SH3BP2

Summary

SH3BP2 (SH3 domain binding protein 2, HGNC:10825) is a protein-coding gene on chromosome 4p16.3, encoding SH3 domain-binding protein 2 (P78314). Binds differentially to the SH3 domains of certain proteins of signal transduction pathways.

The protein encoded by this gene has an N-terminal pleckstrin homology (PH) domain, an SH3-binding proline-rich region, and a C-terminal SH2 domain. The protein binds to the SH3 domains of several proteins including the ABL1 and SYK protein tyrosine kinases , and functions as a cytoplasmic adaptor protein to positively regulate transcriptional activity in T, natural killer (NK), and basophilic cells. Mutations in this gene result in cherubism. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6452 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cherubism (Strong, GenCC)
• GWAS associations: 3
• Clinical variants (ClinVar): 868 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 33
• MANE Select transcript: NM_001122681

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10825
Approved symbol	SH3BP2
Name	SH3 domain binding protein 2
Location	4p16.3
Locus type	gene with protein product
Status	Approved
Aliases	RES4-23, CRBM
Ensembl gene	ENSG00000087266
Ensembl biotype	protein_coding
OMIM	602104
Entrez	6452

Gene structure

Transcript identifiers

Ensembl transcripts: 61 — 41 protein_coding, 13 retained_intron, 4 nonsense_mediated_decay, 3 protein_coding_CDS_not_defined

ENST00000356331, ENST00000435136, ENST00000452765, ENST00000502260, ENST00000503219, ENST00000503393, ENST00000504294, ENST00000504450, ENST00000505941, ENST00000506932, ENST00000508338, ENST00000508385, ENST00000509677, ENST00000510074, ENST00000510193, ENST00000510204, ENST00000511185, ENST00000511237, ENST00000511663, ENST00000511747, ENST00000512014, ENST00000512131, ENST00000513020, ENST00000513069, ENST00000513095, ENST00000515183, ENST00000515737, ENST00000515802, ENST00000714405, ENST00000714406, ENST00000714407, ENST00000893545, ENST00000893546, ENST00000893547, ENST00000893548, ENST00000893549, ENST00000893550, ENST00000893551, ENST00000893552, ENST00000893553, ENST00000893554, ENST00000893555, ENST00000893556, ENST00000893557, ENST00000893558, ENST00000893559, ENST00000893560, ENST00000893561, ENST00000893562, ENST00000893563, ENST00000893564, ENST00000893565, ENST00000893566, ENST00000893567, ENST00000893568, ENST00000893569, ENST00000893570, ENST00000932791, ENST00000932792, ENST00000932793, ENST00000964214

RefSeq mRNA: 4 — MANE Select: NM_001122681 NM_001122681, NM_001145855, NM_001145856, NM_003023

CCDS: CCDS33944, CCDS54715, CCDS54716

Canonical transcript exons

ENST00000503393 — 13 exons

Exon	Start	End
ENSE00001433703	2793085	2793138
ENSE00003540196	2824613	2824730
ENSE00003561695	2820614	2820753
ENSE00003636502	2822935	2823037
ENSE00003787337	2825126	2825196
ENSE00004023868	2832990	2833049
ENSE00004023870	2832331	2832412
ENSE00004023874	2831923	2831978
ENSE00004023882	2831571	2831679
ENSE00004023886	2827230	2827318
ENSE00004023895	2829493	2830147
ENSE00004023896	2827606	2827674
ENSE00004034564	2833697	2841096

Expression profiles

Bgee: expression breadth ubiquitous, 213 present calls, max score 98.56.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.7219 / max 386.1616, expressed in 1794 samples.

FANTOM5 promoters (16 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46631	6.3054	1262
46643	4.5030	909
46629	4.1246	1250
46630	3.6364	1101
46645	3.0003	1118
46637	1.9029	311
46642	1.8604	872
46647	0.3868	144
46633	0.3173	135
46646	0.2780	121

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.56	gold quality
sural nerve	UBERON:0015488	97.91	gold quality
monocyte	CL:0000576	96.79	gold quality
cortical plate	UBERON:0005343	96.61	gold quality
mononuclear cell	CL:0000842	96.53	gold quality
leukocyte	CL:0000738	96.39	gold quality
spleen	UBERON:0002106	95.34	gold quality
skin of abdomen	UBERON:0001416	94.86	gold quality
blood	UBERON:0000178	94.63	gold quality
skin of leg	UBERON:0001511	94.54	gold quality
upper lobe of left lung	UBERON:0008952	93.80	gold quality
ganglionic eminence	UBERON:0004023	93.19	gold quality
tibial nerve	UBERON:0001323	93.03	gold quality
metanephros cortex	UBERON:0010533	92.82	gold quality
right lung	UBERON:0002167	92.01	gold quality
upper lobe of lung	UBERON:0008948	91.99	gold quality
right lobe of liver	UBERON:0001114	91.67	gold quality
buccal mucosa cell	CL:0002336	91.56	gold quality
zone of skin	UBERON:0000014	91.56	gold quality
stromal cell of endometrium	CL:0002255	91.12	gold quality
apex of heart	UBERON:0002098	90.52	gold quality
omental fat pad	UBERON:0010414	90.45	gold quality
lower esophagus mucosa	UBERON:0035834	90.45	gold quality
peritoneum	UBERON:0002358	90.39	gold quality
lymph node	UBERON:0000029	90.29	gold quality
vermiform appendix	UBERON:0001154	89.79	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.57	gold quality
colonic epithelium	UBERON:0000397	88.99	gold quality
small intestine Peyer’s patch	UBERON:0003454	88.90	gold quality
transverse colon	UBERON:0001157	88.68	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-9221	yes	26.72
E-ANND-3	yes	17.48
E-MTAB-8498	yes	10.08
E-GEOD-100618	no	148.81

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A, PARP1

miRNA regulators (miRDB)

228 targeting SH3BP2, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4673	100.00	66.64	1490
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-574-5P	100.00	66.01	989
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-767-5P	99.95	70.85	993
HSA-MIR-548J-3P	99.94	72.61	4881

Literature-anchored findings (GeneRIF, showing 30)

• Regulation of FcepsilonRI-mediated degranulation by an adaptor protein 3BP2 in rat basophilic leukemia RBL-2H3 cells. (PMID:12200378)
• 3BP2 may regulate b cell receptor-mediated gene activation through Vav proteins. (PMID:15345594)
• Adaptor protein SH3BP2 regulates transcription factors through its tyrosine phosphorylation and SH2 domain. (PMID:15751964)
• CD244-3BP2 association regulates cytolytic function but not IFN-gamma release (PMID:16177062)
• no mutations…in giant cell granuloma (PMID:16713042)
• How SH3BP2 affects leukocyte signaling and influences cherubism (PMID:16802602)
• a novel A1517G missense mutation at the SH3BP2 gene in a Chinese family with multiple affected individuals with cherubism was identified (PMID:17147794)
• Mutated in a rare human disease involved in cranial-facial development called cherubism, suggesting a role for 3BP2 in regulating osteoclast and hematopoietic cell function. [REVIEW] (PMID:17156730)
• unexpected role of 3BP2 in endocytic and cytoskeletal regulation through its interaction with CIN85 and HIP-55 (PMID:17306257)
• A new mutation in a family affected with cherubism (PMID:17321449)
• People with Giant Cell Granuloma of the Jaw do not harbour cherubism-related germline SH3BP2 mutations. (PMID:17544554)
• 3BP2 acts downstream of SAP, increases CD244 phosphorylation and links the receptor with PI3K, Vav, PLC gamma, and PKC downstream events in order to achieve maximum natural killer cell killing function. (PMID:18479751)
• Point mutations in the SH3BP2 gene have been revealed in cherubism patients. (PMID:18596838)
• 2 novel mutations were found; heterozygous missense mutation c.1442A>T (Q481L) in exon 11 in one sporadic case of CGCL and heterozygous germline and tumor tissue missense mutation c.320C>T (T107M) in exon 4 in one patient with cherubism. (PMID:19017279)
• The SH-3BP-2 mutation may participate in the differentiation and maturation of osteoclast-like cells in the lesion of cherubism. (PMID:19576004)
• 3BP2 induces the protein complex with cellular signaling molecules through phosphorylation of Tyr(183) and SH2 domain leading to the activation of NFAT in B cells (PMID:19833725)
• No SH3BP2 gene mutation was found in PGCL. (PMID:20002873)
• over expression of SH3BP2 in RAW 264.7 cells potentiates sRANKL-stimulated phosphorylation of PLCgamma1 and PLCgamma2. (PMID:20872577)
• if a primary genetic defect is the cause for CGCG it is either located in SH3BP2 gene exons not yet related to cherubism or in a different gene. (PMID:21680150)
• P416R mutation of 3BP2 causes the gain of function in B cells by increasing the interaction with specific signaling molecules. (PMID:21794028)
• In the first family, a missense mutation Arg415Gln was found in exon 9 of SH3BP2 in all affected individuals. The unaffected individuals did not have the mutation. In the second family, a missense mutation Pro418Thr was identified in exon 9 of the SH3BP2 (PMID:22795151)
• These results demonstrate that PARP1 regulates expression of SH3BP2. (PMID:22820184)
• Authors conclude that a novel p.Asp419Tyr alteration in SH3BP2 to be a cherubism-causing mutation in a Turkish family. (PMID:23083484)
• A c.1244G>A (p.Arg415Gln) mutation in SH3BP2 gene causes cherubism in a Turkish family (PMID:24608212)
• The adaptor 3BP2 is required for KIT receptor expression and human mast cell survival. (PMID:25810396)
• All members featured a heterozygous missense c.1244G>C; p.Arg415Pro SH3BP2 mutation (PMID:28721660)
• The current study shows that SH3BP2 is expressed in primary tumors and cell lines from Gastrointestinal stromal tumors (GISTs) patients and that SH3BP2 silencing leads to a downregulation of oncogenic KIT and PDGFRA expression and an increase in apoptosis in imatinib-sensitive and imatinib-resistant GIST cells. (PMID:29885053)
• SH3BP2-related fibro-osseous disorders of the maxilla and mandible: A systematic review. (PMID:33941395)
• Cherubism in three siblings.", trans “A cherubismus elofordulasa harom testverben. (PMID:35279646)
• Scaffold protein SH3BP2 signalosome is pivotal for immune activation in nephrotic syndrome. (PMID:38127456)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh3bp2	ENSDARG00000021982
mus_musculus	Sh3bp2	ENSMUSG00000054520
rattus_norvegicus	Sh3bp2	ENSRNOG00000013747

Protein

Protein identifiers

SH3 domain-binding protein 2 — P78314 (reviewed: P78314)

All UniProt accessions (12): P78314, A0A384N6E5, A0A499FIV3, A0AAQ5BI11, A0AAQ5BI12, A0AAQ5BI13, D6R995, D6RAB4, D6RBL6, D6RC64, D6RER9, H0YAD9

UniProt curated annotations — full annotation on UniProt →

Function. Binds differentially to the SH3 domains of certain proteins of signal transduction pathways. Binds to phosphatidylinositols; linking the hemopoietic tyrosine kinase fes to the cytoplasmic membrane in a phosphorylation dependent mechanism.

Tissue specificity. Expressed in a variety of tissues including lung, liver, skeletal muscle, kidney and pancreas.

Post-translational modifications. Phosphorylated. Phosphorylation at Tyr-448 may stimulate the activity of the LYN kinase.

Disease relevance. Cherubism (CRBM) [MIM:118400] An autosomal dominant syndrome characterized by excessive bone degradation of the upper and lower jaws, which often begins around three years of age. It is followed by development of fibrous tissue masses, which causes a characteristic facial swelling. The disease is caused by variants affecting the gene represented in this entry.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (4)

UniProt ID	Names	Canonical?
P78314-1	1, Long	yes
P78314-2	2, Short
P78314-3	3
P78314-4	4

RefSeq proteins (4): NP_001116153, NP_001139327, NP_001139328, NP_003014 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR035847	SH3BP2_SH2	Domain
IPR035848	SH3BP2	Family
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017, PF00169

UniProt features (44 total): strand 8, sequence variant 7, modified residue 6, compositionally biased region 5, splice variant 4, sequence conflict 4, domain 2, region of interest 2, turn 2, helix 2, chain 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3TWR	X-RAY DIFFRACTION	1.55
2CR4	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P78314-F1	66.04	0.35

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 (6): 174, 183, 278, 416, 427, 448

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 287 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, GSE45365_NK_CELL_VS_BCELL_UP, GSE18804_SPLEEN_MACROPHAGE_VS_COLON_TUMORAL_MACROPHAGE_UP, MULLIGHAN_NPM1_SIGNATURE_3_UP, BROWNE_HCMV_INFECTION_48HR_DN, BLALOCK_ALZHEIMERS_DISEASE_UP, chr4p16, HOEGERKORP_CD44_TARGETS_DIRECT_UP, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, MORI_MATURE_B_LYMPHOCYTE_UP, GINESTIER_BREAST_CANCER_ZNF217_AMPLIFIED_DN, MODULE_69, GOMF_PHOSPHOPROTEIN_BINDING, KRIGE_RESPONSE_TO_TOSEDOSTAT_24HR_UP, GOMF_PROTEIN_PHOSPHORYLATED_AMINO_ACID_BINDING

GO Biological Process (1): signal transduction (GO:0007165)

GO Molecular Function (3): phosphotyrosine residue binding (GO:0001784), SH3 domain binding (GO:0017124), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein phosphorylated amino acid binding	1
protein domain specific binding	1
binding	1

Protein interactions and networks

STRING

650 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH3BP2	ABL1	P00519	841
SH3BP2	SYK	P43405	836
SH3BP2	TNKS	O95271	774
SH3BP2	RNF146	Q9NTX7	769
SH3BP2	TNKS2	Q9H2K2	768
SH3BP2	VAV1	P15498	735
SH3BP2	ZAP70	P43403	689
SH3BP2	PLCG1	P19174	667
SH3BP2	TNFSF11	O14788	633
SH3BP2	SH3BP5	O60239	622
SH3BP2	PLCG2	P16885	608
SH3BP2	SRC	P12931	597
SH3BP2	CSF1	P09603	589
SH3BP2	PLEK2	Q9NYT0	569
SH3BP2	PLEK	P08567	563

IntAct

60 interactions, top by confidence:

A	B	Type	Score
VAV1	SH3BP2	psi-mi:“MI:0915”(physical association)	0.790
SH3BP2	VAV1	psi-mi:“MI:0915”(physical association)	0.790
SH3BP2	VAV1	psi-mi:“MI:0914”(association)	0.790
VAV1	SH3BP2	psi-mi:“MI:0914”(association)	0.790
VAV2	SH3BP2	psi-mi:“MI:0915”(physical association)	0.670
VAV2	SH3BP2	psi-mi:“MI:0914”(association)	0.670
SH3BP2	DBNL	psi-mi:“MI:0915”(physical association)	0.660
DBNL	SH3BP2	psi-mi:“MI:0915”(physical association)	0.660
DBNL	SH3BP2	psi-mi:“MI:0403”(colocalization)	0.660
SH3BP2	SH3KBP1	psi-mi:“MI:0915”(physical association)	0.640
SH3KBP1	SH3BP2	psi-mi:“MI:0915”(physical association)	0.640
SH3BP2	SH3KBP1	psi-mi:“MI:0403”(colocalization)	0.640
YWHAQ	SH3BP2	psi-mi:“MI:0915”(physical association)	0.640
YWHAQ	SH3BP2	psi-mi:“MI:0407”(direct interaction)	0.640
YWHAQ	SH3BP2	psi-mi:“MI:0403”(colocalization)	0.640

BioGRID (53): IKZF1 (Affinity Capture-Western), ARHGAP10 (Two-hybrid), SH3BP2 (Two-hybrid), SH3BP2 (Affinity Capture-MS), SH3BP2 (Two-hybrid), SH3BP2 (Affinity Capture-RNA), SH3BP2 (Affinity Capture-RNA), SH3BP2 (Two-hybrid), DBNL (Two-hybrid), MYO1F (Two-hybrid), SH3RF1 (Two-hybrid), HCLS1 (Two-hybrid), SH3BP2 (Affinity Capture-MS), SH3BP2 (Affinity Capture-MS), SH3BP2 (Two-hybrid)

ESM2 similar proteins: A0JN71, A4IFK0, A5PMU4, A6QQV9, O15034, O15040, O62666, O62674, O62675, O62676, O62677, O62678, O75995, P49796, P52734, P59672, P78314, P97432, P98174, Q06649, Q0V8R5, Q13905, Q14596, Q3U0J8, Q501R9, Q53GL0, Q5BJM5, Q5F3C8, Q5RC94, Q5SUE8, Q6AI12, Q6ZMT1, Q7Z5H3, Q80U40, Q80UZ0, Q80XA6, Q80YS6, Q8BL80, Q8K352, Q8N556

Diamond homologs: P78314, Q06649

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
PTPN6	down-regulates	SH3BP2	dephosphorylation
PTPN6	“down-regulates activity”	SH3BP2	dephosphorylation
SYK	“up-regulates activity”	SH3BP2	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 26 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
Regulation of KIT signaling	5	120.2×	3e-08
DAP12 signaling	7	103.2×	4e-11
GPVI-mediated activation cascade	8	98.8×	2e-12
FCERI mediated Ca+2 mobilization	6	85.7×	5e-09
FCERI mediated MAPK activation	6	83.0×	5e-09
Antigen activates B Cell Receptor (BCR) leading to generation of second messengers	5	71.4×	4e-07
Signaling by SCF-KIT	5	49.6×	2e-06
FCGR3A-mediated phagocytosis	5	37.4×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
Fc-epsilon receptor signaling pathway	5	146.5×	3e-08
Fc-gamma receptor signaling pathway involved in phagocytosis	5	140.4×	3e-08
B cell receptor signaling pathway	5	80.2×	5e-07
platelet activation	5	53.5×	3e-06
T cell receptor signaling pathway	7	42.5×	3e-08
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	7	21.9×	2e-06
adaptive immune response	5	16.9×	3e-04
cell migration	6	14.8×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	402
Likely benign	258
Benign	127

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
372503	NM_001122681.2(SH3BP2):c.1258G>A (p.Gly420Arg)	Pathogenic
7548	NM_001122681.2(SH3BP2):c.1253C>G (p.Pro418Arg)	Pathogenic
7550	NM_001122681.2(SH3BP2):c.1244G>C (p.Arg415Pro)	Pathogenic
7551	NM_001122681.2(SH3BP2):c.1244G>A (p.Arg415Gln)	Pathogenic
7552	NM_001122681.2(SH3BP2):c.1258G>C (p.Gly420Arg)	Pathogenic
1526420	NM_001122681.2(SH3BP2):c.1259G>C (p.Gly420Ala)	Likely pathogenic
3340405	NM_001122681.2(SH3BP2):c.1255G>A (p.Asp419Asn)	Likely pathogenic

SpliceAI

3444 predictions. Top by Δscore:

Variant	Effect	Δscore
4:2793134:GGCGG:G	donor_gain	1.0000
4:2793135:GCGG:G	donor_gain	1.0000
4:2793135:GCGGG:G	donor_gain	1.0000
4:2793137:GG:G	donor_gain	1.0000
4:2793137:GGGTA:G	donor_loss	1.0000
4:2793138:GG:G	donor_gain	1.0000
4:2793139:G:GA	donor_loss	1.0000
4:2793139:G:GG	donor_gain	1.0000
4:2793140:T:G	donor_loss	1.0000
4:2820607:A:AG	acceptor_gain	1.0000
4:2820609:T:A	acceptor_gain	1.0000
4:2820609:TGCA:T	acceptor_loss	1.0000
4:2820610:GCA:G	acceptor_loss	1.0000
4:2820611:CAGCT:C	acceptor_loss	1.0000
4:2820612:A:AG	acceptor_gain	1.0000
4:2820612:AGCTT:A	acceptor_loss	1.0000
4:2820613:G:GG	acceptor_gain	1.0000
4:2820613:GC:G	acceptor_gain	1.0000
4:2820613:GCT:G	acceptor_gain	1.0000
4:2820613:GCTT:G	acceptor_gain	1.0000
4:2820613:GCTTC:G	acceptor_gain	1.0000
4:2820749:GAAAT:G	donor_gain	1.0000
4:2820750:AAAT:A	donor_gain	1.0000
4:2820751:AAT:A	donor_gain	1.0000
4:2820752:AT:A	donor_gain	1.0000
4:2820754:G:GG	donor_gain	1.0000
4:2822924:A:AG	acceptor_gain	1.0000
4:2822925:C:G	acceptor_gain	1.0000
4:2822931:ACAG:A	acceptor_gain	1.0000
4:2822932:CAGGG:C	acceptor_loss	1.0000

AlphaMissense

3669 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
4:2820722:G:C	K35N	1.000
4:2820722:G:T	K35N	1.000
4:2820753:T:A	W46R	1.000
4:2820753:T:C	W46R	1.000
4:2820667:C:A	A17D	0.999
4:2820676:T:C	L20P	0.999
4:2820715:T:C	L33P	0.999
4:2820720:A:G	K35E	0.999
4:2824653:T:C	F94L	0.999
4:2824655:C:A	F94L	0.999
4:2824655:C:G	F94L	0.999
4:2824660:T:C	F96S	0.999
4:2824708:C:A	A112D	0.999
4:2824726:G:C	R118P	0.999
4:2825129:T:A	W121R	0.999
4:2825129:T:C	W121R	0.999
4:2822946:T:C	F50L	0.998
4:2822948:T:A	F50L	0.998
4:2822948:T:G	F50L	0.998
4:2822976:T:G	Y60D	0.998
4:2824695:T:A	W108R	0.998
4:2824695:T:C	W108R	0.998
4:2824725:C:A	R118S	0.998
4:2820676:T:A	L20Q	0.997
4:2820679:T:C	L21P	0.997
4:2822936:G:C	W46C	0.997
4:2822936:G:T	W46C	0.997
4:2822944:G:C	R49P	0.997
4:2822973:T:G	Y59D	0.997
4:2823015:T:C	F73L	0.997

dbSNP variants (sampled 300 via entrez): RS10000117 (4:2841457 G>A,C,T), RS1000025110 (4:2824884 G>A), RS1000107921 (4:2815054 TG>T), RS1000168086 (4:2815395 C>T), RS10001883 (4:2803652 C>T), RS1000266564 (4:2795263 C>T), RS1000266972 (4:2819135 A>G), RS1000292186 (4:2820296 C>A,T), RS1000297992 (4:2819331 T>A), RS1000358239 (4:2795995 C>T), RS1000379196 (4:2809683 G>A), RS1000465129 (4:2813145 G>A), RS1000465139 (4:2825567 CACAA>C), RS1000595473 (4:2819400 T>A), RS1000771999 (4:2814222 C>T)

Disease associations

OMIM: gene MIM:602104 | disease phenotypes: MIM:118400

GenCC curated gene-disease

Disease	Classification	Inheritance
cherubism	Strong	Autosomal dominant

Mondo (3): cherubism (MONDO:0007315), intellectual disability (MONDO:0001071), congenital heart disease (MONDO:0005453)

Orphanet (2): Cherubism (Orphanet:184), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

33 total (30 of 33 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000164	Abnormality of the dentition
HP:0000189	Narrow palate
HP:0000277	Abnormal mandible morphology
HP:0000293	Full cheeks
HP:0000311	Round face
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000529	Progressive visual loss
HP:0000648	Optic atrophy
HP:0000677	Oligodontia
HP:0000689	Dental malocclusion
HP:0001133	Constriction of peripheral visual field
HP:0001138	Optic neuropathy
HP:0001571	Multiple impacted teeth
HP:0001608	Abnormality of the voice
HP:0002781	Upper airway obstruction
HP:0002870	Obstructive sleep apnea
HP:0003621	Juvenile onset
HP:0006482	Abnormal dental morphology
HP:0007663	Reduced visual acuity
HP:0008872	Feeding difficulties in infancy
HP:0009085	Alveolar ridge overgrowth
HP:0011462	Young adult onset
HP:0011463	Childhood onset
HP:0012062	Bone cyst
HP:0012802	Broad jaw
HP:0030793	Jaw swelling
HP:0030802	Lower eyelid retraction
HP:0033176	Submandibular lymph node enlargement

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004691_6	Huntington’s disease progression	3.000000e-06
GCST005531_93	Multiple sclerosis	1.000000e-06
GCST012335_10	Hodgkin’s lymphoma	2.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0008336	disease progression measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D002636	Cherubism	C05.116.099.708.375.199; C05.500.174; C07.320.173; C16.131.621.207.540.170; C16.320.170
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6920220	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Arthritis;Psoriatic;Psoriasis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6920220	SH3BP2, TNFAIP3	3	3.00	2	Tumor necrosis factor alpha (TNF-alpha) inhibitors;methotrexate
rs10499194	SH3BP2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
bisphenol A	decreases expression, decreases methylation, increases methylation	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Ozone	affects cotreatment, increases expression, affects expression, increases abundance	2
Tretinoin	decreases expression, increases expression	2
GSK-J4	decreases expression	1
FR900359	affects phosphorylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
hydroxyhydroquinone	increases expression	1
sodium arsenite	affects expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
hydroquinone	increases expression	1
methacrylaldehyde	affects cotreatment, increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
prothioconazole	increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Lead	decreases expression	1
Mercury	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_DA61	GM18382	Transformed cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00115375	PHASE2	COMPLETED	Platelet Aggregation Inhibition in Children on Clopidogrel (PICOLO)
NCT00350220	PHASE2	COMPLETED	Transfusion Strategies in Pediatric Cardiothoracic Surgery
NCT00374088	PHASE2	COMPLETED	N-Acetylcysteine in Neonatal Congenital Heart Surgery (INACT Study)
NCT00538785	PHASE2	COMPLETED	A Study to Evaluate MEDI-524 In Children With Hemodynamically Significant Congenital Heart Disease