SH2D3A

Summary

SH2D3A (SH2 domain containing 3A, HGNC:16885) is a protein-coding gene on chromosome 19p13.3, encoding SH2 domain-containing protein 3A (Q9BRG2). May play a role in JNK activation.

Predicted to enable guanyl-nucleotide exchange factor activity and phosphotyrosine residue binding activity. Predicted to be involved in JNK cascade.

Source: NCBI Gene 10045 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 106 total
• MANE Select transcript: NM_005490

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16885
Approved symbol	SH2D3A
Name	SH2 domain containing 3A
Location	19p13.3
Locus type	gene with protein product
Status	Approved
Aliases	NSP1
Ensembl gene	ENSG00000125731
Ensembl biotype	protein_coding
OMIM	604721
Entrez	10045

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 17 protein_coding, 3 protein_coding_CDS_not_defined, 2 retained_intron

ENST00000245908, ENST00000437152, ENST00000595369, ENST00000595681, ENST00000597168, ENST00000597254, ENST00000597687, ENST00000599563, ENST00000892012, ENST00000892013, ENST00000892014, ENST00000892015, ENST00000892016, ENST00000892017, ENST00000892018, ENST00000892019, ENST00000917563, ENST00000917564, ENST00000917565, ENST00000917566, ENST00000917567, ENST00000948758

RefSeq mRNA: 8 — MANE Select: NM_005490 NM_001386583, NM_001386584, NM_001386585, NM_001386586, NM_001386587, NM_001386588, NM_001386589, NM_005490

CCDS: CCDS12173

Canonical transcript exons

ENST00000245908 — 10 exons

Exon	Start	End
ENSE00000858155	6754251	6754425
ENSE00001159383	6753456	6753641
ENSE00001349304	6767387	6767435
ENSE00002982336	6752160	6752753
ENSE00003485815	6754616	6754731
ENSE00003524648	6759594	6759670
ENSE00003585289	6754831	6755315
ENSE00003588201	6754052	6754163
ENSE00003603839	6760638	6760987
ENSE00003633486	6763680	6763816

Expression profiles

Bgee: expression breadth ubiquitous, 217 present calls, max score 98.95.

FANTOM5 (CAGE): breadth broad, TPM avg 4.3841 / max 180.7539, expressed in 665 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
178814	3.6411	612
178815	0.5462	319
178816	0.1968	118

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	98.95	gold quality
lower esophagus mucosa	UBERON:0035834	91.50	gold quality
type B pancreatic cell	CL:0000169	90.99	gold quality
esophagus mucosa	UBERON:0002469	90.60	gold quality
olfactory bulb	UBERON:0002264	90.44	silver quality
mucosa of transverse colon	UBERON:0004991	90.18	gold quality
metanephros cortex	UBERON:0010533	89.55	gold quality
skin of abdomen	UBERON:0001416	89.43	gold quality
skin of leg	UBERON:0001511	88.81	gold quality
granulocyte	CL:0000094	88.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	88.52	gold quality
minor salivary gland	UBERON:0001830	88.31	gold quality
body of pancreas	UBERON:0001150	87.45	gold quality
tendon of biceps brachii	UBERON:0008188	86.53	silver quality
mouth mucosa	UBERON:0003729	86.49	gold quality
right lobe of thyroid gland	UBERON:0001119	86.21	gold quality
zone of skin	UBERON:0000014	86.17	gold quality
saliva-secreting gland	UBERON:0001044	85.98	gold quality
left lobe of thyroid gland	UBERON:0001120	85.53	gold quality
upper lobe of left lung	UBERON:0008952	85.28	gold quality
mucosa of urinary bladder	UBERON:0001259	85.27	silver quality
right uterine tube	UBERON:0001302	84.98	gold quality
transverse colon	UBERON:0001157	84.87	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.73	gold quality
thyroid gland	UBERON:0002046	84.58	gold quality
upper lobe of lung	UBERON:0008948	83.99	gold quality
pancreatic ductal cell	CL:0002079	83.87	gold quality
diaphragm	UBERON:0001103	83.81	gold quality
vagina	UBERON:0000996	83.77	gold quality
small intestine	UBERON:0002108	83.67	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.21

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

21 targeting SH2D3A, 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-4455	100.00	65.48	1587
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-30A-3P	99.87	69.74	2928
HSA-MIR-30D-3P	99.87	69.92	2917
HSA-MIR-30E-3P	99.87	69.68	2942
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-7151-3P	99.04	69.72	2370
HSA-MIR-4297	98.77	66.95	2013
HSA-MIR-7155-5P	98.65	66.14	1290
HSA-MIR-637	97.91	64.05	1517

Literature-anchored findings (GeneRIF, showing 4)

• NSP1 and BCAR3 are more highly expressed than SH2D3C (SHEP1) in breast cancer cells, and the expression patterns suggest differential roles for the three genes during breast cancer progression. (PMID:17270363)
• NSP1 overexpression did not induce anti-estrogen resistance in breast tumor cell lines. (PMID:17427198)
• Nsp1 proteins of human coronaviruses HCoV-OC43 and SARS-CoV2 inhibit stress granule formation. (PMID:36534661)
• In vitro reconstitution of SARS-CoV-2 Nsp1-induced mRNA cleavage reveals the key roles of the N-terminal domain of Nsp1 and the RRM domain of eIF3g. (PMID:37821106)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
danio_rerio		ENSDARG00000086539
drosophila_melanogaster	CG9098	FBGN0031762

Paralogs (2): SH2D3C (ENSG00000095370), BCAR3 (ENSG00000137936)

Protein

Protein identifiers

SH2 domain-containing protein 3A — Q9BRG2 (reviewed: Q9BRG2)

Alternative names: Novel SH2-containing protein 1

All UniProt accessions (2): Q9BRG2, M0QZQ6

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in JNK activation.

Subunit / interactions. Interacts with BCAR1.

Tissue specificity. Weakly expressed in placenta, fetal kidney, fetal lung, adult pancreas, adult kidney and adult lung.

Post-translational modifications. Phosphorylated on tyrosine.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9BRG2-1	1	yes
Q9BRG2-2	2

RefSeq proteins (8): NP_001373512, NP_001373513, NP_001373514, NP_001373515, NP_001373516, NP_001373517, NP_001373518, NP_005481* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036860	SH2_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR044102	SH2_SHEP1/BCAR3/NSP1	Domain
IPR051853	SH2-Ras-GEF_adapter	Family

Pfam: PF00017

UniProt features (17 total): modified residue 5, splice variant 3, sequence variant 3, mutagenesis site 2, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9BRG2-F1	76.71	0.54

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 (5): 123, 125, 147, 180, 201

Mutagenesis-validated functional residues (2):

Position	Phenotype
95	loss of phosphorylation.
231	weak phosphorylation.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 72 (showing top): CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, GOBP_JNK_CASCADE, TGANTCA_AP1_C, RYTTCCTG_ETS2_B, GOBP_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, WANG_HCP_PROSTATE_CANCER, CHARAFE_BREAST_CANCER_LUMINAL_VS_MESENCHYMAL_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, chr19p13, GOMF_PHOSPHOPROTEIN_BINDING, GOMF_PROTEIN_PHOSPHORYLATED_AMINO_ACID_BINDING, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY, PEDERSEN_METASTASIS_BY_ERBB2_ISOFORM_7, PEDERSEN_TARGETS_OF_611CTF_ISOFORM_OF_ERBB2

GO Biological Process (2): JNK cascade (GO:0007254), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (3): phosphotyrosine residue binding (GO:0001784), guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
MAPK cascade	1
intracellular signaling cassette	1
protein phosphorylated amino acid binding	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1

Protein interactions and networks

STRING

1563 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH2D3A	PRSS57	Q6UWY2	997
SH2D3A	NUP93	Q8N1F7	958
SH2D3A	PPIH	O43447	933
SH2D3A	SH2D3C	Q8N5H7	931
SH2D3A	PPIG	Q13427	926
SH2D3A	IRF3	Q14653	920
SH2D3A	SPECC1	Q5M775	912
SH2D3A	NXF1	Q9UBU9	878
SH2D3A	PPP1CA	P08129	864
SH2D3A	FKBP1A	P20071	859
SH2D3A	FKBP1B	P68106	857
SH2D3A	NUP62	P37198	726
SH2D3A	ACE2	Q9BYF1	720
SH2D3A	ASZ1	Q8WWH4	713
SH2D3A	IRF7	Q92985	694

IntAct

19 interactions, top by confidence:

A	B	Type	Score
EGFR	SH2D3A	psi-mi:“MI:0915”(physical association)	0.630
SH2D3A	ERBB2	psi-mi:“MI:0407”(direct interaction)	0.440
SH2D3A	GAB1	psi-mi:“MI:0407”(direct interaction)	0.440
SH2D3A	SFN	psi-mi:“MI:0915”(physical association)	0.400
CENPB	SH2D3A	psi-mi:“MI:0915”(physical association)	0.370
SH2D3A	TSG101	psi-mi:“MI:0915”(physical association)	0.370
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
N	RBM47	psi-mi:“MI:0914”(association)	0.350
	HLA-C	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
YWHAG	FOXO6	psi-mi:“MI:0914”(association)	0.350
SH2D3A	RFXAP	psi-mi:“MI:0914”(association)	0.350
HTRA3	ROCK2	psi-mi:“MI:0914”(association)	0.350
SH2D3A	A2ML1	psi-mi:“MI:0914”(association)	0.350

BioGRID (81): SH2D3A (Two-hybrid), SH2D3A (Synthetic Lethality), CENPB (Two-hybrid), SH2D3A (PCA), SH2D3A (Affinity Capture-Luminescence), SH2D3A (Affinity Capture-MS), SH2D3A (Reconstituted Complex), SH2D3A (Reconstituted Complex), BCAR1 (Affinity Capture-Western), EGFR (Affinity Capture-Western), SH2D3A (Affinity Capture-Western), SH2D3A (Phenotypic Enhancement), BCAR1 (Affinity Capture-MS), SH2D3A (Affinity Capture-MS), SH2D3A (Affinity Capture-MS)

ESM2 similar proteins: A0AVI2, A0FGR9, A0JN53, A1L3T7, A3KGK3, A6NE52, A6QQP7, B5DFG1, D3ZZN9, O75064, O75923, O94812, O95382, O95398, P58660, P97680, Q3U1Y4, Q3ULW6, Q3V3V9, Q4LDD4, Q58EX7, Q5DTI8, Q68DD2, Q6F5E8, Q76MJ5, Q80TT2, Q80UW5, Q86XP0, Q8C6B2, Q8CE13, Q8CIE4, Q8CJ00, Q8IYJ3, Q8R5G7, Q8TE67, Q8WWN8, Q969H4, Q96KV7, Q96P48, Q99MQ3

Diamond homologs: D3ZAZ5, O14796, O70142, O70143, O75791, O75815, O88900, P00519, P00520, P00521, P00522, P00530, P00541, P00542, P00543, P07332, P10447, P14238, P16591, P16879, P29350, P29351, P29353, P29355, P42684, P46109, P47941, P53356, P62993, P62994, P70451, P81718, P87379, P98077, P98083, Q07883, Q08012, Q0IIE2, Q13588, Q4JIM5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1541 predictions. Top by Δscore:

Variant	Effect	Δscore
19:6753637:GGGTC:G	acceptor_gain	1.0000
19:6753638:GGTC:G	acceptor_gain	1.0000
19:6753639:GTC:G	acceptor_gain	1.0000
19:6753639:GTCC:G	acceptor_loss	1.0000
19:6753640:TC:T	acceptor_gain	1.0000
19:6753641:CC:C	acceptor_gain	1.0000
19:6753642:C:CC	acceptor_gain	1.0000
19:6753642:CTGC:C	acceptor_loss	1.0000
19:6753645:C:CT	acceptor_gain	1.0000
19:6754047:CTTA:C	donor_loss	1.0000
19:6754050:A:AC	donor_gain	1.0000
19:6754050:AC:A	donor_gain	1.0000
19:6754050:ACCAG:A	donor_gain	1.0000
19:6754051:C:A	donor_loss	1.0000
19:6754051:C:CC	donor_gain	1.0000
19:6754051:CC:C	donor_gain	1.0000
19:6754051:CCA:C	donor_gain	1.0000
19:6754051:CCAG:C	donor_gain	1.0000
19:6754051:CCAGC:C	donor_gain	1.0000
19:6754611:CTCA:C	donor_loss	1.0000
19:6754612:TCACC:T	donor_loss	1.0000
19:6754613:CA:C	donor_loss	1.0000
19:6754614:A:AC	donor_gain	1.0000
19:6754614:A:AT	donor_loss	1.0000
19:6754615:C:CC	donor_gain	1.0000
19:6754615:C:CG	donor_loss	1.0000
19:6754615:CCT:C	donor_gain	1.0000
19:6754615:CCTCT:C	donor_gain	1.0000
19:6754727:GTGGC:G	acceptor_gain	1.0000
19:6754728:TGGC:T	acceptor_gain	1.0000

AlphaMissense

3658 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:6754140:C:A	W432C	0.973
19:6754140:C:G	W432C	0.973
19:6754083:C:A	K451N	0.966
19:6754083:C:G	K451N	0.966
19:6754098:A:C	F446L	0.966
19:6754098:A:T	F446L	0.966
19:6754100:A:G	F446L	0.966
19:6760952:G:C	F35L	0.960
19:6760952:G:T	F35L	0.960
19:6760954:A:G	F35L	0.960
19:6760802:G:C	F85L	0.958
19:6760802:G:T	F85L	0.958
19:6760804:A:G	F85L	0.958
19:6754142:A:G	W432R	0.946
19:6754142:A:T	W432R	0.946
19:6752691:A:G	W545R	0.945
19:6752691:A:T	W545R	0.945
19:6754099:A:G	F446S	0.943
19:6760911:A:G	I49T	0.941
19:6754153:A:G	L428S	0.939
19:6760947:A:T	V37D	0.936
19:6753484:G:C	F514L	0.935
19:6753484:G:T	F514L	0.935
19:6753486:A:G	F514L	0.935
19:6754634:C:A	R360M	0.935
19:6752707:G:C	F539L	0.934
19:6752707:G:T	F539L	0.934
19:6752709:A:G	F539L	0.934
19:6760953:A:G	F35S	0.924
19:6760877:A:C	F60L	0.923

dbSNP variants (sampled 300 via entrez): RS1000080921 (19:6767316 C>A,T), RS1000715635 (19:6764931 G>T), RS1000748471 (19:6765124 A>C,T), RS1001037304 (19:6753700 G>A), RS1001348955 (19:6762492 T>C), RS1001646188 (19:6757311 T>C), RS1001680480 (19:6763469 T>C,G), RS1001749221 (19:6763726 T>C), RS1001961051 (19:6767488 C>G), RS1002091724 (19:6752796 C>T), RS1002373994 (19:6755857 T>C), RS1002476481 (19:6761235 T>C), RS1002683227 (19:6761876 G>A), RS1002704702 (19:6768179 T>G), RS1002756774 (19:6762142 T>A)

Disease associations

OMIM: gene MIM:604721 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression	5
sodium arsenite	decreases expression, increases abundance, increases expression	3
entinostat	increases expression, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases methylation	2
GSK-J4	decreases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	increases expression	1
coumarin	increases phosphorylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
cylindrospermopsin	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	decreases response to substance	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	decreases expression	1
Drugs, Chinese Herbal	increases expression	1
Lipopolysaccharides	increases expression, affects response to substance	1
Naphthoquinones	increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1

Clinical trials (associated diseases)

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