
CHIA	TPP2	psi-mi:“MI:0914”(association)	0.350
USP3	EIF3F	psi-mi:“MI:0914”(association)	0.350
BABAM1	PYCR3	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
SYNGAP1	IGLON5	psi-mi:“MI:0914”(association)	0.350
GNAS	RANBP6	psi-mi:“MI:0914”(association)	0.350
MAGED2	PTPN6	psi-mi:“MI:0914”(association)	0.350
MAGED2	AMY1A	psi-mi:“MI:0914”(association)	0.350
GNAS	CPT2	psi-mi:“MI:0914”(association)	0.350
	ESYT2	psi-mi:“MI:0914”(association)	0.350

BioGRID (28): GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-RNA), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS), GNAL (Affinity Capture-MS)

ESM2 similar proteins: A2Y3B5, O04278, O04279, O16118, O76584, P04896, P16051, P16052, P18064, P20354, P22454, P24799, P26981, P29797, P30669, P30684, P34042, P34045, P34046, P38405, P38406, P49082, P49084, P63091, P63092, P63093, P63094, P63095, P91907, P93163, P93564, Q05337, Q0DJ33, Q20907, Q292P9, Q40224, Q4VT31, Q4VT38, Q4VT39, Q4VT42

Diamond homologs: A8MTJ3, B0XRA0, B2RSH2, O13055, O13315, O15975, O15976, O16118, O42784, O73819, O74227, O74259, O95837, P04695, P04696, P04896, P04897, P04899, P08239, P08752, P08753, P08754, P09471, P0C7Q4, P10824, P10825, P11488, P16052, P16378, P18872, P19087, P20354, P20612, P21278, P21279, P23625, P24799, P27044, P29348, P29797

SIGNOR signaling

67 interactions.

A	Effect	B	Mechanism
LPAR3	“up-regulates activity”	GNAL	binding
MC3R	“up-regulates activity”	GNAL	binding
ADRB3	“up-regulates activity”	GNAL	binding
AVPR2	“up-regulates activity”	GNAL	binding
PTGDR	“up-regulates activity”	GNAL	binding
PTGER2	“up-regulates activity”	GNAL	binding
GPR174	“up-regulates activity”	GNAL	binding
ADRB1	“up-regulates activity”	GNAL	binding
P2RY2	“up-regulates activity”	GNAL	binding
PTGER4	“up-regulates activity”	GNAL	binding
F2RL2	“up-regulates activity”	GNAL	binding
MCHR1	“up-regulates activity”	GNAL	binding
CCKAR	“up-regulates activity”	GNAL	binding
BDKRB1	“up-regulates activity”	GNAL	binding
CCKBR	“up-regulates activity”	GNAL	binding
ADORA2A	“up-regulates activity”	GNAL	binding
ADORA2B	“up-regulates activity”	GNAL	binding
GPR119	“up-regulates activity”	GNAL	binding
HTR4	“up-regulates activity”	GNAL	binding
OXGR1	“up-regulates activity”	GNAL	binding
DRD5	“up-regulates activity”	GNAL	binding
F2RL3	“up-regulates activity”	GNAL	binding
FFAR4	“up-regulates activity”	GNAL	binding
GRPR	“up-regulates activity”	GNAL	binding
NMBR	“up-regulates activity”	GNAL	binding
TACR1	“up-regulates activity”	GNAL	binding
HRH2	“up-regulates activity”	GNAL	binding
HRH1	“up-regulates activity”	GNAL	binding
UTS2R	“up-regulates activity”	GNAL	binding
EDNRA	“up-regulates activity”	GNAL	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	9
Uncertain significance	116
Likely benign	91
Benign	69

Top pathogenic / likely-pathogenic (25)

Variant ID	HGVS	Classification
1451598	NM_001369387.1(GNAL):c.55_64dup (p.Arg22fs)	Pathogenic
1454252	NM_001369387.1(GNAL):c.91C>T (p.Gln31Ter)	Pathogenic
1457837	NM_182978.4(GNAL):c.710_713del (p.Asp237fs)	Pathogenic
1526592	GRCh37/hg19 18p11.32-11.21(chr18:136226-14384326)	Pathogenic
2138127	NM_182978.4(GNAL):c.667G>A (p.Val223Met)	Pathogenic
2138128	NM_182978.4(GNAL):c.1292T>C (p.Val431Ala)	Pathogenic
2736692	NM_001369387.1(GNAL):c.3G>A (p.Met1Ile)	Pathogenic
3348818	NM_182978.4(GNAL):c.823C>T (p.Arg275Ter)	Pathogenic
374434	NM_182978.4(GNAL):c.462_463del (p.Lys155fs)	Pathogenic
39968	NM_182978.4(GNAL):c.1109C>A (p.Ser370Ter)	Pathogenic
39969	NM_182978.4(GNAL):c.694G>A (p.Glu232Lys)	Pathogenic
39970	NM_182978.4(GNAL):c.514dup (p.Ser172fs)	Pathogenic
39971	NM_182978.4(GNAL):c.822dup (p.Arg275fs)	Pathogenic
39972	NM_001369387.1(GNAL):c.61C>T (p.Arg21Ter)	Pathogenic
503584	GRCh37/hg19 18p11.32-11.21(chr18:13034-15375878)x1	Pathogenic
626333	NM_182978.4(GNAL):c.964C>T (p.Arg322Ter)	Pathogenic
1043845	NM_001369387.1(GNAL):c.37G>T (p.Asp13Tyr)	Likely pathogenic
2503343	NM_182978.4(GNAL):c.401C>T (p.Thr134Ile)	Likely pathogenic
3067873	NM_182978.4(GNAL):c.910G>A (p.Asp304Asn)	Likely pathogenic
3614608	NM_182978.4(GNAL):c.722+1G>A	Likely pathogenic
4071949	NM_182978.4(GNAL):c.931G>A (p.Val311Ile)	Likely pathogenic
4071950	NM_182978.4(GNAL):c.1272C>G (p.Tyr424Ter)	Likely pathogenic
546813	NM_182978.4(GNAL):c.504+1G>T	Likely pathogenic
623662	NM_182978.4(GNAL):c.448G>T (p.Glu150Ter)	Likely pathogenic
813000	NM_182978.4(GNAL):c.389C>T (p.Ser130Phe)	Likely pathogenic

SpliceAI

2537 predictions. Top by Δscore:

Variant	Effect	Δscore
18:11752924:GA:G	donor_gain	1.0000
18:11752926:G:GG	donor_gain	1.0000
18:11753621:A:AG	acceptor_gain	1.0000
18:11753625:CA:C	acceptor_loss	1.0000
18:11753626:A:AG	acceptor_gain	1.0000
18:11753626:A:AT	acceptor_loss	1.0000
18:11753626:AG:A	acceptor_gain	1.0000
18:11753626:AGG:A	acceptor_gain	1.0000
18:11753627:G:GG	acceptor_gain	1.0000
18:11753627:G:T	acceptor_loss	1.0000
18:11753627:GG:G	acceptor_gain	1.0000
18:11753627:GGG:G	acceptor_gain	1.0000
18:11753627:GGGA:G	acceptor_gain	1.0000
18:11753680:GTG:G	donor_gain	1.0000
18:11753682:GGTAA:G	donor_loss	1.0000
18:11753683:G:GA	donor_loss	1.0000
18:11753683:G:GG	donor_gain	1.0000
18:11753684:T:G	donor_loss	1.0000
18:11753814:A:AG	acceptor_gain	1.0000
18:11753815:T:G	acceptor_gain	1.0000
18:11753819:A:AG	acceptor_gain	1.0000
18:11753820:T:G	acceptor_gain	1.0000
18:11753824:A:AG	acceptor_gain	1.0000
18:11753825:G:GT	acceptor_gain	1.0000
18:11753825:GA:G	acceptor_gain	1.0000
18:11753825:GAC:G	acceptor_gain	1.0000
18:11753825:GACA:G	acceptor_gain	1.0000
18:11753825:GACAA:G	acceptor_gain	1.0000
18:11753943:CAGGT:C	donor_loss	1.0000
18:11753945:GGTAA:G	donor_loss	1.0000

AlphaMissense

3040 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:11752853:G:A	G49E	1.000
18:11752853:G:T	G49V	1.000
18:11752858:G:C	G51R	1.000
18:11752858:G:T	G51C	1.000
18:11752859:G:A	G51D	1.000
18:11752864:T:C	S53P	1.000
18:11752865:C:T	S53F	1.000
18:11752867:G:A	G54R	1.000
18:11752867:G:C	G54R	1.000
18:11752867:G:T	G54W	1.000
18:11752868:G:A	G54E	1.000
18:11752868:G:C	G54A	1.000
18:11752868:G:T	G54V	1.000
18:11752870:A:C	K55Q	1.000
18:11752871:A:T	K55I	1.000
18:11752872:A:C	K55N	1.000
18:11752872:A:T	K55N	1.000
18:11752873:A:C	S56R	1.000
18:11752873:A:T	S56C	1.000
18:11752874:G:T	S56I	1.000
18:11752875:C:A	S56R	1.000
18:11752875:C:G	S56R	1.000
18:11752877:C:T	T57I	1.000
18:11752886:A:T	K60I	1.000
18:11752890:G:C	Q61H	1.000
18:11752890:G:T	Q61H	1.000
18:11752892:T:C	M62T	1.000
18:11753664:T:A	N85K	1.000
18:11753664:T:G	N85K	1.000
18:11753674:G:C	A89P	1.000

dbSNP variants (sampled 300 via entrez): RS1000052676 (18:11870717 A>G), RS1000067009 (18:11846532 A>C), RS1000096811 (18:11770309 C>T), RS1000108106 (18:11741113 T>C), RS1000135534 (18:11760686 T>C), RS1000140486 (18:11709834 G>A), RS1000180603 (18:11788047 A>C), RS1000182964 (18:11845719 GAAAT>G), RS1000188433 (18:11780948 G>A), RS1000190385 (18:11763578 T>C), RS1000242750 (18:11763987 T>G), RS1000273443 (18:11848522 T>A), RS1000305774 (18:11799663 T>A), RS1000310623 (18:11841505 G>A,T), RS1000311337 (18:11746413 C>A)

Disease associations

OMIM: gene MIM:139312 | disease phenotypes: MIM:615073

GenCC curated gene-disease

Disease	Classification	Inheritance
dystonia 25	Definitive	Autosomal dominant

Mondo (2): dystonic disorder (MONDO:0003441), dystonia 25 (MONDO:0014033)

Orphanet (1): Autosomal dominant focal dystonia, DYT25 type (Orphanet:329466)

HPO phenotypes

11 total (12 of 11 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000473	Torticollis
HP:0001618	Dysphonia
HP:0002451	Limb dystonia
HP:0002530	Axial dystonia
HP:0003581	Adult onset
HP:0003621	Juvenile onset
HP:0004373	Focal dystonia
HP:0012049	Laryngeal dystonia
HP:0012179	Craniofacial dystonia
HP:0031008	Lingual dystonia
HP:0001332	Dystonia

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST001890_8	QT interval (drug interaction)	8.000000e-06
GCST003055_2	Tandem gait	4.000000e-07
GCST003121_6	Alcohol dependence	2.000000e-06
GCST004068_29	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	2.000000e-06
GCST007335_30	Age at first sexual intercourse	1.000000e-08
GCST007621_4	Sensation seeking	3.000000e-07
GCST009391_1710	Metabolite levels	3.000000e-08
GCST009391_2058	Metabolite levels	9.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004682	QT interval
EFO:0009749	age at first sexual intercourse measurement
EFO:0006946	behavioural disinhibition measurement
EFO:0010341	cholesteryl ester 16:0 measurement
EFO:0010345	cholesteryl ester 18:2 measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	affects cotreatment, increases expression	4
Valproic Acid	increases expression, increases methylation	4
geraniol	increases response to substance, increases activity, increases reaction, increases secretion	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	decreases expression, increases methylation	2
Aflatoxin B1	increases methylation	2
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
aminomethylphosphonic acid (AMPA)	decreases expression	1
triphenyl phosphate	affects expression	1
azelaic acid	decreases reaction, increases response to substance, increases activity	1
2-heptanone	increases response to substance, increases activity	1
decanaldehyde	increases response to substance, increases activity	1
nickel sulfate	increases expression	1
caprylic aldehyde	increases response to substance, increases activity	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, affects response to substance, increases expression	1
denatonium	decreases reaction, increases secretion	1
citronellal	decreases reaction, increases response to substance, increases activity, increases abundance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bourgeonal	increases response to substance, increases activity	1
abrine	decreases expression	1
alpha-methyl-3,4-methylene-dioxyhydrocinnamic aldehyde	increases response to substance, increases activity	1
dorsomorphin	increases expression, affects cotreatment	1
NSC 689534	increases expression, affects binding	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	increases expression	1
Cyclic AMP	increases abundance, increases activity, increases response to substance	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases expression, increases abundance	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia
NCT00608231	PHASE2/PHASE3	WITHDRAWN	Dexmedetomidine Effects on Microelectrode Recording in Deep Brain Stimulation
NCT04277247	PHASE2/PHASE3	UNKNOWN	Botulinum Toxin Type A for Foot Dystonia-associated Pain in Parkinson’s Disease
NCT02015039	PHASE1/PHASE2	COMPLETED	Pilot Trial of Botulinum Toxin and Occupational Therapy for Writer’s Cramp
NCT02911103	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Deep Brain Stimulation Surgery for Focal Hand Dystonia
NCT04727177	EARLY_PHASE1	UNKNOWN	Precision-targeted Transcranial Magnetic Stimulation in the Treatment of Primary Dystonia
NCT00006336	Not specified	COMPLETED	Sensory Training to Treat Focal Dystonia
NCT00017875	Not specified	COMPLETED	Transcranial Magnetic Stimulation (TMS) Studies of Dystonia
NCT00029601	Not specified	COMPLETED	Surround Inhibition in Patients With Dystonia
NCT00031369	Not specified	TERMINATED	Brain Anatomy in Dystonia
NCT00047957	Not specified	COMPLETED	Brain Inhibition of Muscle Movement in Normal Volunteers
NCT00050024	Not specified	COMPLETED	Transcranial Magnetic Stimulation and Electrical Stimulation of Nerves to Study Focal Dystonia
NCT00072956	Not specified	COMPLETED	The Physiology of Tricks
NCT00082615	Not specified	COMPLETED	Neurophysiological Markers in Patients With Craniofacial Dystonia and Their Relatives
NCT00102999	Not specified	COMPLETED	Brain Function in Focal Dystonia
NCT00285870	Not specified	COMPLETED	Quantification of Upper Extremity Hypertonia
NCT00355927	Not specified	UNKNOWN	Sedation During Microelectrode Recordings Before Deep Brain Stimulation for Movement Disorders.