SIRPG

Summary

SIRPG (signal regulatory protein gamma, HGNC:15757) is a protein-coding gene on chromosome 20p13, encoding Signal-regulatory protein gamma (Q9P1W8). Probable immunoglobulin-like cell surface receptor.

The protein encoded by this gene is a member of the signal-regulatory protein (SIRP) family, and also belongs to the immunoglobulin superfamily. SIRP family members are receptor-type transmembrane glycoproteins known to be involved in the negative regulation of receptor tyrosine kinase-coupled signaling processes. Alternatively spliced transcript variants encoding different isoforms have been described.

Source: NCBI Gene 55423 — RefSeq curated summary.

At a glance

• Gene–disease (curated): male infertility with azoospermia or oligozoospermia due to single gene mutation (Limited, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 105 total — 1 likely-pathogenic
• MANE Select transcript: NM_018556

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15757
Approved symbol	SIRPG
Name	signal regulatory protein gamma
Location	20p13
Locus type	gene with protein product
Status	Approved
Aliases	bA77C3.1, SIRP-B2, SIRPgamma, CD172g
Ensembl gene	ENSG00000089012
Ensembl biotype	protein_coding
OMIM	605466
Entrez	55423

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 6 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000216927, ENST00000303415, ENST00000344103, ENST00000381580, ENST00000381583, ENST00000478145, ENST00000497407, ENST00000885694

RefSeq mRNA: 3 — MANE Select: NM_018556 NM_001039508, NM_018556, NM_080816

CCDS: CCDS13020, CCDS13021, CCDS33434

Canonical transcript exons

ENST00000303415 — 6 exons

Exon	Start	End
ENSE00001165592	1629152	1629636
ENSE00001328167	1657642	1657779
ENSE00001681257	1635267	1635599
ENSE00001765869	1636188	1636505
ENSE00003459720	1649052	1649408
ENSE00003610532	1630222	1630306

Expression profiles

Bgee: expression breadth ubiquitous, 149 present calls, max score 98.68.

FANTOM5 (CAGE): breadth broad, TPM avg 2.6774 / max 214.4057, expressed in 362 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
186026	2.6774	362
186044	1.9927	118
186043	0.4620	73
186029	0.4102	179
186027	0.1564	70
186028	0.1548	84
186024	0.0730	37
186042	0.0068	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	98.68	gold quality
buccal mucosa cell	CL:0002336	88.99	silver quality
lymph node	UBERON:0000029	87.98	gold quality
granulocyte	CL:0000094	82.66	gold quality
blood	UBERON:0000178	82.11	gold quality
vermiform appendix	UBERON:0001154	81.09	gold quality
spleen	UBERON:0002106	80.52	gold quality
mucosa of transverse colon	UBERON:0004991	79.70	gold quality
epithelium of nasopharynx	UBERON:0001951	77.10	gold quality
caecum	UBERON:0001153	75.55	gold quality
left testis	UBERON:0004533	73.15	gold quality
right testis	UBERON:0004534	72.89	gold quality
small intestine Peyer’s patch	UBERON:0003454	72.14	gold quality
thymus	UBERON:0002370	70.91	silver quality
rectum	UBERON:0001052	70.85	gold quality
bone marrow cell	CL:0002092	70.27	gold quality
bone marrow	UBERON:0002371	70.03	gold quality
testis	UBERON:0000473	70.00	gold quality
gall bladder	UBERON:0002110	69.29	gold quality
small intestine	UBERON:0002108	68.51	gold quality
tendon of biceps brachii	UBERON:0008188	67.68	gold quality
superficial temporal artery	UBERON:0001614	67.57	silver quality
tonsil	UBERON:0002372	67.43	gold quality
parotid gland	UBERON:0001831	66.92	gold quality
tongue squamous epithelium	UBERON:0006919	65.77	gold quality
trabecular bone tissue	UBERON:0002483	62.89	gold quality
transverse colon	UBERON:0001157	61.56	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	60.39	gold quality
biceps brachii	UBERON:0001507	59.99	gold quality
right coronary artery	UBERON:0001625	59.56	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.65
E-HCAD-30	no	68.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

41 targeting SIRPG, 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-4425	100.00	67.59	1049
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-4505	99.27	67.81	2678
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-6877-3P	98.98	65.83	560

Literature-anchored findings (GeneRIF, showing 8)

• a novel member of the signal regulatory protein (SIRP) family- with unique characteristics from both alpha and beta genes- termed SIRPgamma (PMID:15294972)
• CD47 is enriched at endothelial junctions, and its interaction with SIRPgamma is required for human T-cell transendothelial migration (PMID:18524990)
• tumor necrosis factor receptor superfamily, member 14 (TNFRSF14) and signal regulatory protein, gamma (SIRPG) appear to contribute to gender difference in incidence of systemic lupus erythematosus. (PMID:19473566)
• SIRPgamma in complex with FabOX117 forms a dimer in the crystal. Binding to the Fab fixes the position of domain 1 relative to domains 2/3 exposing a surface which favours formation of a homotypic dimer. (PMID:23826770)
• The independent non-obstructive azoospermia risk alleles are driven by variants in the protein-coding sequence of the two genes, SIRPA and SIRPG. (PMID:24162948)
• The SNP rs2281808 TT variant reduced SIRPgamma expression on T-cells. SIRPgamma(low) CD8 T-cells in CT and TT individuals were in a heightened effector state with lower activation threshold and had greater gene expression of molecules associated with migratory and cytotoxic potential. SIRPgamma(low) CD8 T-cells were deficient in transcription factors associated with long-term functional memory formation. (PMID:30337675)
• Altered expression of SIRPgamma on the T-cells of relapsing remitting multiple sclerosis and type 1 diabetes patients could potentiate effector responses from T-cells. (PMID:32853219)
• Genetic Control of Splicing at SIRPG Modulates Risk of Type 1 Diabetes. (PMID:34799406)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sirpa	ENSMUSG00000037902
mus_musculus	Sirpb1c	ENSMUSG00000074677
mus_musculus	Gm5150	ENSMUSG00000078780
mus_musculus	Sirpd	ENSMUSG00000078783
mus_musculus	Sirpb1b	ENSMUSG00000095028
mus_musculus	Sirpb1a	ENSMUSG00000095788
rattus_norvegicus	Sirpa	ENSRNOG00000004763
rattus_norvegicus	LOC100909964	ENSRNOG00000043478
rattus_norvegicus	AABR07008876.1	ENSRNOG00000053292

Paralogs (4): SIRPB1 (ENSG00000101307), SIRPD (ENSG00000125900), SIRPB2 (ENSG00000196209), SIRPA (ENSG00000198053)

Protein

Protein identifiers

Signal-regulatory protein gamma — Q9P1W8 (reviewed: Q9P1W8)

Alternative names: CD172 antigen-like family member B, Signal-regulatory protein beta-2

All UniProt accessions (1): Q9P1W8

UniProt curated annotations — full annotation on UniProt →

Function. Probable immunoglobulin-like cell surface receptor. On binding with CD47, mediates cell-cell adhesion. Engagement on T-cells by CD47 on antigen-presenting cells results in enhanced antigen-specific T-cell proliferation and costimulates T-cell activation.

Subunit / interactions. Interacts with CD47.

Subcellular location. Membrane.

Tissue specificity. Detected in liver, and at very low levels in brain, heart, lung, pancreas, kidney, placenta and skeletal muscle. Expressed on CD4+ T-cells, CD8+ T-cells, CD56-bright natural killer (NK) cells, CD20+ cells, and all activated NK cells. Mainly present in the paracortical T-cell area of lymph nodes, with only sparse positive cells in the mantle and in the germinal center of B-cell follicles. In the thymus, primarily expressed in the medulla on mature T-lymphocytes that have undergone thymic selection.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9P1W8-1	1	yes
Q9P1W8-2	2
Q9P1W8-3	3
Q9P1W8-4	4

RefSeq proteins (3): NP_001034597, NP_061026, NP_543006 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003597	Ig_C1-set	Domain
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013106	Ig_V-set	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR051755	Ig-like_CS_Receptor	Family

Pfam: PF07654, PF07686

UniProt features (48 total): strand 25, glycosylation site 4, disulfide bond 3, splice variant 3, domain 3, sequence variant 2, topological domain 2, helix 2, signal peptide 1, chain 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
2JJW	X-RAY DIFFRACTION	1.7
4I2X	X-RAY DIFFRACTION	2.48

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9P1W8-F1	85.93	0.70

Antibody-complex structures (SAbDab): 1 — 4I2X

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (3): 53–119, 168–226, 271–329

Glycosylation sites (4): 309, 317, 243, 268

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-202733	Cell surface interactions at the vascular wall
R-HSA-391160	Signal regulatory protein family interactions
R-HSA-109582	Hemostasis
R-HSA-1500931	Cell-Cell communication

MSigDB gene sets: 159 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_CELL_CELL_SIGNALING, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_CELL_ACTIVATION, GOBP_POSITIVE_REGULATION_OF_PHAGOCYTOSIS, GOBP_REGULATION_OF_ENDOCYTOSIS, GOBP_LEUKOCYTE_CELL_CELL_ADHESION, GOBP_POSITIVE_REGULATION_OF_CELL_CELL_ADHESION, GOBP_REGULATION_OF_PHAGOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_TRANSPORT, GOBP_REGULATION_OF_TRANSPORT

GO Biological Process (8): cell adhesion (GO:0007155), cell-cell signaling (GO:0007267), positive regulation of cell population proliferation (GO:0008284), negative regulation of cell population proliferation (GO:0008285), positive regulation of cell-cell adhesion (GO:0022409), intracellular signal transduction (GO:0035556), positive regulation of phagocytosis (GO:0050766), positive regulation of T cell activation (GO:0050870)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Hemostasis	1
Cell-Cell communication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell population proliferation	2
regulation of cell population proliferation	2
cellular process	1
cell communication	1
signaling	1
positive regulation of cellular process	1
negative regulation of cellular process	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
intracellular anatomical structure	1
signal transduction	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
T cell activation	1
regulation of T cell activation	1
positive regulation of lymphocyte activation	1
positive regulation of leukocyte cell-cell adhesion	1
binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1428 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SIRPG	CD47	Q08722	998
SIRPG	TYROBP	O43914	737
SIRPG	CD3E	P07766	483
SIRPG	LGALS9	O00182	447
SIRPG	CD44	P16070	442
SIRPG	SH2D1A	O60880	437
SIRPG	SIRPA	P78324	434
SIRPG	UBASH3A	P57075	431
SIRPG	LCK	P06239	412
SIRPG	TMIGD2	Q96BF3	354
SIRPG	UBE2U	Q5VVX9	352
SIRPG	RIPK1	Q13546	349
SIRPG	CD6	P30203	348
SIRPG	ASAP1	Q9ULH1	348
SIRPG	SLA2	Q9H6Q3	344

IntAct

12 interactions, top by confidence:

A	B	Type	Score
SIRPG	CD47	psi-mi:“MI:0915”(physical association)	0.710
SIRPG	CD47	psi-mi:“MI:0407”(direct interaction)	0.710
SIRPG	FOS	psi-mi:“MI:0915”(physical association)	0.560
SIRPG	GATM	psi-mi:“MI:0915”(physical association)	0.560
SIRPG	SIRPA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (8): SIRPA (Affinity Capture-MS), SPCS2 (Affinity Capture-MS), LTF (Affinity Capture-MS), SIRPA (Affinity Capture-MS), LTF (Affinity Capture-MS), SIRPA (Affinity Capture-MS), SIRPG (Protein-peptide), SIRPG (Affinity Capture-MS)

ESM2 similar proteins: A0A140LHF2, A0JPB1, A8E0Y8, D3YX43, O00241, P01833, P01854, P01874, P01879, P01880, P0C788, P0DOX3, P0DOX4, P0DOX6, P0DUB1, P15083, P20273, P20768, P27931, P35590, P35916, P35917, P35969, P43121, P43303, P53767, P81265, Q06805, Q06806, Q15109, Q5FWR8, Q5TFQ8, Q5U5A3, Q62230, Q62786, Q6AYD4, Q8K135, Q8R2Y2, Q91ZT1, Q925F2

Diamond homologs: O00241, O46631, P01691, P01844, P01845, P01847, P01915, P04230, P04231, P18211, P18468, P18469, P18470, P20040, P78324, P97710, P97797, Q5JXA9, Q5TFQ8, Q9H106, Q9P1W8, Q9PWR4, P55899, Q29980, P01835, P35737, P01634, P01645, P01646, P01861, P20760, P01693, P01635, P01683, P14432

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	74
Likely benign	15
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
564643	GRCh37/hg19 20p13(chr20:61568-2010334)x1	Likely pathogenic

SpliceAI

1719 predictions. Top by Δscore:

Variant	Effect	Δscore
20:1477404:C:CC	acceptor_gain	1.0000
20:1630220:A:AC	donor_gain	1.0000
20:1630221:C:CC	donor_gain	1.0000
20:1630221:CAG:C	donor_gain	1.0000
20:1630221:CAGT:C	donor_gain	1.0000
20:1477399:TTTTG:T	acceptor_gain	0.9900
20:1477400:TTTG:T	acceptor_gain	0.9900
20:1477401:TTG:T	acceptor_gain	0.9900
20:1477402:TG:T	acceptor_gain	0.9900
20:1479804:T:TC	acceptor_gain	0.9900
20:1491270:CTTA:C	donor_loss	0.9900
20:1491271:TTACC:T	donor_loss	0.9900
20:1491272:TACCT:T	donor_loss	0.9900
20:1491273:A:AT	donor_loss	0.9900
20:1491274:C:CT	donor_loss	0.9900
20:1630213:TGTAC:T	donor_loss	0.9900
20:1630214:GTAC:G	donor_loss	0.9900
20:1630215:TACT:T	donor_loss	0.9900
20:1630216:ACTTA:A	donor_loss	0.9900
20:1630217:CT:C	donor_loss	0.9900
20:1630218:TTACA:T	donor_loss	0.9900
20:1630219:TAC:T	donor_loss	0.9900
20:1630220:ACAGT:A	donor_gain	0.9900
20:1630221:C:A	donor_loss	0.9900
20:1630221:CA:C	donor_gain	0.9900
20:1630221:CAGTC:C	donor_gain	0.9900
20:1630307:C:CC	acceptor_gain	0.9900
20:1631228:G:C	donor_gain	0.9900
20:1649043:TGTAC:T	donor_loss	0.9900
20:1649044:GTACT:G	donor_loss	0.9900

AlphaMissense

2499 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
20:1635520:G:C	F276L	0.984
20:1635520:G:T	F276L	0.984
20:1635522:A:G	F276L	0.984
20:1636417:G:C	F173L	0.978
20:1636417:G:T	F173L	0.978
20:1636419:A:G	F173L	0.978
20:1649284:C:A	W66C	0.959
20:1649284:C:G	W66C	0.959
20:1649286:A:G	W66R	0.949
20:1649286:A:T	W66R	0.949
20:1649324:C:G	C53S	0.949
20:1649325:A:T	C53S	0.949
20:1636392:A:G	W182R	0.945
20:1636392:A:T	W182R	0.945
20:1649176:A:C	F102L	0.940
20:1649176:A:T	F102L	0.940
20:1649178:A:G	F102L	0.940
20:1649126:C:G	C119S	0.937
20:1649127:A:T	C119S	0.937
20:1649119:C:A	K121N	0.934
20:1649119:C:G	K121N	0.934
20:1649116:A:C	F122L	0.933
20:1649116:A:T	F122L	0.933
20:1649118:A:G	F122L	0.933
20:1636309:G:C	S209R	0.924
20:1636309:G:T	S209R	0.924
20:1636311:T:G	S209R	0.924
20:1649281:G:C	F67L	0.924
20:1649281:G:T	F67L	0.924
20:1649283:A:G	F67L	0.924

dbSNP variants (sampled 300 via entrez): RS1000130160 (20:1687227 G>A,T), RS1000145278 (20:1629266 C>G), RS1000397217 (20:1681068 A>G), RS1000450687 (20:1660430 C>G), RS1000457737 (20:1676986 G>A), RS1000537367 (20:1661121 C>T), RS1000545787 (20:1639097 T>C), RS1000549613 (20:1630526 G>A,T), RS1000571927 (20:1677293 C>T), RS1000588431 (20:1661342 A>G), RS1000690414 (20:1655238 G>A), RS1000739203 (20:1671598 TG>T), RS1000755057 (20:1634577 A>G), RS1000829942 (20:1650232 C>A), RS1000841577 (20:1665563 C>A)

Disease associations

OMIM: gene MIM:605466 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
male infertility with azoospermia or oligozoospermia due to single gene mutation	Limited	Autosomal recessive

Mondo (1): (MONDO:0018393)

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001979_3	Circulating myeloperoxidase levels (serum)	4.000000e-08
GCST005576_19	Intracranial aneurysm	2.000000e-06
GCST006585_981	Blood protein levels	2.000000e-19
GCST008499_2	Meningococcal C functional antibody titers post childhood immunization	7.000000e-07
GCST008499_3	Meningococcal C functional antibody titers post childhood immunization	8.000000e-06
GCST008499_4	Meningococcal C functional antibody titers post childhood immunization	6.000000e-07
GCST010396_302	Gut microbiota (bacterial taxa, hurdle binary method)	5.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005243	myeloperoxidase measurement
EFO:0004645	response to vaccine
EFO:0007874	gut microbiome measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

13 total (human), top 13 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
butyraldehyde	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
(+)-JQ1 compound	decreases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Diuron	decreases expression	1
Endosulfan	decreases expression	1
Formaldehyde	decreases expression	1
Methyl Methanesulfonate	decreases expression	1
Nickel	increases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_KA61	CHO-K1/SIRP gamma	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

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