RALGAPA1

Summary

RALGAPA1 (Ral GTPase activating protein catalytic subunit alpha 1, HGNC:17770) is a protein-coding gene on chromosome 14q13.2, encoding Ral GTPase-activating protein subunit alpha-1 (Q6GYQ0). Catalytic subunit of the heterodimeric RalGAP1 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.

This gene encodes a major subunit of the RAL-GTPase activating protein. A similar protein in mouse binds E12, a transcriptional regulator of immunoglobulin genes. The mouse protein also functions in skeletal muscle by binding to the regulatory 14-3-3 proteins upon stimulation with insulin or muscle contraction. A pseudogene of this gene has been identified on chromosome 9.

Source: NCBI Gene 253959 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 7
• Clinical variants (ClinVar): 331 total — 7 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 34
• MANE Select transcript: NM_001346249

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17770
Approved symbol	RALGAPA1
Name	Ral GTPase activating protein catalytic subunit alpha 1
Location	14q13.2
Locus type	gene with protein product
Status	Approved
Aliases	GRIPE, DKFZp667F074, KIAA0884, Tulip1, RalGAPalpha1
Ensembl gene	ENSG00000174373
Ensembl biotype	protein_coding
OMIM	608884
Entrez	253959

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 8 protein_coding, 7 retained_intron, 5 protein_coding_CDS_not_defined

ENST00000307138, ENST00000382366, ENST00000389698, ENST00000553892, ENST00000553917, ENST00000554259, ENST00000554355, ENST00000554573, ENST00000554652, ENST00000554704, ENST00000555828, ENST00000556106, ENST00000556192, ENST00000556837, ENST00000556839, ENST00000557069, ENST00000557104, ENST00000557638, ENST00000637992, ENST00000680220

RefSeq mRNA: 11 — MANE Select: NM_001346249 NM_001283043, NM_001283044, NM_001330075, NM_001346243, NM_001346245, NM_001346246, NM_001346247, NM_001346248, NM_001346249, NM_014990, NM_194301

CCDS: CCDS32064, CCDS32065, CCDS61439, CCDS61440, CCDS81797, CCDS91864, CCDS91865

Canonical transcript exons

ENST00000680220 — 42 exons

Exon	Start	End
ENSE00001124237	35634574	35634757
ENSE00001124279	35605586	35605709
ENSE00001217684	35635464	35635598
ENSE00001217688	35651805	35651873
ENSE00001217692	35654367	35654477
ENSE00001217697	35655807	35655915
ENSE00001217704	35659138	35659196
ENSE00001217706	35664642	35664767
ENSE00001217711	35671389	35671517
ENSE00001217744	35625361	35625432
ENSE00001217759	35672867	35673022
ENSE00001296584	35760829	35761006
ENSE00001335827	35549110	35549234
ENSE00001335830	35572560	35572718
ENSE00001335837	35627090	35627951
ENSE00001385543	35595634	35595789
ENSE00001491888	35674180	35674278
ENSE00001491889	35674516	35674709
ENSE00001491926	35762710	35762753
ENSE00001491927	35770942	35770999
ENSE00001491928	35775006	35775055
ENSE00001491930	35775635	35775745
ENSE00001506671	35548508	35548538
ENSE00001506677	35677950	35678102
ENSE00003463677	35683809	35683985
ENSE00003488306	35752024	35752162
ENSE00003503448	35742368	35742565
ENSE00003504466	35721688	35721849
ENSE00003516961	35738513	35738650
ENSE00003525880	35570617	35570744
ENSE00003567894	35756793	35756908
ENSE00003572358	35725024	35725153
ENSE00003579620	35684929	35685145
ENSE00003579683	35723027	35723264
ENSE00003607238	35748585	35748824
ENSE00003631641	35686542	35686666
ENSE00003663236	35750482	35750690
ENSE00003670527	35700162	35700302
ENSE00003685521	35728362	35728510
ENSE00003797780	35688459	35690003
ENSE00003911862	35538356	35539690
ENSE00003914688	35808730	35809295

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 98.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.6304 / max 292.9029, expressed in 1784 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
142899	18.3233	1769
142898	3.2447	1196
142900	1.0144	500
142897	0.0480	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.01	gold quality
calcaneal tendon	UBERON:0003701	96.24	gold quality
corpus callosum	UBERON:0002336	95.82	gold quality
lateral nuclear group of thalamus	UBERON:0002736	95.51	gold quality
sural nerve	UBERON:0015488	95.38	gold quality
inferior olivary complex	UBERON:0002127	95.29	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	95.26	gold quality
adrenal tissue	UBERON:0018303	95.18	gold quality
substantia nigra pars compacta	UBERON:0001965	94.68	gold quality
choroid plexus epithelium	UBERON:0003911	94.53	gold quality
lateral globus pallidus	UBERON:0002476	94.42	gold quality
substantia nigra pars reticulata	UBERON:0001966	94.41	gold quality
cerebellar hemisphere	UBERON:0002245	93.82	gold quality
cerebellar cortex	UBERON:0002129	93.80	gold quality
cerebellum	UBERON:0002037	93.79	gold quality
primary visual cortex	UBERON:0002436	93.78	gold quality
globus pallidus	UBERON:0001875	93.73	gold quality
medial globus pallidus	UBERON:0002477	93.72	gold quality
seminal vesicle	UBERON:0000998	93.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.67	gold quality
caput epididymis	UBERON:0004358	93.55	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.54	gold quality
medulla oblongata	UBERON:0001896	93.47	gold quality
CA1 field of hippocampus	UBERON:0003881	93.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.40	gold quality
entorhinal cortex	UBERON:0002728	93.37	gold quality
blood vessel layer	UBERON:0004797	93.28	gold quality
subthalamic nucleus	UBERON:0001906	93.23	gold quality
occipital lobe	UBERON:0002021	93.18	gold quality
postcentral gyrus	UBERON:0002581	93.14	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-122	yes	20.92
E-ANND-3	yes	6.27
E-MTAB-7303	no	68.06

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TCF3

miRNA regulators (miRDB)

100 targeting RALGAPA1, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
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-570-3P	99.96	72.41	4910
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3682-5P	99.93	67.97	1163
HSA-MIR-7-1-3P	99.91	71.53	4384
HSA-MIR-7-2-3P	99.91	71.40	4394
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4493	99.90	66.48	977
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-548AR-3P	99.85	71.26	3889

Literature-anchored findings (GeneRIF, showing 5)

• RanGAP1 remains associated with RanBP2/Nup358 and the SUMO E2-conjugating enzyme Ubc9 in mitosis. (PMID:15037602)
• Reduced TULIP1 was found in lymphocytes from a developmentally delayed epileptic patient with a microdeletion of 14q13.1q13.3 and in cell lysates from other patients with a missense P297 mutation. (PMID:19733229)
• GARNL1/RalGAPalpha1 is amajor RalGAPalphasubunit in skeletal muscle, and is regulated by protein phosphorylation and 14-3-3 binding upon stimulation with insulin or muscle contraction. (PMID:24768767)
• Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities. (PMID:32004447)
• Toxoplasma gondii mitochondrial association factor 1b interactome reveals novel binding partners including Ral GTPase accelerating protein alpha1. (PMID:38141762)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ralgapa1	ENSDARG00000076889
mus_musculus	Ralgapa1	ENSMUSG00000021027
rattus_norvegicus	Ralgapa1	ENSRNOG00000046256
drosophila_melanogaster	CG5521	FBGN0039466
caenorhabditis_elegans	hgap-1	WBGENE00021209

Paralogs (2): TSC2 (ENSG00000103197), RALGAPA2 (ENSG00000188559)

Protein

Protein identifiers

Ral GTPase-activating protein subunit alpha-1 — Q6GYQ0 (reviewed: Q6GYQ0)

Alternative names: GAP-related-interacting partner to E12, GTPase-activating Rap/Ran-GAP domain-like 1, Tuberin-like protein 1, p240

All UniProt accessions (5): Q6GYQ0, A0A1B0GUI1, A0A7P0TAR5, H0YJ04, H0YJB5

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic subunit of the heterodimeric RalGAP1 complex which acts as a GTPase activator for the Ras-like small GTPases RALA and RALB.

Subunit / interactions. Component of the heterodimeric RalGAP1 complex with RALGAPB. Heterodimerization is required for activity. Interacts with the HLH region of TCF3/isoform E12.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Widely expressed.

Disease relevance. Neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (NEDHRIT) [MIM:618797] An autosomal recessive disorder characterized by profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, infantile spasms, and moderate dysmorphic facial features. Brain imaging shows thin corpus or dysplastic corpus callosum, and additional unspecific abnormalities including gray matter heterotopias, ectopic posterior pituitary, signal abnormalities in basal ganglia, and stratum subependymale. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (7)

UniProt ID	Names	Canonical?
Q6GYQ0-1	1	yes
Q6GYQ0-2	2
Q6GYQ0-3	3
Q6GYQ0-4	4
Q6GYQ0-5	5
Q6GYQ0-6	6
Q6GYQ0-7	7

RefSeq proteins (11): NP_001269972, NP_001269973, NP_001317004, NP_001333172, NP_001333174, NP_001333175, NP_001333176, NP_001333177, NP_001333178, NP_055805, NP_919277 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000331	Rap/Ran_GAP_dom	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR027107	Tuberin/Ral-act_asu	Family
IPR035974	Rap/Ran-GAP_sf	Homologous_superfamily
IPR046859	RGPA/RALGAPB_N	Domain

Pfam: PF02145, PF20412

UniProt features (46 total): modified residue 16, splice variant 7, compositionally biased region 6, region of interest 6, sequence variant 5, sequence conflict 2, chain 1, domain 1, mutagenesis site 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6GYQ0-F1	70.17	0.30

Functional residue map

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

Post-translational modifications (16): 711, 721, 754, 773, 778, 797, 860, 861, 864, 986, 990, 994, 1000, 1002, 1004, 1478

Mutagenesis-validated functional residues (1):

Position	Phenotype
1903	has no effect on interaction with ralgapb but causes loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9013407	RHOH GTPase cycle

MSigDB gene sets: 249 (showing top): GCM_MAP4K4, GCM_PTPRD, GCM_GSPT1, GOBP_ACTIVATION_OF_GTPASE_ACTIVITY, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, LINDGREN_BLADDER_CANCER_CLUSTER_3_DN, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A5, BROWNE_HCMV_INFECTION_24HR_UP, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY, ONKEN_UVEAL_MELANOMA_UP, GOBP_POSITIVE_REGULATION_OF_MOLECULAR_FUNCTION

GO Biological Process (3): regulation of small GTPase mediated signal transduction (GO:0051056), activation of GTPase activity (GO:0090630), positive regulation of GTPase activity (GO:0043547)

GO Molecular Function (2): GTPase activator activity (GO:0005096), protein heterodimerization activity (GO:0046982)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase activity	2
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
positive regulation of GTPase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
enzyme activator activity	1
GTPase regulator activity	1
protein dimerization activity	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

990 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RALGAPA1	LRPAP1	P30533	810
RALGAPA1	RALGAPB	Q86X10	717
RALGAPA1	ARHGAP4	P98171	622
RALGAPA1	RALA	P11233	506
RALGAPA1	TBC1D4	O60343	478
RALGAPA1	SLC25A13	Q9UJS0	470
RALGAPA1	RGL2	O15211	448
RALGAPA1	ARHGAP5	Q13017	421
RALGAPA1	RALGPS1	Q5JS13	417
RALGAPA1	RGL3	Q3MIN7	412
RALGAPA1	PARVA	Q9NVD7	405
RALGAPA1	CCDC191	Q8NCU4	391
RALGAPA1	GRAMD1A	Q96CP6	391
RALGAPA1	BTAF1	O14981	390
RALGAPA1	RALB	P11234	390

IntAct

42 interactions, top by confidence:

A	B	Type	Score
SLMAP	STRN	psi-mi:“MI:2364”(proximity)	0.710
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
GFOD1	PER1	psi-mi:“MI:0914”(association)	0.530
GFOD1	RALGAPA2	psi-mi:“MI:0914”(association)	0.530
NKIRAS2	RALGAPA2	psi-mi:“MI:0914”(association)	0.530
RALGAPA1	PDIA4	psi-mi:“MI:0915”(physical association)	0.400
ERBB3	RALGAPA1	psi-mi:“MI:0915”(physical association)	0.370
SPG11	RALGAPA1	psi-mi:“MI:0915”(physical association)	0.370
RALGAPA1	MAF1b1	psi-mi:“MI:0915”(physical association)	0.370
	ZNF316	psi-mi:“MI:0914”(association)	0.350
RRP1B	YY2	psi-mi:“MI:0914”(association)	0.350
rep	TBKBP1	psi-mi:“MI:0914”(association)	0.350
MYC		psi-mi:“MI:0914”(association)	0.350
AP2M1	C1orf226	psi-mi:“MI:0914”(association)	0.350
AP2B1	SYNJ1	psi-mi:“MI:0914”(association)	0.350
SGIP1	AP2A2	psi-mi:“MI:0914”(association)	0.350
NKIRAS2	RAP1GDS1	psi-mi:“MI:0914”(association)	0.350
DLG3	DLG1	psi-mi:“MI:0914”(association)	0.350
SGIP1	SPAG6	psi-mi:“MI:0914”(association)	0.350
MEA1	RAD23A	psi-mi:“MI:0914”(association)	0.350
AP2M1	PER1	psi-mi:“MI:0914”(association)	0.350
GFOD1	SBF1	psi-mi:“MI:0914”(association)	0.350
GFOD1	B4GAT1	psi-mi:“MI:0914”(association)	0.350
NKIRAS2	GABARAPL2	psi-mi:“MI:0914”(association)	0.350
RALGAPB	DHX15	psi-mi:“MI:0914”(association)	0.350
CEP63	CCDC66	psi-mi:“MI:2364”(proximity)	0.270
LAMP1	TRAPPC13	psi-mi:“MI:2364”(proximity)	0.270
RAB11A	SEC16A	psi-mi:“MI:2364”(proximity)	0.270
NDN	PABPC1	psi-mi:“MI:2364”(proximity)	0.270
DUSP23	RALGAPA1	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (101): RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Affinity Capture-MS), RALGAPA1 (Affinity Capture-RNA), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Proximity Label-MS), RALGAPA1 (Affinity Capture-RNA), RALGAPA1 (Affinity Capture-RNA)

ESM2 similar proteins: A0JP85, A1A5H6, A2AGH6, A5GFY4, A5YKK6, B1AY13, B4KJ11, E9Q8I9, O75448, O94915, O95155, P55824, Q0KK59, Q23658, Q24134, Q2PW47, Q2QCI8, Q4V8B3, Q5F3M0, Q5RCU2, Q5RFA0, Q5TBA9, Q60PC0, Q6GLR7, Q6GYQ0, Q6PI53, Q6ZQ08, Q7ZYV9, Q80TJ1, Q80X82, Q80YV3, Q8BHR2, Q8BL99, Q8IXH7, Q8R0Z2, Q8R1A4, Q922L6, Q92797, Q93074, Q96N67

Diamond homologs: A3KGS3, O55007, P49815, P86409, P86411, Q2PPJ7, Q3V0G7, Q54SS8, Q61037, Q6GYP7, Q6GYQ0, Q9UUG9, Q9VB98, A2ALS5, G3X9J0, O35412, O43166, O60292, P47736, P49816, Q54EH3, Q55AN8, Q5JCS6, Q5SVL6, Q5VVW2, Q5ZJY3, Q5ZMV8, Q684P5, Q75J96, Q80TE4, Q8C0T5, Q9P2F8, A5PF44, Q54TK4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
RALGAPA1	“form complex”	RalGAP1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 57 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	133.2×	4e-12
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	117.6×	5e-12
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	117.6×	5e-12
Activation of BH3-only proteins	7	86.9×	5e-11
RHO GTPases activate PKNs	7	55.5×	1e-09
Intrinsic Pathway for Apoptosis	7	51.2×	2e-09
FOXO-mediated transcription	5	42.0×	2e-06
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	38.6×	5e-12

GO biological processes:

GO term	Partners	Fold	FDR
synaptic vesicle endocytosis	5	42.4×	3e-05
protein targeting	5	35.9×	4e-05
intracellular protein localization	7	14.4×	7e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	7
Likely pathogenic	5
Uncertain significance	243
Likely benign	34
Benign	11

Top pathogenic / likely-pathogenic (12)

Variant ID	HGVS	Classification
1333352	NM_001346249.2(RALGAPA1):c.1409_1410del (p.Asp470fs)	Pathogenic
2233678	NM_001346249.2(RALGAPA1):c.5455C>T (p.Gln1819Ter)	Pathogenic
691794	NM_001346249.2(RALGAPA1):c.1126C>T (p.Arg376Ter)	Pathogenic
691795	NM_001346249.2(RALGAPA1):c.6510del (p.Phe2170fs)	Pathogenic
691796	NM_001346249.2(RALGAPA1):c.610G>T (p.Glu204Ter)	Pathogenic
691797	NM_001346249.2(RALGAPA1):c.7250C>G (p.Ser2417Ter)	Pathogenic
691798	NM_001346249.2(RALGAPA1):c.4745A>G (p.Asn1582Ser)	Pathogenic
2582399	NM_001346249.2(RALGAPA1):c.5042_5043dup (p.Met1682Ter)	Likely pathogenic
2584515	NM_001346249.2(RALGAPA1):c.1449+1G>T	Likely pathogenic
2584516	NM_001346249.2(RALGAPA1):c.7152_7155dup (p.Phe2386fs)	Likely pathogenic
3780528	NM_001346249.2(RALGAPA1):c.3152T>G (p.Leu1051Ter)	Likely pathogenic
4537871	NM_001346249.2(RALGAPA1):c.1952C>A (p.Ser651Ter)	Likely pathogenic

SpliceAI

7781 predictions. Top by Δscore:

Variant	Effect	Δscore
14:35552235:TAG:T	donor_gain	1.0000
14:35552236:AGA:A	donor_gain	1.0000
14:35571786:G:C	donor_gain	1.0000
14:35572559:CCT:C	donor_gain	1.0000
14:35572714:CTCAA:C	acceptor_gain	1.0000
14:35572715:TCAA:T	acceptor_gain	1.0000
14:35572716:CAA:C	acceptor_gain	1.0000
14:35572716:CAAC:C	acceptor_gain	1.0000
14:35572717:AA:A	acceptor_gain	1.0000
14:35572719:C:CC	acceptor_gain	1.0000
14:35605587:T:TA	donor_gain	1.0000
14:35605587:TCCCA:T	donor_gain	1.0000
14:35605628:T:TA	donor_gain	1.0000
14:35605705:CTCGG:C	acceptor_gain	1.0000
14:35605707:CGG:C	acceptor_gain	1.0000
14:35605707:CGGCT:C	acceptor_loss	1.0000
14:35605708:GG:G	acceptor_gain	1.0000
14:35605708:GGC:G	acceptor_loss	1.0000
14:35605709:GCTA:G	acceptor_loss	1.0000
14:35605710:C:CC	acceptor_gain	1.0000
14:35605710:CT:C	acceptor_loss	1.0000
14:35605711:T:A	acceptor_loss	1.0000
14:35625360:CCA:C	donor_gain	1.0000
14:35627952:C:CC	acceptor_gain	1.0000
14:35635458:GTTTA:G	donor_loss	1.0000
14:35635459:TTTAC:T	donor_loss	1.0000
14:35635460:TTACC:T	donor_loss	1.0000
14:35635461:TAC:T	donor_loss	1.0000
14:35635462:ACCTT:A	donor_loss	1.0000
14:35635463:CCT:C	donor_loss	1.0000

AlphaMissense

16824 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:35572682:A:G	W1910R	1.000
14:35572682:A:T	W1910R	1.000
14:35625385:A:G	L1796P	1.000
14:35672970:A:G	L1151P	1.000
14:35672977:A:C	Y1149D	1.000
14:35672979:G:T	A1148E	1.000
14:35672980:C:G	A1148P	1.000
14:35672991:C:T	G1144D	1.000
14:35672992:C:G	G1144R	1.000
14:35674187:A:G	L1131P	1.000
14:35674191:A:G	W1130R	1.000
14:35674191:A:T	W1130R	1.000
14:35674535:A:G	L1094P	1.000
14:35674544:A:G	L1091P	1.000
14:35674621:C:A	W1065C	1.000
14:35674621:C:G	W1065C	1.000
14:35674623:A:G	W1065R	1.000
14:35674623:A:T	W1065R	1.000
14:35674648:C:A	W1056C	1.000
14:35674648:C:G	W1056C	1.000
14:35674650:A:G	W1056R	1.000
14:35674650:A:T	W1056R	1.000
14:35723145:C:A	W662C	1.000
14:35723145:C:G	W662C	1.000
14:35723147:A:G	W662R	1.000
14:35723147:A:T	W662R	1.000
14:35723207:A:G	W642R	1.000
14:35723207:A:T	W642R	1.000
14:35723233:A:G	L633P	1.000
14:35723249:A:G	W628R	1.000

dbSNP variants (sampled 300 via entrez): RS1000013026 (14:35756687 G>C,T), RS1000015403 (14:35800093 A>C), RS1000037115 (14:35577981 C>T), RS1000050321 (14:35605982 G>A), RS1000054288 (14:35592778 A>C,G), RS1000056106 (14:35788730 T>C), RS1000067416 (14:35795524 A>C), RS1000099139 (14:35551001 A>C,G), RS1000099495 (14:35550148 C>T), RS1000105547 (14:35741796 C>T), RS1000115022 (14:35694101 A>T), RS1000116371 (14:35696041 G>A), RS1000122747 (14:35735036 A>G,T), RS1000133816 (14:35591154 T>C), RS1000171167 (14:35647700 C>T)

Disease associations

OMIM: gene MIM:608884 | disease phenotypes: MIM:618797

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation	Strong	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (3): neurodevelopmental disorder with hypotonia, neonatal respiratory insufficiency, and thermodysregulation (MONDO:0032921), long QT syndrome (MONDO:0002442), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

34 total (30 of 34 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000154	Wide mouth
HP:0000212	Gingival overgrowth
HP:0000248	Brachycephaly
HP:0000294	Low anterior hairline
HP:0000369	Low-set ears
HP:0000463	Anteverted nares
HP:0000490	Deeply set eye
HP:0000518	Cataract
HP:0000574	Thick eyebrow
HP:0000958	Dry skin
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001270	Motor delay
HP:0001344	Absent speech
HP:0001601	Laryngomalacia
HP:0001622	Premature birth
HP:0002059	Cerebral atrophy
HP:0002079	Hypoplasia of the corpus callosum
HP:0002282	Gray matter heterotopia
HP:0002421	Poor head control
HP:0002643	Neonatal respiratory distress
HP:0002779	Tracheomalacia
HP:0004429	Recurrent viral infections
HP:0005280	Depressed nasal bridge
HP:0005469	Flat occiput
HP:0009890	High anterior hairline
HP:0010808	Protruding tongue
HP:0011228	Horizontal eyebrow

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST012227_587	Hip circumference adjusted for BMI	4.000000e-08
GCST012229_209	Hip index	1.000000e-09
GCST90002383_256	Hematocrit	1.000000e-17
GCST90002384_336	Hemoglobin	7.000000e-16
GCST90002393_487	Monocyte count	5.000000e-09
GCST90002403_503	Red blood cell count	4.000000e-11
GCST90013406_129	Liver enzyme levels (alkaline phosphatase)	3.000000e-12

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0008039	BMI-adjusted hip circumference
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0005091	monocyte count
EFO:0004305	erythrocyte count
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008133	Long QT Syndrome	C14.280.067.565; C14.280.123.625; C16.131.240.400.715; C23.550.073.547

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, increases expression, affects expression	3
(+)-JQ1 compound	increases expression	2
Benzo(a)pyrene	decreases expression, decreases methylation	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
arsenite	affects binding, decreases reaction	1
aflatoxin B2	decreases methylation	1
cupric chloride	affects expression	1
coumarin	increases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Vehicle Emissions	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Coumestrol	decreases expression	1
Dimethyl Sulfoxide	decreases expression	1
Endosulfan	decreases expression	1
Folic Acid	decreases expression	1
Hydrogen Peroxide	affects expression	1
Mercury	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Rotenone	decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02513940	PHASE4	COMPLETED	Influence of Testosterone Administration on Drug-Induced QT Interval Prolongation and Torsades de Pointes
NCT03834883	PHASE4	COMPLETED	Reducing the Risk of Drug-Induced QT Interval Lengthening in Women
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04675788	PHASE4	COMPLETED	Novel Approaches for Minimizing Drug-Induced QT Interval Lengthening
NCT01648205	PHASE2	COMPLETED	Long-term Efficacy Study of Sodium Channel Blocker in LQT3 Patients
NCT02412709	PHASE2	UNKNOWN	Long QT Syndrome Screening in Newborns
NCT04581408	PHASE2	COMPLETED	Mutation-specific Therapy for the Long QT Syndrome
NCT00316459	PHASE1	COMPLETED	Study Evaluating the Effects of Multiple Oral Doses of ERB-041 on Cardiac Repolarization in Healthy Subjects
NCT01849003	PHASE1	COMPLETED	Study of the Effect of GS-6615 in Subjects With LQT-3
NCT02365532	PHASE1	COMPLETED	Effect of Oral GS-6615 on Dofetilide-Induced QT Prolongation, Safety, and Tolerability in Healthy Adults
NCT02412098	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Hepatic Function
NCT02441829	PHASE1	COMPLETED	Pharmacokinetics of Eleclazine in Adults With Normal and Impaired Renal Function
NCT05759962	PHASE1	COMPLETED	Phase 1 Study of LQT-1213 in Healthy Adults
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
NCT05906732	PHASE1/PHASE2	TERMINATED	Study of LQT-1213 on QTc-induced Prolongation in Healthy Adult Subjects (Part1) and on Congenital Long QT in Patients Diagnosed With Type 2 or 3 Long QT Syndrome (Part 2).
NCT00005176	Not specified	COMPLETED	Long QT Syndrome-Population Genetics and Cardiac Studies
NCT00005250	Not specified	COMPLETED	Linkage Study of Long QT Syndrome In An Amish Kindred
NCT00005367	Not specified	COMPLETED	Epidemiology of Long QTand Asian Sudden Death in Sleep
NCT00221832	Not specified	UNKNOWN	Molecular Genetic Screening and Identification of Congenital Arrhythmogenic Diseases
NCT00292032	Not specified	COMPLETED	Registry of Unexplained Cardiac Arrest
NCT00335036	Not specified	TERMINATED	Pediatric Lead Extractability and Survival Evaluation (PLEASE)
NCT00399412	Not specified	COMPLETED	ECG Signal Collection From Long QT Syndrome, Wide QRS Complexes, Heart Failure, and Cardiac Resynchronization Patients
NCT00488254	Not specified	COMPLETED	The Long QT Syndrome in Pregnancy
NCT00588965	Not specified	COMPLETED	Effect of Beta-blocker Therapy on QTc Response in Exercise and Recovery in Normal Subjects
NCT01705925	Not specified	COMPLETED	Multicenter Evaluation of Children and Young Adults With Genotype Positive Long QT Syndrome
NCT01903564	Not specified	COMPLETED	Fetal and Neonatal Magnetophysiology
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02413450	Not specified	ENROLLING_BY_INVITATION	Derivation of Human Induced Pluripotent Stem (iPS) Cells to Heritable Cardiac Arrhythmias
NCT02425189	Not specified	COMPLETED	The Canadian National Long QT Syndrome Registry
NCT02439645	Not specified	TERMINATED	A Registry to Determine the Clinical and Genetic Risk Factors for Torsade De Pointes
NCT02439658	Not specified	UNKNOWN	Genetics of QT Prolongation With Antiarrhythmics
NCT02549664	Not specified	COMPLETED	Exercise in Genetic Cardiovascular Conditions
NCT02581241	Not specified	COMPLETED	Abnormal QT-Response to the Sudden Tachycardia Provoked by Standing in Individuals With Drug-induced Long QT Syndrome
NCT02680080	Not specified	COMPLETED	Effect of Grapefruit on QT Interval in Healthy Volunteers and Patients With Congenital Long QT Syndrome
NCT02775513	Not specified	UNKNOWN	Metabolism of Patients With Genetically Caused Cardiac Arrhythmia
NCT02814981	Not specified	UNKNOWN	Hydroxyzine and Risk of Prolongation of QT Interval
NCT02876380	Not specified	COMPLETED	Prospective Identification of Long QT Syndrome in Fetal Life
NCT03182777	Not specified	COMPLETED	Safety of Local Dental Anesthesia in Patients With Cardiac Channelopathies
NCT03544918	Not specified	COMPLETED	Prevalence of Congenital Long QT Syndrome and Acquired QT Prolongation in a Hospital Cohort