SH2D1A

Summary

SH2D1A (SH2 domain containing 1A, HGNC:10820) is a protein-coding gene on chromosome Xq25, encoding SH2 domain-containing protein 1A (O60880). Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. It is haploinsufficient (ClinGen: sufficient evidence).

This gene encodes a protein that plays a major role in the bidirectional stimulation of T and B cells. This protein contains an SH2 domain and a short tail. It associates with the signaling lymphocyte-activation molecule, thereby acting as an inhibitor of this transmembrane protein by blocking the recruitment of the SH2-domain-containing signal-transduction molecule SHP-2 to its docking site. This protein can also bind to other related surface molecules that are expressed on activated T, B and NK cells, thereby modifying signal transduction pathways in these cells. Mutations in this gene cause lymphoproliferative syndrome X-linked type 1 or Duncan disease, a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus, with symptoms including severe mononucleosis and malignant lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 4068 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked lymphoproliferative disease due to SH2D1A deficiency (Definitive, ClinGen)
• Clinical variants (ClinVar): 201 total — 40 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 33
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_002351

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10820
Approved symbol	SH2D1A
Name	SH2 domain containing 1A
Location	Xq25
Locus type	gene with protein product
Status	Approved
Aliases	XLP, MTCP1, DSHP, XLPD, EBVS, SAP
Ensembl gene	ENSG00000183918
Ensembl biotype	protein_coding
OMIM	300490
Entrez	4068

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 1 retained_intron

ENST00000360027, ENST00000371139, ENST00000477673, ENST00000491950, ENST00000494073, ENST00000635645, ENST00000647259, ENST00000698112, ENST00000698113, ENST00000698114, ENST00000698115, ENST00000698116, ENST00000698117, ENST00000698118, ENST00000698119, ENST00000698120

RefSeq mRNA: 2 — MANE Select: NM_002351 NM_001114937, NM_002351

CCDS: CCDS14608, CCDS48162

Canonical transcript exons

ENST00000371139 — 4 exons

Exon	Start	End
ENSE00001411506	124370176	124370320
ENSE00001917567	124371351	124373160
ENSE00001920695	124346563	124346779
ENSE00003972756	124365761	124365824

Expression profiles

Bgee: expression breadth ubiquitous, 170 present calls, max score 94.12.

FANTOM5 (CAGE): breadth broad, TPM avg 6.7552 / max 586.9458, expressed in 200 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
197499	3.7837	164
197500	1.2172	128
197501	0.8574	116
197498	0.6436	97
197497	0.0693	38
197493	0.0634	25
197494	0.0507	24
197496	0.0440	26
197495	0.0259	13

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
thymus	UBERON:0002370	94.12	gold quality
lymph node	UBERON:0000029	88.65	gold quality
granulocyte	CL:0000094	87.53	gold quality
blood	UBERON:0000178	82.51	gold quality
vermiform appendix	UBERON:0001154	80.83	gold quality
spleen	UBERON:0002106	77.87	gold quality
bone marrow	UBERON:0002371	77.72	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	74.11	silver quality
gall bladder	UBERON:0002110	74.08	gold quality
caecum	UBERON:0001153	73.75	gold quality
bone marrow cell	CL:0002092	73.48	silver quality
epithelium of nasopharynx	UBERON:0001951	73.03	silver quality
tonsil	UBERON:0002372	72.19	gold quality
pancreatic ductal cell	CL:0002079	71.95	silver quality
superficial temporal artery	UBERON:0001614	71.34	silver quality
buccal mucosa cell	CL:0002336	71.27	gold quality
secondary oocyte	CL:0000655	70.73	silver quality
lower esophagus	UBERON:0013473	70.04	gold quality
lower esophagus muscularis layer	UBERON:0035833	70.00	gold quality
right lung	UBERON:0002167	69.61	gold quality
palpebral conjunctiva	UBERON:0001812	69.54	gold quality
leukocyte	CL:0000738	69.22	gold quality
tendon	UBERON:0000043	68.21	gold quality
colonic epithelium	UBERON:0000397	67.79	silver quality
tendon of biceps brachii	UBERON:0008188	67.67	gold quality
calcaneal tendon	UBERON:0003701	67.51	gold quality
mononuclear cell	CL:0000842	67.08	gold quality
trabecular bone tissue	UBERON:0002483	66.60	silver quality
monocyte	CL:0000576	66.40	gold quality
rectum	UBERON:0001052	65.87	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 7.

Experiment	Marker?	Max mean expression
E-MTAB-7407	yes	377.94
E-CURD-122	yes	55.38
E-HCAD-1	yes	38.87
E-HCAD-10	yes	24.44
E-ANND-3	yes	15.16
E-CURD-46	yes	14.29
E-CURD-112	yes	4.51

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF5, CEBPB, ETS1, ETS2, NFKB, PAX1, STAT3, TP53

miRNA regulators (miRDB)

72 targeting SH2D1A, 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-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-205-3P	99.92	69.92	3165
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-182-5P	99.87	74.03	2589
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-4719	99.73	72.10	3329
HSA-MIR-4802-3P	99.72	70.13	1273
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-1283	99.69	72.42	3009
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-1260A	99.61	66.67	1098
HSA-MIR-1260B	99.61	66.67	1098
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Here the effect of SH2D1A protein missense mutations identified in 10 XLP families was analyzed. (PMID:11477068)
• SH2D1A expression reflects activation of T and NK cells in cord blood lymphocytes infected with EBV and treated with the immunomodulator PSK. (PMID:11803050)
• dependence of association with 2B4 on phosphoinositide 3-kinase (PMID:11815622)
• SAP is expressed in activated T and NK cells (PMID:12008045)
• Review. X-linked lymphoproliferative disease maps to Xq25. The gene (SH2D1A)was identified, the protein crystal structure solved, target molecules identified, protein/protein interactions characterized, & a mouse model of the gene mutation developed. (PMID:12152986)
• role in signaling through the signaling lymphocyte activation molecule family of immune receptors (PMID:12458214)
• Data show that the SLAM-associated protein (SAP) SH2 domain binds to the SH3 domain of FynT and directly couples FynT to SLAM. (PMID:12545174)
• SH2D1A is in 5 EBV-negative classical Hodgkin’s disease (HD)-derived cell lines (PMID:12594824)
• SLAM-associated protein functions as an essential integrator in early TCR signal transduction (PMID:12766168)
• SAP regulates signal transduction of the SLAM-family receptors by recruiting SRC kinases. (PMID:14523387)
• Mutations, which either directly interfere with binding of SAP or indirectly affect binding due to improper protein folding, underlie the X-linked lymphoproliferative (XLP) syndrome. (PMID:14674764)
• Mycobacterium tuberculosis-induced IFN-gamma is abolished in T cells from patients with active tuberculosis expressing SAP. (PMID:14707094)
• in X-linked lymphoproliferative disease, the lack of SAP affects specific signaling pathways resulting in severe disruption of cytotoxic T-cell function (PMID:14726378)
• significantly up-regulated on CD4 and CD8 T cells during acute infectious mononucleosis; regulates lymphocyte activation via signals from cell-surface CD244 (2B4) and SLAM (CD150) (PMID:15195244)
• CD150 and SH2D1A are coexpressed during a narrow window of B-cell maturation and SH2D1A may be involved in regulation of B-cell differentiation via switching of CD150-mediated signaling pathways. (PMID:15315965)
• The subcellular localization of the signaling lymphocyte activation molecule-associated protein (SAP)/2B4 complex is reported during recognition of susceptible Epstein Barr virus-infected 721.221 cells by human natural killer cells. (PMID:15356108)
• results suggest that SAP contributes to the execution of some p53 functions (PMID:15378026)
• activation of peripheral blood cells with agonistic anti-CD3 antibody and exogenous IL-2, as used for generation of cytokine-induced killer cells, results in significant SLAM and SAP activation 5 days after TCR stimulation (PMID:15661039)
• the SAP/2B4 pathway plays a key role in CTL lytic activity against EBV-positive targets by promoting the polarization of the lytic machinery (PMID:15677558)
• crucial role during the development of natural killer T (NKT) cells; seventeen individuals with X-linked lymphoproliferative disease who harbored germline mutations in SH2D1A, also lacked NKT cells (PMID:15711562)
• SAP is a potent regulator of NKT cell development (PMID:15738056)
• diseases share a common signal pathway, through either the mutation or LMP1-mediated suppression of the SAP gene (PMID:16002423)
• SAP may serve as a negative regulator of Trk receptor activation and downstream signaling (PMID:16223723)
• These data strongly suggest that, in addition to the known SAP-interacting kinase Fyn, PIX may be another key player in SAP-mediated T cell activation. (PMID:16983070)
• Regulation of SLAM-associated protein (SAP)has functional consequences for the stimulation of natural killer (NK) cell cytotoxicity by 2B4 (CD244). (PMID:17171759)
• the mutation at end of exon 2 results in loss of SH2D1A function (PMID:17455312)
• We report a patient with limbic encephalitis caused by SAP deficiency. A mutation in the SH2D1A gene on Xq25 could not be detected. (PMID:17620557)
• Enhancement of anti-tumor activity in vitro and in vivo by CD150 and SAP (PMID:17692919)
• The regulation of inteferon gamma production during tuberculosis by CD31 and signaling lymphocytic activation molecule-associated protein interactions is reported. (PMID:17922402)
• Mutations in SH2D1A is not associated with familial hemophagocytic lymphohistiocytosis (PMID:18000860)
• genetic analysis of SBDS and SH2D1A in Japanese children with AA (PMID:18024409)
• Of 9 CVID patients…No mutations of SAP, ICOS, TACI, BAFFR, and CD19 were identified (PMID:18051214)
• SAP expression in T cells, but not in B cells or natural killer (NK) cells, is required for a normal humoral immune response. This is also consistent with the phenotype of sap(fl/fl)lck-cre transgenic mice. (PMID:18212118)
• 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)
• SAP is essential for late B cell help and the development of long-term humoral immunity. New approach to the therapeutic method for EBV might be opened by the regulation of this molecule (SAP). (PMID:18587224)
• SAP forms a ternary complex with the kinase Lyn and the inhibitory IgG Fc receptor FcgammaRIIB to regulate B cell proliferation and survival. (PMID:18662772)
• The down-regulation of the SAP gene by ATF5 may represent a common mechanism for the pathogenesis of Hemophagocytic syndrome that is associated with either Epstein-Barr virus infection or immune disorders with dysregulated T-cell activation. (PMID:18832568)
• SAP regulate T cell activity and proliferation through interactions with SH3 domain-containing proteins Large Neutral Amino Acid-Transporter 1 and FYN protein. (PMID:18951976)
• SAP plays a role in the development of innate-like T-cell lineages, including natural killer T cells, & in the regulation of the interactions between B cells & T cells that are required for germinal-centre formation & long-term humoral immunity. Review. (PMID:19079134)
• SAP is inducibly expressed in the human BJAB cells, and co-localizes and interacts with CD22. SAP binding to the inhibitory immunoreceptor CD22 regulates calcium mobilization in B cells. (PMID:19150402)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	sh2d1ab	ENSDARG00000074854
mus_musculus	Sh2d1a	ENSMUSG00000005696
rattus_norvegicus	Sh2d1a	ENSRNOG00000080232
drosophila_melanogaster	CG9784	FBGN0030761
drosophila_melanogaster	CG6805	FBGN0034179
drosophila_melanogaster	Synj	FBGN0034691
drosophila_melanogaster	sp3	FBGN0038890
caenorhabditis_elegans		WBGENE00006763
caenorhabditis_elegans	sac-2	WBGENE00012353

Paralogs (13): SYNJ2 (ENSG00000078269), FIG4 (ENSG00000112367), OCRL (ENSG00000122126), INPP5K (ENSG00000132376), INPP5E (ENSG00000148384), SYNJ1 (ENSG00000159082), INPPL1 (ENSG00000165458), INPP5D (ENSG00000168918), INPP5J (ENSG00000185133), SH2D1B (ENSG00000198574), INPP5F (ENSG00000198825), INPP5B (ENSG00000204084), SACM1L (ENSG00000211456)

Protein

Protein identifiers

SH2 domain-containing protein 1A — O60880 (reviewed: O60880)

Alternative names: Duncan disease SH2-protein, Signaling lymphocytic activation molecule-associated protein, T-cell signal transduction molecule SAP

All UniProt accessions (3): A0A2R8Y573, A0A8V8TLH8, O60880

UniProt curated annotations — full annotation on UniProt →

Function. Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7. In SLAM signaling seems to cooperate with SH2D1B/EAT-2. Initially it has been proposed that association with SLAMF1 prevents SLAMF1 binding to inhibitory effectors including INPP5D/SHIP1 and PTPN11/SHP-2. However, by simultaneous interactions, recruits FYN which subsequently phosphorylates and activates SLAMF1. Positively regulates CD244/2B4- and CD84-mediated natural killer (NK) cell functions. Can also promote CD48-, SLAMF6 -, LY9-, and SLAMF7-mediated NK cell activation. In the context of NK cell-mediated cytotoxicity enhances conjugate formation with target cells. May also regulate the activity of the neurotrophin receptors NTRK1, NTRK2 and NTRK3.

Subunit / interactions. Interacts with NTRK1, NTRK2 and NTRK3. Interacts with CD84, CD244, LY9, SLAMF1 and FYN.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed at a high level in thymus and lung, with a lower level of expression in spleen and liver. Expressed in peripheral blood leukocytes, including T-lymphocytes. Tends to be expressed at lower levels in peripheral blood leukocytes in patients with rheumatoid arthritis.

Disease relevance. Lymphoproliferative syndrome, X-linked, 1 (XLP1) [MIM:308240] A rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (6)

UniProt ID	Names	Canonical?
O60880-1	A	yes
O60880-2	B
O60880-3	C
O60880-4	D
O60880-5	E
O60880-6	F

RefSeq proteins (2): NP_001108409, NP_002342* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000980	SH2	Domain
IPR017289	SH2_prot_1A	Family
IPR035876	SH2D1A_SH2	Domain
IPR036860	SH2_dom_sf	Homologous_superfamily

Pfam: PF00017

UniProt features (49 total): sequence variant 26, strand 8, splice variant 5, region of interest 2, mutagenesis site 2, helix 2, chain 1, domain 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
1D4T	X-RAY DIFFRACTION	1.1
1D1Z	X-RAY DIFFRACTION	1.4
1D4W	X-RAY DIFFRACTION	1.8
1M27	X-RAY DIFFRACTION	2.5
1KA6	SOLUTION NMR
1KA7	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60880-F1	84.53	0.67

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 (1): 89

Mutagenesis-validated functional residues (2):

Position	Phenotype
32	strongly reduced affinity for slamf1.
78	disrupts interaction with fyn.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System

MSigDB gene sets: 478 (showing top): GOBP_REGULATION_OF_T_CELL_RECEPTOR_SIGNALING_PATHWAY, MORF_MTA1, GOBP_REGULATION_OF_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, WWTAAGGC_UNKNOWN, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_64, GOBP_ANTIGEN_RECEPTOR_MEDIATED_SIGNALING_PATHWAY, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, MORF_HDAC2, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GNF2_ZAP70, GOBP_CELL_CELL_SIGNALING, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_UP, PUJANA_CHEK2_PCC_NETWORK

GO Biological Process (11): adaptive immune response (GO:0002250), humoral immune response (GO:0006959), cellular defense response (GO:0006968), cell-cell signaling (GO:0007267), natural killer cell activation (GO:0030101), natural killer cell mediated cytotoxicity (GO:0042267), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), regulation of immune response (GO:0050776), negative regulation of T cell receptor signaling pathway (GO:0050860), immune system process (GO:0002376), innate immune response (GO:0045087)

GO Molecular Function (2): protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (2): cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
immune response	4
cellular anatomical structure	2
defense response	1
cell communication	1
signaling	1
lymphocyte activation	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
positive regulation of leukocyte mediated cytotoxicity	1
positive regulation of natural killer cell mediated immunity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
regulation of immune system process	1
regulation of response to stimulus	1
T cell receptor signaling pathway	1
regulation of T cell receptor signaling pathway	1
negative regulation of antigen receptor-mediated signaling pathway	1
biological_process	1
defense response to symbiont	1
protein binding	1
molecular adaptor activity	1
binding	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

1392 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SH2D1A	SLAMF1	Q13291	999
SH2D1A	SLAMF6	Q96DU3	968
SH2D1A	CD84	Q9UIB8	948
SH2D1A	CD244	Q9BZW8	942
SH2D1A	LY9	Q9HBG7	932
SH2D1A	FYN	P06241	880
SH2D1A	CD48	P09326	862
SH2D1A	XIAP	P98170	769
SH2D1A	STX11	O75558	767
SH2D1A	STXBP2	Q15833	764
SH2D1A	UNC13D	Q70J99	763
SH2D1A	CD2	P06729	736
SH2D1A	IFNG	P01579	727
SH2D1A	CD40LG	P29965	705
SH2D1A	SLAMF7	Q9NQ25	684

IntAct

98 interactions, top by confidence:

A	B	Type	Score
SLAMF1	SH2D1A	psi-mi:“MI:0914”(association)	0.940
SH2D1A	SLAMF1	psi-mi:“MI:0914”(association)	0.940
SH2D1A	SLAMF1	psi-mi:“MI:0407”(direct interaction)	0.940
SH2D1A	SLAMF1	psi-mi:“MI:0915”(physical association)	0.940
SH2D1A	CD244	psi-mi:“MI:0407”(direct interaction)	0.870
CD244	SH2D1A	psi-mi:“MI:0915”(physical association)	0.870
SLAMF6	SH2D1A	psi-mi:“MI:0915”(physical association)	0.870
SLAMF6	SH2D1A	psi-mi:“MI:0914”(association)	0.870
SH2D1A	CD244	psi-mi:“MI:0915”(physical association)	0.870
SH2D1A	SLAMF6	psi-mi:“MI:0915”(physical association)	0.870
SH2D1A	LHX4	psi-mi:“MI:0915”(physical association)	0.740
LHX4	SH2D1A	psi-mi:“MI:0915”(physical association)	0.740

BioGRID (58): TNK2 (Two-hybrid), LHX4 (Two-hybrid), PTK2 (Two-hybrid), ZNHIT1 (Two-hybrid), ATF3 (Two-hybrid), SH2D1A (Two-hybrid), CCDC74A (Two-hybrid), LETMD1 (Two-hybrid), NGEF (Two-hybrid), OLIG1 (Two-hybrid), SLAMF1 (Two-hybrid), LHX4 (Two-hybrid), TNK2 (Two-hybrid), VCP (Affinity Capture-Western), SH2D1A (Affinity Capture-Western)

ESM2 similar proteins: B2RZ59, O12990, O14543, O14796, O35324, O35718, O60880, O88583, O88890, O88900, P05433, P08487, P0CE43, P10686, P19174, P43403, P43404, P43405, P46108, P46109, P47941, P81718, P87378, P97504, Q00655, Q04929, Q06AA1, Q09178, Q14449, Q22070, Q2I6J0, Q3ZBB1, Q45HK4, Q5ICW4, Q5U2U2, Q60760, Q62077, Q62120, Q62689, Q63768

Diamond homologs: A0A8I3NFE2, A0FI79, A0JNB0, A1Y2K1, A6QLK6, B2RZ59, B5KFD7, D3ZGS3, D7PF45, F1RDG9, G5ECJ6, O14306, O14796, O15357, O35324, O60880, O88890, O88900, P00519, P00520, P00521, P00522, P03949, P06239, P06241, P09851, P0CE43, P10447, P17713, P20936, P29350, P29351, P32019, P34370, P39688, P42684, P42685, P42686, P50904, P53356

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 34 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
PI3K/AKT Signaling in Cancer	5	73.7×	4e-07
Negative regulation of the PI3K/AKT network	5	55.7×	1e-06
Constitutive Signaling by Aberrant PI3K in Cancer	8	40.6×	3e-09
FCGR3A-mediated phagocytosis	5	37.4×	5e-06
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	31.0×	2e-08
PIP3 activates AKT signaling	8	21.4×	2e-07
RAF/MAP kinase cascade	8	19.5×	3e-07
Intracellular signaling by second messengers	5	18.3×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
ephrin receptor signaling pathway	6	64.5×	2e-07
T cell activation	6	48.6×	6e-07
epidermal growth factor receptor signaling pathway	5	38.7×	2e-05
cell surface receptor protein tyrosine kinase signaling pathway	5	27.1×	8e-05
neuron differentiation	7	21.9×	4e-06
adaptive immune response	7	18.4×	1e-05
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	6	14.7×	2e-04
immune response	7	10.3×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	40
Likely pathogenic	15
Uncertain significance	58
Likely benign	31
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1076142	NC_000023.10:g.(?123480147)(123480649_?)del	Pathogenic
10898	NM_002351.5(SH2D1A):c.163C>T (p.Arg55Ter)	Pathogenic
10899	NM_002351.5(SH2D1A):c.172C>T (p.Gln58Ter)	Pathogenic
10900	NM_002351.5(SH2D1A):c.149_201+106del	Pathogenic
10901	NM_002351.5(SH2D1A):c.95G>C (p.Arg32Thr)	Pathogenic
10902	NM_002351.5(SH2D1A):c.138-1G>T	Pathogenic
10903	NM_002351.5(SH2D1A):c.385T>A (p.Ter129Arg)	Pathogenic
10904	NM_002351.5(SH2D1A):c.302C>T (p.Pro101Leu)	Pathogenic
10906	NM_002351.5(SH2D1A):c.-10C>T	Pathogenic
10907	NC_000023.11:g.(?124346562)(124346780_124365760)del	Pathogenic
10908	NM_002351.5(SH2D1A):c.3G>T (p.Met1Ile)	Pathogenic
10910	NM_002351.5(SH2D1A):c.164G>T (p.Arg55Leu)	Pathogenic
1341073	GRCh37/hg19 Xq25(chrX:123350855-123986893)x0	Pathogenic
1458979	NM_002351.5(SH2D1A):c.191G>A (p.Trp64Ter)	Pathogenic
1459603	NM_002351.5(SH2D1A):c.245dup (p.Asn82fs)	Pathogenic
1459977	NC_000023.10:g.(?123480493)(123505241_?)del	Pathogenic
1518501	NM_002351.5(SH2D1A):c.201+2T>C	Pathogenic
1686182	NM_002351.5(SH2D1A):c.160T>A (p.Tyr54Asn)	Pathogenic
1686183	NM_002351.5(SH2D1A):c.202-1G>C	Pathogenic
1805004	NM_002351.5(SH2D1A):c.251T>C (p.Ile84Thr)	Pathogenic
2138715	NM_002351.5(SH2D1A):c.261dup (p.Gln88fs)	Pathogenic
2138716	NM_002351.5(SH2D1A):c.295C>T (p.Gln99Ter)	Pathogenic
2424418	NC_000023.10:g.(?123499591)(123499694_?)del	Pathogenic
2424420	NC_000023.10:g.(?123494030)(123499653_?)del	Pathogenic
2442798	NM_002351.5(SH2D1A):c.1A>G (p.Met1Val)	Pathogenic
2706624	NM_002351.5(SH2D1A):c.126C>A (p.Cys42Ter)	Pathogenic
2737364	NM_002351.5(SH2D1A):c.138-1G>A	Pathogenic
2737365	NM_002351.5(SH2D1A):c.201+1G>A	Pathogenic
3244970	NC_000023.10:g.(?123499591)(123505241_?)del	Pathogenic
3244981	NC_000023.10:g.(?123504006)(123505241_?)del	Pathogenic

SpliceAI

3751 predictions. Top by Δscore:

Variant	Effect	Δscore
X:124346775:GTGCT:G	donor_gain	1.0000
X:124346780:G:GG	donor_gain	1.0000
X:155064034:C:CC	acceptor_gain	1.0000
X:155071624:G:GT	donor_gain	1.0000
X:155071624:G:T	donor_gain	1.0000
X:155073361:A:AG	acceptor_gain	1.0000
X:155077284:G:GT	donor_gain	1.0000
X:155077285:C:T	donor_gain	1.0000
X:155089338:A:G	donor_gain	1.0000
X:155090782:A:AG	acceptor_gain	1.0000
X:155090783:G:GG	acceptor_gain	1.0000
X:155090838:GA:G	donor_gain	1.0000
X:155116709:A:AG	acceptor_gain	1.0000
X:155116710:G:GG	acceptor_gain	1.0000
X:155119997:A:AG	acceptor_gain	1.0000
X:155119998:G:GG	acceptor_gain	1.0000
X:155120115:G:GT	donor_gain	1.0000
X:155120630:G:T	donor_gain	1.0000
X:124346777:GCT:G	donor_gain	0.9900
X:124370174:A:AG	acceptor_gain	0.9900
X:124370175:G:GA	acceptor_gain	0.9900
X:124370175:GACA:G	acceptor_gain	0.9900
X:124370318:CAGG:C	donor_loss	0.9900
X:124370319:AGGT:A	donor_loss	0.9900
X:124370320:GGTAT:G	donor_loss	0.9900
X:124370321:G:GA	donor_loss	0.9900
X:124370322:T:G	donor_loss	0.9900
X:124371347:TTAGG:T	acceptor_loss	0.9900
X:124371348:TA:T	acceptor_loss	0.9900
X:124371349:A:AT	acceptor_loss	0.9900

AlphaMissense

818 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:124346737:G:T	R32M	1.000
X:124370203:T:C	F77L	1.000
X:124370205:C:A	F77L	1.000
X:124370205:C:G	F77L	1.000
X:124370222:T:C	L83P	1.000
X:124346722:G:A	G27D	0.999
X:124346722:G:T	G27V	0.999
X:124346727:T:G	Y29D	0.999
X:124346731:T:C	L30S	0.999
X:124346737:G:C	R32T	0.999
X:124346738:G:C	R32S	0.999
X:124346738:G:T	R32S	0.999
X:124365813:T:A	W64R	0.999
X:124365813:T:C	W64R	0.999
X:124370251:G:C	G93R	0.999
X:124370267:T:A	L98Q	0.999
X:124346701:T:C	L20P	0.998
X:124346734:T:C	L31P	0.998
X:124346766:T:C	C42R	0.998
X:124346767:G:A	C42Y	0.998
X:124346768:C:G	C42W	0.998
X:124346772:T:C	C44R	0.998
X:124365783:T:G	Y54D	0.998
X:124365790:T:A	V56E	0.998
X:124365820:C:A	A66D	0.998
X:124370204:T:C	F77S	0.998
X:124370222:T:A	L83H	0.998
X:124370252:G:T	G93V	0.998
X:124346721:G:C	G27R	0.997
X:124346742:A:C	S34R	0.997

dbSNP variants (sampled 300 via entrez): RS1000414683 (X:124370889 G>A), RS1000802647 (X:124358397 C>T), RS1000870655 (X:124371504 T>C), RS1000917195 (X:124359057 A>G), RS1001176599 (X:124353380 G>A), RS1001372120 (X:124351966 G>T), RS1001412210 (X:124370399 T>G), RS1001475759 (X:124364666 C>A), RS1001578611 (X:124364100 C>A), RS1001586074 (X:124351288 A>G), RS1001807787 (X:124361889 T>A), RS1001860228 (X:124361258 C>T), RS1002030800 (X:124360913 G>T), RS1002408439 (X:124366717 C>A), RS1002503836 (X:124348061 T>C)

Disease associations

OMIM: gene MIM:300490 | disease phenotypes: MIM:308240, MIM:301022, MIM:301043

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked lymphoproliferative disease due to SH2D1A deficiency	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
X-linked lymphoproliferative disease due to SH2D1A deficiency	Definitive	XL

Mondo (6): X-linked lymphoproliferative disease due to SH2D1A deficiency (MONDO:0024551), X-linked lymphoproliferative syndrome (MONDO:0010627), autoinflammatory syndrome (MONDO:0019751), Mullegama-Klein-Martinez syndrome (MONDO:0026722), holoprosencephaly 13, X-linked (MONDO:0026763), lymphoproliferative syndrome (MONDO:0016537)

Orphanet (4): X-linked lymphoproliferative disease (Orphanet:2442), X-linked lymphoproliferative disease due to SAP deficiency (Orphanet:538931), Autoinflammatory syndrome (Orphanet:93665), OBSOLETE: Lymphoproliferative syndrome (Orphanet:238510)

HPO phenotypes

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

HPO	Term
HP:0001287	Meningitis
HP:0001399	Hepatic failure
HP:0001419	X-linked recessive inheritance
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001915	Aplastic anemia
HP:0001954	Recurrent fever
HP:0002205	Recurrent respiratory infections
HP:0002240	Hepatomegaly
HP:0002383	Infectious encephalitis
HP:0002480	Hepatic encephalopathy
HP:0002633	Vasculitis
HP:0002665	Lymphoma
HP:0002716	Lymphadenopathy
HP:0002721	Immunodeficiency
HP:0002961	Dysgammaglobulinemia
HP:0003073	Hypoalbuminemia
HP:0003496	Increased circulating IgM level
HP:0004313	Decreased circulating immunoglobulin concentration
HP:0004315	Decreased circulating IgG concentration
HP:0004787	Fulminant hepatitis
HP:0010975	Abnormal B cell count
HP:0011227	Elevated circulating C-reactive protein concentration
HP:0011463	Childhood onset
HP:0011839	Abnormal total T cell count
HP:0012156	Hemophagocytosis
HP:0012177	Abnormal natural killer cell physiology
HP:0030080	Burkitt lymphoma

GWAS associations

0 associations (top):

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D008232	Lymphoproliferative Disorders	C15.604.515; C20.683.515

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2321636 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
GSK-J4	increases expression	1
triphenyl phosphate	affects expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
rofecoxib	decreases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Polychlorinated Biphenyls	affects expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2330422	Binding	Inhibition of recombinant 6-His-tagged SLAM associated protein SH2 domain (unknown origin) expressed in Escherichia coli BL21(DE3) binding to biotinyl-KKSLTIpYAQVQK-NH2 attached to NeutrAvidin-coated plates using p-nitrophenyl phosphate as	Development and evaluation of novel phosphotyrosine mimetic inhibitors targeting the Src homology 2 domain of signaling lymphocytic activation molecule (SLAM) associated protein. — J Med Chem

Cellosaurus cell lines

4 cell lines: 2 transformed cell line, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_2Z24	ID00050	Transformed cell line	Male
CVCL_2Z25	ID00051	Transformed cell line	Male
CVCL_D1QI	Abcam K-562 SH2D1A KO	Cancer cell line	Female
CVCL_WQ52	Abcam Jurkat SH2D1A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04402489	PHASE3	COMPLETED	Study to Evaluate Efficacy, Safety, and Tolerability of MT-7117 in Subjects With Erythropoietic Protoporphyria or X-Linked Protoporphyria
NCT05005975	PHASE3	RECRUITING	Extension Study to Evaluate Safety and Tolerability of Oral Dersimelagon (MT-7117) in Subjects With Erythropoietic Protoporphyria (EPP) or X-Linked Protoporphyria (XLP)
NCT00033475	PHASE3	COMPLETED	Reduced Immunosuppressive Therapy With or Without Donor White Blood Cells in Treating Patients With Lymphoproliferative Disease After Organ Transplantation
NCT00053053	PHASE3	COMPLETED	Comparison of Nutritional Supplements in Preventing Weight Loss in Patients With Cancer
NCT00058331	PHASE3	COMPLETED	Epoetin Alfa in Treating Anemia in Patients With Solid Tumors
NCT00070382	PHASE3	COMPLETED	Darbepoetin Alfa Compared With Epoetin Alfa in Treating Anemia in Patients Receiving Chemotherapy for Cancer
NCT00516503	PHASE3	COMPLETED	Baclofen-Amitriptyline Hydrochloride-Ketamine Gel in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00661999	PHASE3	COMPLETED	Darbepoetin Alfa With or Without Iron in Treating Anemia Caused By Chemotherapy in Patients With Cancer
NCT00666211	PHASE3	COMPLETED	Opioid Titration Order Sheet or Standard Care in Treating Patients With Cancer Pain
NCT00719563	PHASE3	COMPLETED	American Ginseng in Treating Patients With Fatigue Caused by Cancer
NCT00750009	PHASE3	COMPLETED	Personalized Information or Basic Information in Helping Patients Make Decisions About Participating in a Clinical Trial
NCT03394365	PHASE3	RECRUITING	A Phase 3 Study of Tabelecleucel for Participants With Epstein-Barr Virus-Associated Post-Transplant Lymphoproliferative Disease After Failure With Rituximab or Rituximab and Chemotherapy
NCT05431179	PHASE3	WITHDRAWN	A Study of Zilovertamab and Ibrutinib in Patients With Relapsed or Refractory Mantle Cell Lymphoma
NCT01821781	PHASE2	ACTIVE_NOT_RECRUITING	Immune Disorder HSCT Protocol
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00001379	PHASE2	COMPLETED	Treatment and Natural History Study of Lymphomatoid Granulomatosis
NCT00001438	PHASE2	COMPLETED	A Pilot Study of the Combination of Retinoic Acid and Interferon-Alpha2a for the Treatment of Lymphoproliferative Disorders in Children With Immunodeficiency Syndromes
NCT00066469	PHASE2	COMPLETED	Cyclophosphamide, Rituximab, and Either Prednisone or Methylprednisolone in Treating Patients With Lymphoproliferative Disease After Solid Organ Transplantation
NCT00092222	PHASE2	ACTIVE_NOT_RECRUITING	Virotherapy and Natural History Study of KHSV-Associated Multricentric Castleman s Disease With Correlates of Disease Activity
NCT00255749	PHASE2	COMPLETED	Epoetin Alfa in Treating Patients With Anemia Who Are Undergoing Chemotherapy for Cancer
NCT00387530	PHASE2	WITHDRAWN	Phenylbutyrate and Valganciclovir in Treating Patients With Relapsed or Refractory Epstein-Barr Virus-Positive Cancer
NCT00416624	PHASE2	COMPLETED	Epoetin Alfa or Darbepoetin Alfa in Treating Patients With Anemia Caused by Chemotherapy
NCT00436618	PHASE2	COMPLETED	Everolimus in Treating Patients With Lymphoma That Has Relapsed or Not Responded to Previous Treatment
NCT00621036	PHASE2	WITHDRAWN	Vaccine Therapy and GM-CSF in Treating Patients With CNS Lymphoma
NCT00869323	PHASE2	TERMINATED	Bortezomib and Rituximab in Treating Patients With Post-Transplant Lymphoproliferative Disorders
NCT00992732	PHASE2	TERMINATED	Study of HQK-1004 and Valganciclovir to Treat Epstein-Barr Virus (EBV) - Positive Lymphoid Malignancies or Lymphoproliferative Disorders
NCT01116232	PHASE2	TERMINATED	Sirolimus, Tacrolimus, Thymoglobulin and Rituximab as Graft-versus-Host-Disease Prophylaxis in Patients Undergoing Haploidentical and HLA Partially Matched Donor Hematopoietic Cell Transplantation
NCT01118013	PHASE2	TERMINATED	Donor Stem Cell Transplant in Treating Patients With Relapsed Hematologic Malignancies or Secondary Myelodysplasia Previously Treated With High-Dose Chemotherapy and Autologous Stem Cell Transplant
NCT02579967	PHASE2	RECRUITING	Pilot Trial of Allogeneic Blood or Marrow Transplantation for Primary Immunodeficiencies
NCT02861417	PHASE2	ACTIVE_NOT_RECRUITING	Busulfan, Fludarabine Phosphate, and Post-Transplant Cyclophosphamide in Treating Patients With Blood Cancer Undergoing Donor Stem Cell Transplant
NCT03258567	PHASE2	RECRUITING	Nivolumab in Epstein-Barr Virus (EBV)-Positive Lymphoproliferative Disorders and EBV-Positive Non-HodgkinLymphomas
NCT03373019	PHASE2	UNKNOWN	Chidamide Combined With R-GDP in Treating Patients With Relapsed or Refractory Diffuse Large B-cell Lymphoma (DLBCL)
NCT03663933	PHASE2	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Disorders of T-cell Proliferation and/or Dysregulation
NCT03744676	PHASE2	COMPLETED	A Safety Trial of Lisocabtagene Maraleucel (JCAR017) for Relapsed and Refractory (R/R) B-cell Non-Hodgkin Lymphoma (NHL) in the Outpatient Setting (TRANSCEND-OUTREACH-007)
NCT03922724	PHASE2	RECRUITING	Allogeneic Hematopoietic Cell Transplantation for Peripheral T Cell Lymphoma
NCT04339777	PHASE2	RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Inborn Errors of Immunity
NCT04463615	PHASE2	COMPLETED	Leflunomide for the Treatment of Relapsed or Refractory CD30+ Lymphoproliferative Disorders
NCT04554914	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate Tabelecleucel in Participants With Epstein Barr Virus (EBV) Associated Diseases
NCT04858256	PHASE2	RECRUITING	Pacritinib in Relapsed/Refractory T-cell Lymphoproliferative Neoplasms
NCT04883437	PHASE2	RECRUITING	Acalabrutinib and Obinutuzumab for the Treatment of Previously Untreated Follicular Lymphoma or Other Indolent Non-Hodgkin Lymphomas