RAPGEF6

Summary

RAPGEF6 (Rap guanine nucleotide exchange factor 6, HGNC:20655) is a protein-coding gene on chromosome 5q31.1, encoding Rap guanine nucleotide exchange factor 6 (Q8TEU7). Guanine nucleotide exchange factor (GEF) for Rap1A, Rap2A and M-Ras GTPases.

Enables several functions, including GTP-dependent protein binding activity; guanyl-nucleotide exchange factor activity; and phosphatidic acid binding activity. Involved in microvillus assembly; positive regulation of GTPase activity; and protein localization to plasma membrane. Located in several cellular components, including apical plasma membrane; centrosome; and endocytic vesicle.

Source: NCBI Gene 51735 — RefSeq curated summary.

At a glance

• GWAS associations: 17
• Clinical variants (ClinVar): 232 total — 1 pathogenic
• MANE Select transcript: NM_016340

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20655
Approved symbol	RAPGEF6
Name	Rap guanine nucleotide exchange factor 6
Location	5q31.1
Locus type	gene with protein product
Status	Approved
Aliases	RA-GEF-2, PDZ-GEF2
Ensembl gene	ENSG00000158987
Ensembl biotype	protein_coding
OMIM	610499
Entrez	51735

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 14 protein_coding, 3 retained_intron, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000296859, ENST00000308008, ENST00000503398, ENST00000504039, ENST00000504575, ENST00000504919, ENST00000507093, ENST00000509018, ENST00000510071, ENST00000512052, ENST00000512611, ENST00000513227, ENST00000514179, ENST00000515170, ENST00000627212, ENST00000671916, ENST00000934140, ENST00000952736, ENST00000952737

RefSeq mRNA: 6 — MANE Select: NM_016340 NM_001164386, NM_001164387, NM_001164388, NM_001164389, NM_001164390, NM_016340

CCDS: CCDS34225, CCDS54897, CCDS54898, CCDS54899, CCDS54900, CCDS54901

Canonical transcript exons

ENST00000509018 — 28 exons

Exon	Start	End
ENSE00002019759	131423921	131427291
ENSE00002288980	131634962	131635229
ENSE00003523608	131428902	131429216
ENSE00003775487	131461705	131462088
ENSE00003776478	131508071	131508207
ENSE00003776620	131442349	131442537
ENSE00003776709	131433430	131433658
ENSE00003777020	131498443	131498607
ENSE00003777127	131521390	131521521
ENSE00003777217	131489546	131489654
ENSE00003777219	131603271	131603327
ENSE00003777845	131510314	131510491
ENSE00003778414	131548047	131548190
ENSE00003778443	131472587	131472744
ENSE00003778493	131592383	131592466
ENSE00003778713	131453054	131453177
ENSE00003779075	131455801	131456012
ENSE00003779417	131504626	131504778
ENSE00003779789	131492582	131492785
ENSE00003780388	131439581	131439715
ENSE00003780401	131430859	131431349
ENSE00003780562	131495553	131495660
ENSE00003780987	131479513	131479753
ENSE00003782242	131446483	131446703
ENSE00003782454	131604623	131604693
ENSE00003783011	131561978	131562047
ENSE00003783659	131505364	131505522
ENSE00003783742	131464041	131464281

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 95.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.3486 / max 325.6449, expressed in 1796 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
63265	19.8664	1796
63262	0.4822	102

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
corpus callosum	UBERON:0002336	95.88	gold quality
epithelial cell of pancreas	CL:0000083	93.95	gold quality
calcaneal tendon	UBERON:0003701	93.87	gold quality
sperm	CL:0000019	93.74	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.50	gold quality
cerebellar vermis	UBERON:0004720	93.10	gold quality
superficial temporal artery	UBERON:0001614	92.96	gold quality
subthalamic nucleus	UBERON:0001906	92.76	gold quality
ileal mucosa	UBERON:0000331	92.72	gold quality
Brodmann (1909) area 46	UBERON:0006483	91.72	gold quality
trigeminal ganglion	UBERON:0001675	91.64	gold quality
superior vestibular nucleus	UBERON:0007227	91.54	gold quality
epithelium of nasopharynx	UBERON:0001951	91.27	gold quality
tonsil	UBERON:0002372	91.26	gold quality
nasopharynx	UBERON:0001728	91.25	gold quality
inferior vagus X ganglion	UBERON:0005363	91.17	gold quality
endothelial cell	CL:0000115	91.12	gold quality
bone marrow cell	CL:0002092	91.12	gold quality
pons	UBERON:0000988	91.02	gold quality
bone marrow	UBERON:0002371	90.83	gold quality
lateral globus pallidus	UBERON:0002476	90.77	gold quality
medulla oblongata	UBERON:0001896	90.70	gold quality
skin of hip	UBERON:0001554	90.63	gold quality
dorsal plus ventral thalamus	UBERON:0001897	90.43	gold quality
sural nerve	UBERON:0015488	90.14	gold quality
primary visual cortex	UBERON:0002436	90.08	gold quality
occipital lobe	UBERON:0002021	89.98	gold quality
upper leg skin	UBERON:0004262	89.94	gold quality
trabecular bone tissue	UBERON:0002483	89.86	gold quality
lower lobe of lung	UBERON:0008949	89.80	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-122	yes	18.39
E-ANND-3	yes	4.98
E-GEOD-70580	no	1327.30

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

164 targeting RAPGEF6, 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-1252-5P	100.00	69.80	2774
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-433-3P	99.98	69.37	1203
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-23A-3P	99.95	74.24	3163

Literature-anchored findings (GeneRIF, showing 7)

• the second PDZ domain from human phosphatase hPTP1E in complex with a C-terminal peptide from the guanine nucleotide exchange factor RA-GEF-2 has been determined (PMID:12095257)
• haplotypes underlying the SPEC2/PDZ-GEF2/acyl-CoA synthetase long-chain family member 6 region are associated with schizophrenia (PMID:17030554)
• PDZ-GEF2 plays a critical role in the maturation of adherens junctions. (PMID:18585005)
• When males and females were analysed separately, SNP4 (rs31251) in PDZ-GEF2 is associated with schizophrenia in females in Han Chinese. (PMID:18718982)
• JAM-A dimerization facilitates formation of a complex with Afadin and PDZ-GEF2 that activates Rap1A, which regulates beta1 integrin levels and cell migration. (PMID:19176753)
• BAG3 overexpression increases cell adhesion in Cos7 cells, but not in PDZGEF2 gene knockdown cells indicating that PDZGEF2 is a critical partner for BAG3 in regulating cell adhesion (PMID:20800573)
• local accumulation of PDZGEF at the apical membrane during establishment of epithelial polarity is mediated by electrostatic interactions between positively charged side chains in the PDZ domain and negatively charged phosphatidic acid. (PMID:24858808)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rapgef6	ENSDARG00000010945
mus_musculus	Rapgef6	ENSMUSG00000037533
rattus_norvegicus	Rapgef6	ENSRNOG00000009995

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

Rap guanine nucleotide exchange factor 6 — Q8TEU7 (reviewed: Q8TEU7)

Alternative names: PDZ domain-containing guanine nucleotide exchange factor 2, RA-GEF-2

All UniProt accessions (7): Q8TEU7, A0A5F9ZHG7, B7Z7Y1, D6RB02, D6RD23, D6RE77, D6RIH0

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor (GEF) for Rap1A, Rap2A and M-Ras GTPases. Does not interact with cAMP.

Subunit / interactions. Interacts with the second PDZ domain of human PTP1e.

Subcellular location. Cytoplasm. Cell membrane.

Tissue specificity. Isoform 3 has highest expression levels in the brain, heart, liver, lung and placenta and is barely detectable in skeletal muscle, kidney and pancreas.

Isoforms (6)

UniProt ID	Names	Canonical?
Q8TEU7-1	1, PDZ-GEF2A	yes
Q8TEU7-2	2, PDZ-GEF2B
Q8TEU7-3	3
Q8TEU7-4	4
Q8TEU7-5	5
Q8TEU7-6	6

RefSeq proteins (6): NP_001157858, NP_001157859, NP_001157860, NP_001157861, NP_001157862, NP_057424* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000159	RA_dom	Domain
IPR000595	cNMP-bd_dom	Domain
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001478	PDZ	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR014710	RmlC-like_jellyroll	Homologous_superfamily
IPR018490	cNMP-bd_dom_sf	Homologous_superfamily
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily

Pfam: PF00027, PF00595, PF00617, PF00618, PF00788

UniProt features (51 total): strand 11, region of interest 6, splice variant 6, compositionally biased region 5, sequence variant 5, sequence conflict 5, domain 4, helix 3, modified residue 2, turn 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3LNY	X-RAY DIFFRACTION	1.3
2D93	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8TEU7-F1	61.83	0.22

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 (1): 280–399

Post-translational modifications (2): 1, 3

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 321 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_ESTABLISHMENT_OF_ENDOTHELIAL_INTESTINAL_BARRIER, AAGCCAT_MIR135A_MIR135B, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_NEUROGENESIS, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, USF_C, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, MONNIER_POSTRADIATION_TUMOR_ESCAPE_UP, TERAMOTO_OPN_TARGETS_CLUSTER_7, IRF7_01

GO Biological Process (7): Ras protein signal transduction (GO:0007265), microvillus assembly (GO:0030033), regulation of GTPase activity (GO:0043087), protein localization to plasma membrane (GO:0072659), positive regulation of microvillus assembly (GO:1903698), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), GTP-dependent protein binding (GO:0030742), small GTPase binding (GO:0031267), phosphatidic acid binding (GO:0070300), protein binding (GO:0005515)

GO Cellular Component (7): centrosome (GO:0005813), cytosol (GO:0005829), plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), endocytic vesicle (GO:0030139), cytoplasm (GO:0005737), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
small GTPase-mediated signal transduction	1
microvillus organization	1
plasma membrane bounded cell projection assembly	1
GTPase activity	1
regulation of hydrolase activity	1
protein localization to membrane	1
protein localization to cell periphery	1
microvillus assembly	1
regulation of microvillus assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
protein binding	1
GTPase binding	1
phospholipid binding	1
anion binding	1
binding	1
centriole	1
microtubule organizing center	1
cytoplasm	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
cytoplasmic vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1460 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAPGEF6	RAP1A	P10113	862
RAPGEF6	MRAS	O14807	843
RAPGEF6	AFDN	P55196	824
RAPGEF6	PTPN13	Q12923	817
RAPGEF6	RAP2A	P10114	815
RAPGEF6	F11R	Q9Y624	809
RAPGEF6	CDC42SE2	Q9NRR3	638
RAPGEF6	BAG3	O95817	594
RAPGEF6	IL16	Q14005	489
RAPGEF6	TIAM1	Q13009	480
RAPGEF6	NRAS	P01111	446
RAPGEF6	LRPAP1	P30533	438
RAPGEF6	RABIF	P47224	433
RAPGEF6	ACSL6	Q9UKU0	425
RAPGEF6	RAP1B	P09526	422

IntAct

572 interactions, top by confidence:

A	B	Type	Score
RAPGEF6	APBA3	psi-mi:“MI:0407”(direct interaction)	0.690
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
RAPGEF6	RAPGEF2	psi-mi:“MI:0915”(physical association)	0.610
RAPGEF2	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.610
YWHAE	PIK3C2A	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
AURKA	WDR62	psi-mi:“MI:0914”(association)	0.530
APBA3	DUSP11	psi-mi:“MI:0914”(association)	0.530
APBA3	CLSTN1	psi-mi:“MI:0914”(association)	0.530
ZNRD2	CCDC85C	psi-mi:“MI:0914”(association)	0.530
HSPA8	ARHGEF10	psi-mi:“MI:2364”(proximity)	0.480
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
RAPGEF6	PDZD2	psi-mi:“MI:0407”(direct interaction)	0.440
SNX27	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	FRMPD2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	MAST2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	TAMALIN	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	RHPN1	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	MAGI2	psi-mi:“MI:0407”(direct interaction)	0.440
RAPGEF6	PTPN3	psi-mi:“MI:0407”(direct interaction)	0.440
IL16	RAPGEF6	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (103): RAPGEF6 (Affinity Capture-RNA), RAPGEF6 (Affinity Capture-RNA), RAPGEF6 (Affinity Capture-RNA), RAPGEF6 (Affinity Capture-RNA), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Proximity Label-MS), RAPGEF6 (Proximity Label-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-MS), RAPGEF6 (Affinity Capture-RNA), RAPGEF6 (Affinity Capture-MS)

ESM2 similar proteins: A0A0G2K344, D3ZGS3, F1M386, F1MSG6, F1PBJ0, G5EF51, O00329, O02697, O35242, O35904, O70481, O88763, O94830, P32871, P42336, P42337, P42338, P42339, P42347, P42348, P48736, P50520, P54676, P70600, Q01968, Q14289, Q14BI7, Q16JS8, Q3MHU3, Q3UYK3, Q4KWH5, Q4KWH8, Q5D891, Q5ZI89, Q6AZN6, Q6GQ76, Q6NVF0, Q6PF93, Q7Z392, Q80Y98

Diamond homologs: A2CEA7, A7A0P0, B3LTF3, B5VMS9, C8ZCV7, F1M386, F1MSG6, F1PBJ0, G5EDB9, O14827, O77086, P04821, P0CF32, P0CF33, P0CF34, P27671, P28818, P43069, P70392, Q02342, Q13972, Q54FF3, Q552M5, Q86G47, Q8CHG7, Q8IS18, Q8IS20, Q8IZJ4, Q8TEU7, Q99JE4, Q9Y4G8, A2AR50, B0M0P8, B0UXH6, Q4R7W3, Q54PQ4, Q54S40, Q54TK8, Q55EC7, Q55FD8

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
RAPGEF6	up-regulates	HRAS	“guanine nucleotide exchange factor”
RAPGEF6	up-regulates	NRAS	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 180 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
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	47.6×	6e-10
Activation of BAD and translocation to mitochondria	7	47.2×	5e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	41.6×	1e-08
Ras activation upon Ca2+ influx through NMDA receptor	8	40.4×	2e-09
Activation of BH3-only proteins	7	30.8×	1e-07
RHO GTPases activate PKNs	9	25.3×	5e-09
Unblocking of NMDA receptors, glutamate binding and activation	5	24.1×	4e-05
Synaptic adhesion-like molecules	5	24.1×	4e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of postsynaptic membrane neurotransmitter receptor levels	6	18.7×	3e-04
establishment or maintenance of epithelial cell apical/basal polarity	5	18.3×	8e-04
positive regulation of excitatory postsynaptic potential	5	16.6×	1e-03
establishment of protein localization	5	13.6×	2e-03
mitotic spindle organization	7	12.0×	4e-04
protein targeting	5	11.5×	4e-03
MAPK cascade	9	8.7×	3e-04
Ras protein signal transduction	6	7.8×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	192
Likely benign	5
Benign	5

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
1335875	NC_000005.9:g.(?130766131)(131044371_131044893)del	Pathogenic

SpliceAI

6279 predictions. Top by Δscore:

Variant	Effect	Δscore
5:131427288:TTTT:T	acceptor_gain	1.0000
5:131427289:TTT:T	acceptor_gain	1.0000
5:131427289:TTTC:T	acceptor_loss	1.0000
5:131427290:TT:T	acceptor_gain	1.0000
5:131427291:TC:T	acceptor_loss	1.0000
5:131427292:C:CA	acceptor_loss	1.0000
5:131427292:C:CC	acceptor_gain	1.0000
5:131427293:T:A	acceptor_loss	1.0000
5:131431348:ACC:A	acceptor_loss	1.0000
5:131431349:CCTA:C	acceptor_loss	1.0000
5:131431350:CT:C	acceptor_loss	1.0000
5:131439575:TCTTA:T	donor_loss	1.0000
5:131439576:CTTA:C	donor_loss	1.0000
5:131439577:TTAC:T	donor_loss	1.0000
5:131439577:TTACC:T	donor_loss	1.0000
5:131439578:TA:T	donor_loss	1.0000
5:131439579:A:C	donor_loss	1.0000
5:131439579:ACCTT:A	donor_loss	1.0000
5:131439580:C:A	donor_loss	1.0000
5:131439711:TGTAT:T	acceptor_gain	1.0000
5:131439713:TAT:T	acceptor_gain	1.0000
5:131439713:TATC:T	acceptor_loss	1.0000
5:131439714:ATCT:A	acceptor_loss	1.0000
5:131439715:TC:T	acceptor_loss	1.0000
5:131439716:C:CC	acceptor_gain	1.0000
5:131439717:T:C	acceptor_loss	1.0000
5:131453049:CCTA:C	donor_loss	1.0000
5:131453050:CTA:C	donor_loss	1.0000
5:131453051:TA:T	donor_loss	1.0000
5:131453051:TAC:T	donor_loss	1.0000

AlphaMissense

10638 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:131453132:C:G	R1041T	1.000
5:131455811:A:C	F1022L	1.000
5:131455811:A:T	F1022L	1.000
5:131455813:A:G	F1022L	1.000
5:131455886:T:A	R997S	1.000
5:131455886:T:G	R997S	1.000
5:131455887:C:A	R997I	1.000
5:131455887:C:G	R997T	1.000
5:131455929:A:G	L983P	1.000
5:131461731:G:C	N946K	1.000
5:131461731:G:T	N946K	1.000
5:131461966:A:G	L868P	1.000
5:131462080:A:G	L830S	1.000
5:131462084:A:C	Y829D	1.000
5:131464089:A:G	L811P	1.000
5:131464137:A:G	L795P	1.000
5:131464137:A:T	L795H	1.000
5:131492751:G:T	A521D	1.000
5:131492763:A:G	L517S	1.000
5:131495563:A:G	L506P	1.000
5:131495639:A:G	W481R	1.000
5:131495639:A:T	W481R	1.000
5:131504672:C:G	R403P	1.000
5:131508198:A:G	L272P	1.000
5:131510352:A:G	L256P	1.000
5:131446560:A:G	L1115P	0.999
5:131446591:C:G	A1105P	0.999
5:131453111:C:G	R1048P	0.999
5:131453131:T:A	R1041S	0.999
5:131453131:T:G	R1041S	0.999

dbSNP variants (sampled 300 via entrez): RS1000007553 (5:131570794 G>A), RS1000012867 (5:131583886 A>C), RS1000021388 (5:131441664 C>T), RS1000025536 (5:131607953 G>A), RS1000032886 (5:131567988 T>C), RS1000034507 (5:131480054 A>G), RS1000050570 (5:131455220 A>G), RS1000056777 (5:131607716 G>A), RS1000070651 (5:131480127 T>C), RS1000071291 (5:131437547 A>G), RS1000079932 (5:131595726 T>C), RS1000120165 (5:131570611 T>C), RS1000122865 (5:131461691 T>C,G), RS1000126782 (5:131527664 T>C), RS1000128569 (5:131611191 A>C,G)

Disease associations

OMIM: gene MIM:610499 | disease phenotypes: MIM:619705

GenCC curated gene-disease

Mondo (1): immunodeficiency 93 and hypertrophic cardiomyopathy (MONDO:0030528)

Orphanet (1): Agammaglobulinemia-early-onset hypertrophic cardiomyopathy-neutropenia syndrome (Orphanet:693647)

HPO phenotypes

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

GWAS associations

17 associations (top):

Study	Trait	p-value
GCST002817_20	Alzheimer’s disease in APOE e4- carriers	6.000000e-07
GCST002875_174	Diisocyanate-induced asthma	1.000000e-06
GCST003766_67	Subjective well-being	1.000000e-08
GCST004131_32	Inflammatory bowel disease	4.000000e-27
GCST004132_10	Crohn’s disease	6.000000e-36
GCST004133_36	Ulcerative colitis	2.000000e-06
GCST004862_152	Itch intensity from mosquito bite adjusted by bite size	3.000000e-09
GCST004862_58	Itch intensity from mosquito bite adjusted by bite size	1.000000e-09
GCST004863_100	Mosquito bite size	5.000000e-06
GCST004863_101	Mosquito bite size	5.000000e-16
GCST004864_31	Perceived unattractiveness to mosquitoes	6.000000e-06
GCST004865_89	Itch intensity from mosquito bite adjusted by bite size	2.000000e-10
GCST010042_137	Asthma	9.000000e-12
GCST010043_128	Asthma	2.000000e-14
GCST010701_41	Cortical surface area (MOSTest)	1.000000e-20
GCST010702_96	Subcortical volume (MOSTest)	2.000000e-08
GCST010703_160	Brain morphology (MOSTest)	3.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0006995	response to diisocyanate
EFO:0007869	wellbeing measurement
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0008380	perceived unattractiveness to mosquitos measurement
EFO:0004346	neuroimaging measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Formaldehyde	decreases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
FR900359	affects phosphorylation	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
testosterone undecanoate	affects cotreatment, decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
cobaltous chloride	affects expression	1
ochratoxin A	decreases expression	1
benzo(e)pyrene	decreases methylation	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
coumarin	increases phosphorylation	1
cupric oxide	decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
Sunitinib	increases expression	1
Acrolein	increases oxidation, increases abundance, affects cotreatment	1
Arsenic	affects methylation	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Indomethacin	decreases expression	1
Lead	affects expression	1
Methapyrilene	decreases methylation	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Quercetin	decreases phosphorylation	1
Selenium	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Vitamin E	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1

Clinical trials (associated diseases)

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