GNA14

Summary

GNA14 (G protein subunit alpha 14, HGNC:4382) is a protein-coding gene on chromosome 9q21.2, encoding Guanine nucleotide-binding protein subunit alpha-14 (O95837). Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.

This gene encodes a member of the guanine nucleotide-binding, or G protein family. G proteins are heterotrimers consisting of alpha, beta and gamma subunits. The encoded protein is a member of the alpha family of G proteins, more specifically the alpha q subfamily of G proteins. The encoded protein may play a role in pertussis-toxin resistant activation of phospholipase C-beta and its downstream effectors.

Source: NCBI Gene 9630 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 74 total — 3 pathogenic
• Phenotypes (HPO): 23
• MANE Select transcript: NM_004297

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4382
Approved symbol	GNA14
Name	G protein subunit alpha 14
Location	9q21.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000156049
Ensembl biotype	protein_coding
OMIM	604397
Entrez	9630

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 1 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000341700, ENST00000464095

RefSeq mRNA: 1 — MANE Select: NM_004297 NM_004297

CCDS: CCDS6657

Canonical transcript exons

ENST00000341700 — 7 exons

Exon	Start	End
ENSE00001089403	77434368	77434522
ENSE00001089405	77431321	77431449
ENSE00001089406	77529069	77529253
ENSE00001379870	77423079	77424169
ENSE00001471166	77647670	77648322
ENSE00003460048	77425562	77425715
ENSE00003576236	77428907	77429036

Expression profiles

Bgee: expression breadth ubiquitous, 208 present calls, max score 93.63.

FANTOM5 (CAGE): breadth broad, TPM avg 2.8761 / max 81.4718, expressed in 560 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101075	1.2890	414
101077	0.5223	213
101078	0.4919	283
101076	0.2701	170
101073	0.1515	82
101074	0.0925	40
101068	0.0588	26

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	93.63	gold quality
oocyte	CL:0000023	91.67	gold quality
bronchial epithelial cell	CL:0002328	90.12	gold quality
epithelium of bronchus	UBERON:0002031	88.46	gold quality
bronchus	UBERON:0002185	87.43	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.88	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	85.82	gold quality
spinal cord	UBERON:0002240	83.92	gold quality
smooth muscle tissue	UBERON:0001135	83.83	gold quality
left lobe of thyroid gland	UBERON:0001120	81.93	gold quality
cauda epididymis	UBERON:0004360	81.92	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	81.77	gold quality
right lobe of thyroid gland	UBERON:0001119	81.52	gold quality
thyroid gland	UBERON:0002046	81.42	gold quality
body of uterus	UBERON:0009853	81.39	gold quality
metanephros cortex	UBERON:0010533	81.22	gold quality
myometrium	UBERON:0001296	81.15	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	80.14	gold quality
upper lobe of left lung	UBERON:0008952	78.16	gold quality
upper lobe of lung	UBERON:0008948	78.02	gold quality
right lung	UBERON:0002167	77.87	gold quality
rectum	UBERON:0001052	77.63	gold quality
sperm	CL:0000019	77.55	silver quality
mucosa of urinary bladder	UBERON:0001259	77.22	silver quality
male germ cell	CL:0000015	77.14	silver quality
lower lobe of lung	UBERON:0008949	76.35	silver quality
muscle layer of sigmoid colon	UBERON:0035805	75.83	gold quality
left ovary	UBERON:0002119	75.79	gold quality
left ventricle myocardium	UBERON:0006566	75.63	gold quality
gall bladder	UBERON:0002110	75.59	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7008	yes	96.42
E-CURD-119	yes	30.12
E-ANND-3	yes	5.34

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GLI3

miRNA regulators (miRDB)

67 targeting GNA14, 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-8485	100.00	77.57	4731
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520G-5P	99.99	66.76	658
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-3913-5P	99.78	67.26	968
HSA-MIR-1287-3P	99.63	66.93	492

Literature-anchored findings (GeneRIF, showing 17)

• activation of the IKK/NFkappaB signaling cascade by SSTR2 requires a complicated network consisting of Galpha(14), protein kinase C, CamkII, ERK, and c-Src (PMID:16115892)
• G14alpha and G16alpha are palmitoylated at distinct polycysteine sequences, and that the adjacent polybasic domain is not required for Galpha palmitoylation but is important for localization and functional activity of heterotrimeric G proteins (PMID:17620339)
• The ability of CCR1 to signal through Galpha(14/16) thus provides a linkage for chemokines to regulate NF-kappaB-dependent responses. (PMID:19687291)
• TPR1 is required for Galpha14 to stimulate Ras-dependent signaling pathways, but not for the propagation of signals along Ras-independent pathways. (PMID:22711498)
• TNF-alpha/TNFR1 signaling promotes gastric tumorigenesis through induction of Noxo1 and Gna14 in tumor cells. (PMID:23975421)
• Study suggests that the previously identified PLCbeta-interacting residues are insufficient to ensure productive interaction of Galpha14 with PLCbeta, while an intact N-terminal half of Galpha14 is apparently required for PLCbeta interaction. (PMID:26377666)
• The findings of the work indicate a role for Galphaq and/or Galpha14 and in CCR2a/CCR2b-stimulated Rho A GTPase-mediated serum response factor activation. (PMID:26823487)
• findings identify GNA14 mutations as a cause of childhood vascular tumors, offer insight into mechanisms of oncogenic transformation by mutations affecting Gaq family members, and identify potential targets for therapeutic intervention (PMID:27476652)
• 14 of 15 (93%) anastomosing haemangiomas in the case series showed recurrent mutations in GNAQ or GNA14. (PMID:29574926)
• All hepatic small vessel neoplasms in our series demonstrated recurrent mutations in GNAQ or GNA14 in a mutually exclusive manner (PMID:29975248)
• Galphaq/14-regulated CCR2 non canonical receptor signaling was analyzed. the 8th helix of both CCR2a and CCR2b is critically involved in selectively activating Galphaq/14-regulated signaling. (PMID:30321592)
• These data suggest that GNA14 distinctively mediates fetoplacental endothelial cell migration and permeability (PMID:30387149)
• our study demonstrated recurrent GNA14/GNAQ/GNA11 mutations were present in the majority of cherry hemangiomas and established its neoplastic nature (PMID:31189994)
• Hypermethylation of GNA14 and its tumor-suppressive role in hepatitis B virus-related hepatocellular carcinoma. (PMID:33500727)
• GNA14 stimulation of KLF7 promotes malignant growth of endometrial cancer through upregulation of HAS2. (PMID:33892667)
• GNA14’s interaction with RACK1 inhibits hepatocellular carcinoma progression through reducing MAPK/JNK and PI3K/AKT signaling pathway. (PMID:34657150)
• GNA14 and GNAQ somatic mutations cause spinal and intracranial extra-axial cavernous hemangiomas. (PMID:38917801)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	gna14a	ENSDARG00000025013
mus_musculus	Gna14	ENSMUSG00000024697
rattus_norvegicus	Gna14	ENSRNOG00000014840
drosophila_melanogaster	cta	FBGN0000384
drosophila_melanogaster	Galphai	FBGN0001104
drosophila_melanogaster	Galphaf	FBGN0010223
drosophila_melanogaster	CG17760	FBGN0033756
drosophila_melanogaster	CG30054	FBGN0050054
caenorhabditis_elegans		WBGENE00001664
caenorhabditis_elegans		WBGENE00001665
caenorhabditis_elegans		WBGENE00001666
caenorhabditis_elegans		WBGENE00001667
caenorhabditis_elegans		WBGENE00001668
caenorhabditis_elegans		WBGENE00001670
caenorhabditis_elegans		WBGENE00001671
caenorhabditis_elegans		WBGENE00001673
caenorhabditis_elegans		WBGENE00001674
caenorhabditis_elegans		WBGENE00001675
caenorhabditis_elegans	gpa-14	WBGENE00001676
caenorhabditis_elegans	gpa-16	WBGENE00001678
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), GNAL (ENSG00000141404), GNA12 (ENSG00000146535), GNAQ (ENSG00000156052), GNAT3 (ENSG00000214415)

Protein

Protein identifiers

Guanine nucleotide-binding protein subunit alpha-14 — O95837 (reviewed: O95837)

All UniProt accessions (1): O95837

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide-binding proteins (G proteins) are involved as modulators or transducers in various transmembrane signaling systems.

Subunit / interactions. G proteins are composed of 3 units; alpha, beta and gamma. The alpha chain contains the guanine nucleotide binding site.

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

RefSeq proteins (1): NP_004288* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000654	Gprotein_alpha_Q	Family
IPR001019	Gprotein_alpha_su	Family
IPR011025	GproteinA_insert	Homologous_superfamily
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00503

UniProt features (15 total): binding site 7, region of interest 5, chain 1, domain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95837-F1	93.68	0.86

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 (7): 182; 201–205; 270–273; 327; 42–49; 49; 176–182

Post-translational modifications (1): 179

Function

Pathways and Gene Ontology

Reactome pathways

9 pathways

ID	Pathway
R-HSA-112043	PLC beta mediated events
R-HSA-202040	G-protein activation
R-HSA-399997	Acetylcholine regulates insulin secretion
R-HSA-416476	G alpha (q) signalling events
R-HSA-418592	ADP signalling through P2Y purinoceptor 1
R-HSA-428930	Thromboxane signalling through TP receptor
R-HSA-434316	Fatty Acids bound to GPR40 (FFAR1) regulate insulin secretion
R-HSA-456926	Thrombin signalling through proteinase activated receptors (PARs)
R-HSA-6814122	Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding

MSigDB gene sets: 250 (showing top): GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BENPORATH_ES_WITH_H3K27ME3, GOBP_CELL_CHEMOTAXIS, GOBP_INFLAMMATORY_RESPONSE, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, GOZGIT_ESR1_TARGETS_DN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_POSITIVE_REGULATION_OF_RESPONSE_TO_EXTERNAL_STIMULUS, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_TAXIS, MODULE_289, SHEDDEN_LUNG_CANCER_GOOD_SURVIVAL_A4, REACTOME_G_PROTEIN_ACTIVATION, DELYS_THYROID_CANCER_DN, GOBP_REGULATION_OF_RESPONSE_TO_STRESS

GO Biological Process (9): action potential (GO:0001508), signal transduction (GO:0007165), adenylate cyclase-modulating G protein-coupled receptor signaling pathway (GO:0007188), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), positive regulation of inflammatory response (GO:0050729), phospholipase C-activating dopamine receptor signaling pathway (GO:0060158), cell chemotaxis (GO:0060326), inflammatory response (GO:0006954), G protein-coupled receptor signaling pathway (GO:0007186)

GO Molecular Function (9): 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), guanyl nucleotide binding (GO:0019001)

GO Cellular Component (4): cytoplasm (GO:0005737), heterotrimeric G-protein complex (GO:0005834), plasma membrane (GO:0005886), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signal amplification	2
G-protein mediated events	1
Opioid Signalling	1
Regulation of insulin secretion	1
GPCR downstream signalling	1
Free fatty acids regulate insulin secretion	1
Platelet activation, signaling and aggregation	1
Chaperonin-mediated protein folding	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor signaling pathway	2
regulation of membrane potential	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
adenylate cyclase activity	1
phospholipase C activator activity	1
inflammatory response	1
positive regulation of defense response	1
positive regulation of response to external stimulus	1
regulation of inflammatory response	1
phospholipase C-activating G protein-coupled receptor signaling pathway	1
G protein-coupled dopamine receptor signaling pathway	1
chemotaxis	1
cell migration	1
cellular response to chemical stimulus	1
defense response	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
purine nucleotide binding	1
intracellular anatomical structure	1
cellular 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

Protein interactions and networks

STRING

1044 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GNA14	TAS1R3	Q7RTX0	685
GNA14	GNA15	P30679	641
GNA14	PLCB2	Q00722	583
GNA14	GRK2	P25098	536
GNA14	AVPR1A	P37288	520
GNA14	TAS1R2	Q8TE23	502
GNA14	TAS1R1	Q7RTX1	479
GNA14	PLCB1	Q9NQ66	476
GNA14	PLCB3	Q01970	470
GNA14	TRPM5	Q9NZQ8	466
GNA14	PLCB4	Q15147	452
GNA14	PRKCD	Q05655	448
GNA14	GNB5	O14775	444
GNA14	ARHGEF25	Q86VW2	436
GNA14	PSAT1	Q9Y617	434

IntAct

25 interactions, top by confidence:

A	B	Type	Score
GNA14	DNAL4	psi-mi:“MI:0915”(physical association)	0.560
DNAL4	GNA14	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	GNA14	psi-mi:“MI:0915”(physical association)	0.560
GNA14	SETDB1	psi-mi:“MI:0915”(physical association)	0.560
KAT5	GNA14	psi-mi:“MI:0915”(physical association)	0.560
LMO3	GNA14	psi-mi:“MI:0915”(physical association)	0.560
JMJD6	GNA14	psi-mi:“MI:0915”(physical association)	0.370
DUSP22	POTEF	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
RAB11A	SCAMP1	psi-mi:“MI:0914”(association)	0.350
AFG2B	MMP24OS	psi-mi:“MI:0914”(association)	0.350
SNW1		psi-mi:“MI:0914”(association)	0.350

BioGRID (12): DNAL4 (Two-hybrid), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), GNA14 (Affinity Capture-MS), JMJD6 (Two-hybrid)

ESM2 similar proteins: A8MTJ3, G1XJZ0, O14438, O15975, O70443, O73819, O95837, P04695, P04696, P0C7Q4, P11488, P16894, P19086, P19087, P19627, P20353, P20612, P21278, P21279, P28052, P29348, P29992, P30677, P38407, P38408, P38409, P41776, P43444, P45645, P50148, P50149, P82471, P87033, P87034, Q18434, Q21917, Q28294, Q28300, Q2PKF4, Q2XSV9

Diamond homologs: A2Y3B5, A8MTJ3, B0XRA0, B2RSH2, O04278, O04279, O13055, O13315, O14438, O15976, O42784, O74227, O74259, O95837, P04695, P04696, P04897, P04899, P08239, P08752, P08753, P08754, P09471, P0C7Q4, P0CN96, P0CN97, P10824, P10825, P11488, P16378, P16894, P18064, P18872, P19087, P20353, P20612, P26981, P27044, P27045, P28051

SIGNOR signaling

90 interactions.

A	Effect	B	Mechanism
FPR2	“up-regulates activity”	GNA14	binding
KISS1R	“up-regulates activity”	GNA14	binding
NMUR1	“up-regulates activity”	GNA14	binding
APLNR	“up-regulates activity”	GNA14	binding
FPR1	“up-regulates activity”	GNA14	binding
OPRD1	“up-regulates activity”	GNA14	binding
SSTR2	“up-regulates activity”	GNA14	binding
TBXA2R	“up-regulates activity”	GNA14	binding
P2RY13	“up-regulates activity”	GNA14	binding
ADRB1	“up-regulates activity”	GNA14	binding
MC1R	“up-regulates activity”	GNA14	binding
LTB4R	“up-regulates activity”	GNA14	binding
CHRM1	“up-regulates activity”	GNA14	binding
TACR2	“up-regulates activity”	GNA14	binding
MLNR	“up-regulates activity”	GNA14	binding
AGTR1	“up-regulates activity”	GNA14	binding
CHRM3	“up-regulates activity”	GNA14	binding
CYSLTR1	“up-regulates activity”	GNA14	binding
GALR2	“up-regulates activity”	GNA14	binding
CYSLTR2	“up-regulates activity”	GNA14	binding
ADRA1B	“up-regulates activity”	GNA14	binding
ADRA1D	“up-regulates activity”	GNA14	binding
ADRB2	“up-regulates activity”	GNA14	binding
PTGFR	“up-regulates activity”	GNA14	binding
PTGER1	“up-regulates activity”	GNA14	binding
ADRA1A	“up-regulates activity”	GNA14	binding
HTR1A	“up-regulates activity”	GNA14	binding
PRLHR	“up-regulates activity”	GNA14	binding
BDKRB2	“up-regulates activity”	GNA14	binding
LPAR1	“up-regulates activity”	GNA14	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	56
Likely benign	0
Benign	3

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
4076053	GRCh37/hg19 9q21.2(chr9:79995119-80139796)x1	Pathogenic
4689	NC_000009.12:g.77390734_77428010del	Pathogenic
548667	NM_004297.4(GNA14):c.614A>T (p.Gln205Leu)	Pathogenic

SpliceAI

2916 predictions. Top by Δscore:

Variant	Effect	Δscore
9:77431450:C:CC	acceptor_gain	1.0000
9:77434364:TCACT:T	donor_loss	1.0000
9:77434365:CACT:C	donor_loss	1.0000
9:77434366:A:AC	donor_gain	1.0000
9:77434367:C:CG	donor_gain	1.0000
9:77434367:CT:C	donor_gain	1.0000
9:77434367:CTA:C	donor_gain	1.0000
9:77434367:CTAT:C	donor_gain	1.0000
9:77434396:C:CA	donor_gain	1.0000
9:77529065:TTA:T	donor_loss	1.0000
9:77529066:TA:T	donor_loss	1.0000
9:77529068:C:T	donor_loss	1.0000
9:77529089:A:AC	donor_gain	1.0000
9:77529090:C:CC	donor_gain	1.0000
9:77529094:AT:A	donor_gain	1.0000
9:77529101:G:C	donor_gain	1.0000
9:77529250:GTTC:G	acceptor_gain	1.0000
9:77529252:TC:T	acceptor_gain	1.0000
9:77529252:TCC:T	acceptor_loss	1.0000
9:77529253:CC:C	acceptor_gain	1.0000
9:77529253:CCT:C	acceptor_loss	1.0000
9:77529254:C:CC	acceptor_gain	1.0000
9:77529255:T:A	acceptor_loss	1.0000
9:77593734:T:TA	donor_gain	1.0000
9:77424177:CAAG:C	acceptor_gain	0.9900
9:77424180:G:GC	acceptor_gain	0.9900
9:77424186:T:TC	acceptor_gain	0.9900
9:77425557:CTTA:C	donor_loss	0.9900
9:77425558:TTA:T	donor_loss	0.9900
9:77425559:TA:T	donor_loss	0.9900

AlphaMissense

2363 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:77425626:C:A	K271N	1.000
9:77425626:C:G	K271N	1.000
9:77425627:T:A	K271M	1.000
9:77425629:G:C	N270K	1.000
9:77425629:G:T	N270K	1.000
9:77428958:G:C	F224L	1.000
9:77428958:G:T	F224L	1.000
9:77428960:A:G	F224L	1.000
9:77428982:A:C	F216L	1.000
9:77428982:A:T	F216L	1.000
9:77428984:A:G	F216L	1.000
9:77428994:C:A	W212C	1.000
9:77428994:C:G	W212C	1.000
9:77428996:A:G	W212R	1.000
9:77428996:A:T	W212R	1.000
9:77429003:T:A	R209S	1.000
9:77429003:T:G	R209S	1.000
9:77429004:C:G	R209T	1.000
9:77429015:T:A	Q205H	1.000
9:77429015:T:G	Q205H	1.000
9:77429019:C:T	G204D	1.000
9:77429020:C:A	G204C	1.000
9:77429020:C:G	G204R	1.000
9:77429022:C:A	G203V	1.000
9:77429022:C:T	G203D	1.000
9:77429023:C:G	G203R	1.000
9:77429028:T:C	D201G	1.000
9:77429029:C:G	D201H	1.000
9:77529216:C:A	Q54H	1.000
9:77529216:C:G	Q54H	1.000

dbSNP variants (sampled 300 via entrez): RS1000035097 (9:77514766 A>G), RS1000053305 (9:77631293 A>C,G), RS1000067730 (9:77460268 C>T), RS1000088709 (9:77574830 CAG>C), RS1000112376 (9:77476614 C>T), RS1000112606 (9:77553156 G>A), RS1000118567 (9:77637135 A>G), RS1000132541 (9:77438643 A>G), RS1000147747 (9:77440446 C>G), RS1000149387 (9:77430283 T>C), RS1000150549 (9:77493794 A>G,T), RS1000159646 (9:77530531 T>G), RS1000163912 (9:77628550 A>G), RS1000183741 (9:77493546 T>A), RS1000185824 (9:77589678 C>A)

Disease associations

OMIM: gene MIM:604397 | disease phenotypes: MIM:607859, MIM:200150

GenCC curated gene-disease

Mondo (5): cerebrofacial arteriovenous metameric syndrome (MONDO:0015405), tufted angioma (MONDO:0011927), VPS13A-related neurodegenerative disease (MONDO:0008695), kaposiform hemangioendothelioma (MONDO:0016236), pyogenic granuloma (MONDO:0022096)

Orphanet (4): Cerebrofacial arteriovenous metameric syndrome (Orphanet:141189), Tufted angioma (Orphanet:1063), Choreoacanthocytosis (Orphanet:2388), Kaposiform hemangioendothelioma (Orphanet:2122)

HPO phenotypes

23 total (24 of 23 shown, HPO-id order):

HPO	Term
HP:0000329	Facial hemangioma
HP:0000565	Esotropia
HP:0000967	Petechiae
HP:0000969	Edema
HP:0000975	Hyperhidrosis
HP:0000979	Purpura
HP:0000998	Hypertrichosis
HP:0001004	Lymphedema
HP:0001873	Thrombocytopenia
HP:0001903	Anemia
HP:0001937	Microangiopathic hemolytic anemia
HP:0003401	Paresthesia
HP:0005520	Chronic disseminated intravascular coagulation
HP:0005548	Megakaryocytopenia
HP:0008069	Neoplasm of the skin
HP:0010990	Abnormality of the common coagulation pathway
HP:0011355	Localized skin lesion
HP:0011900	Hypofibrinogenemia
HP:0012531	Pain
HP:0025474	Erythematous plaque
HP:0030350	Erythematous papule
HP:0031490	Hemangioma of the lip
HP:0033106	Elevated circulating D-dimer concentration
HP:0012329	Tufted angioma

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST002337_87	Amyotrophic lateral sclerosis (sporadic)	4.000000e-06
GCST005851_18	Delirium	1.000000e-06
GCST008103_162	Bipolar disorder	6.000000e-06
GCST009090_5	Thoracic aortic calcification levels	6.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0010273	thoracic aortic calcification measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D017789	Granuloma, Pyogenic	C23.550.382.937
C537007	Kaposiform Hemangioendothelioma (supp.)
C536924	Tufted angioma (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
arsenite	increases methylation	2
mercuric bromide	increases expression, affects cotreatment	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
beauvericin	affects cotreatment, decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
sodium arsenite	affects methylation	1
triadimefon	decreases expression	1
3-chloro-4-(dichloromethyl)-5-hydroxy-2(5H)-furanone	affects response to substance	1
CGP 52608	increases reaction, affects binding	1
enniatins	affects cotreatment, decreases expression	1
monomethylarsonous acid	increases methylation	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Carbamazepine	affects expression	1
Dactinomycin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	increases expression	1
Nickel	increases expression	1
Oxygen	increases expression	1
Rotenone	increases expression	1
Silicon Dioxide	decreases expression	1
Tetrachlorodibenzodioxin	increases expression	1
Valproic Acid	affects expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04921722	PHASE4	UNKNOWN	Percutaneous Administration of Sirolimus in the Treatment of Superficial Complicated Vascular Anomalies
NCT04077515	PHASE4	COMPLETED	Safety and Efficacy of Low-dose Sirolimus to Kaposiform Hemangioendothelioma
NCT04448873	PHASE4	COMPLETED	Guided Discontinuation Versus Maintenance Treatment of Sirolimus in Pediatric Patients With Kaposiform Hemangioendothelioma
NCT00975819	PHASE2	COMPLETED	Safety and Efficacy Study of Sirolimus in Complicated Vascular Anomalies
NCT02110069	PHASE2	TERMINATED	A Study to Compare Vincristine to Sirolimus for Treatment of High Risk Vascular Tumors
NCT03188068	PHASE2	COMPLETED	Sirolimus Versus Sirolimus Plus Prednisolone for Kaposiform Hemangioendothelioma
NCT04775173	PHASE2	COMPLETED	Efficacy and Safety of Different Concentrations of Sirolimus in the Treatment of Kaposiform Hemangioendothelioma.
NCT07131644	PHASE2	NOT_YET_RECRUITING	Sirolimus Discontinuation Strategies in Kaposiform Hemangioendothelioma
NCT02399527	Not specified	RECRUITING	Lymphatic Anomalies Registry for the Assessment of Outcome Data
NCT03001180	Not specified	RECRUITING	Identification of Biomarkers for Patients with Vascular Anomalies
NCT05351216	Not specified	RECRUITING	The Effect of Sirolimus on Immunizations During the Treatment of Kaposiform Hemangioendothelioma
NCT05692427	Not specified	RECRUITING	Evaluation of Cryotherapy in Granuloma Pyogenicum