SMAP2

Summary

SMAP2 (small ArfGAP2, HGNC:25082) is a protein-coding gene on chromosome 1p34.2, encoding Stromal membrane-associated protein 2 (Q8WU79). GTPase activating protein that acts on ARF1.

Predicted to enable GTPase activator activity. Located in cytosol and nucleoplasm.

Source: NCBI Gene 64744 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 21 total
• MANE Select transcript: NM_022733

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25082
Approved symbol	SMAP2
Name	small ArfGAP2
Location	1p34.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000084070
Ensembl biotype	protein_coding
OMIM	616916
Entrez	64744

Gene structure

Transcript identifiers

Ensembl transcripts: 10 — 9 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000372708, ENST00000372718, ENST00000435168, ENST00000487871, ENST00000539317, ENST00000614549, ENST00000851553, ENST00000851555, ENST00000913385, ENST00000913386

RefSeq mRNA: 4 — MANE Select: NM_022733 NM_001198978, NM_001198979, NM_001198980, NM_022733

CCDS: CCDS451, CCDS55592, CCDS55593, CCDS72763

Canonical transcript exons

ENST00000372718 — 10 exons

Exon	Start	End
ENSE00000540397	40413016	40413102
ENSE00000768397	40409757	40409835
ENSE00000768412	40416176	40416341
ENSE00000768419	40416780	40417096
ENSE00001458467	40373727	40374223
ENSE00003569195	40408653	40408738
ENSE00003598201	40415272	40415381
ENSE00003646230	40406736	40406869
ENSE00003790922	40414159	40414240
ENSE00003849313	40421976	40423322

Expression profiles

Bgee: expression breadth ubiquitous, 241 present calls, max score 99.01.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.0314 / max 2818.6493, expressed in 1823 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2362	55.5690	1823
2363	3.4924	583
2359	3.2369	325
2364	0.5957	240
2360	0.4852	159
2366	0.2920	106
2365	0.2285	95
2379	0.0823	14
2378	0.0493	14

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood	UBERON:0000178	99.01	gold quality
leukocyte	CL:0000738	98.93	gold quality
vermiform appendix	UBERON:0001154	98.93	gold quality
granulocyte	CL:0000094	98.91	gold quality
monocyte	CL:0000576	98.91	gold quality
spleen	UBERON:0002106	98.63	gold quality
lymph node	UBERON:0000029	98.05	gold quality
right lung	UBERON:0002167	98.01	gold quality
bone marrow cell	CL:0002092	97.45	gold quality
right frontal lobe	UBERON:0002810	96.26	gold quality
upper lobe of left lung	UBERON:0008952	95.95	gold quality
gall bladder	UBERON:0002110	95.90	gold quality
anterior cingulate cortex	UBERON:0009835	95.81	gold quality
prefrontal cortex	UBERON:0000451	95.76	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.75	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.74	gold quality
thymus	UBERON:0002370	95.31	gold quality
upper lobe of lung	UBERON:0008948	95.18	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.18	gold quality
smooth muscle tissue	UBERON:0001135	95.16	gold quality
caecum	UBERON:0001153	94.95	gold quality
frontal cortex	UBERON:0001870	94.90	gold quality
neocortex	UBERON:0001950	94.72	gold quality
nucleus accumbens	UBERON:0001882	94.61	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.61	gold quality
cerebellar hemisphere	UBERON:0002245	94.56	gold quality
cerebellar cortex	UBERON:0002129	94.52	gold quality
caudate nucleus	UBERON:0001873	94.38	gold quality
amygdala	UBERON:0001876	94.36	gold quality
hypothalamus	UBERON:0001898	94.21	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-CURD-119	yes	954.98
E-MTAB-8142	yes	36.22
E-GEOD-135922	yes	33.95
E-HCAD-35	yes	7.42
E-MTAB-6142	no	56.93
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting SMAP2, 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-188-3P	100.00	68.76	1240
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-10527-5P	99.91	72.28	3754
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-6817-3P	99.79	68.35	2126
HSA-MIR-26A-5P	99.78	73.52	2303
HSA-MIR-26B-5P	99.78	73.51	2305
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-6764-5P	99.75	67.89	2304

Literature-anchored findings (GeneRIF, showing 4)

• analyses revealed that three common polymorphisms, rs2982510, rs2294752, and rs446738, were putatively associated with the increased susceptibility to AIA (PMID:20831471)
• In the current study, there were identified sequences in the carboxy-terminal region of SMAP2 that are critical for its specific subcellular localization and its specificity for Arf proteins. (PMID:21147065)
• Results also demonstrated a physical association between SMAP1 and SMAP2, which might serve as a basis for a functional interaction, and identified the intramolecular domains responsible for this association (PMID:25281535)
• SMAP2 immunoprecipitated clathrin and AP-1 through a putative clathrin-binding domain and a CALM-binding domain, and SMAP2 mutants that did not interact with clathrin or AP-1 could not localize to recycling endosomes (PMID:26136365)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	smap2	ENSDARG00000061446
mus_musculus	Smap2	ENSMUSG00000032870
rattus_norvegicus	Smap2	ENSRNOG00000011421
drosophila_melanogaster	CG8243	FBGN0033349

Paralogs (28): ARAP2 (ENSG00000047365), ACAP1 (ENSG00000072818), ASAP3 (ENSG00000088280), ARFGAP1 (ENSG00000101199), ADAP1 (ENSG00000105963), AGFG2 (ENSG00000106351), GIT1 (ENSG00000108262), SMAP1 (ENSG00000112305), ACAP2 (ENSG00000114331), ARAP3 (ENSG00000120318), ACAP3 (ENSG00000131584), AGAP3 (ENSG00000133612), AGAP2 (ENSG00000135439), APPL2 (ENSG00000136044), GIT2 (ENSG00000139436), ARFGAP2 (ENSG00000149182), ASAP2 (ENSG00000151693), ASAP1 (ENSG00000153317), APPL1 (ENSG00000157500), AGAP1 (ENSG00000157985), AGAP5 (ENSG00000172650), AGFG1 (ENSG00000173744), ADAP2 (ENSG00000184060), ARAP1 (ENSG00000186635), AGAP4 (ENSG00000188234), AGAP6 (ENSG00000204149), AGAP9 (ENSG00000204172), ARFGAP3 (ENSG00000242247)

Protein

Protein identifiers

Stromal membrane-associated protein 2 — Q8WU79 (reviewed: Q8WU79)

Alternative names: Stromal membrane-associated protein 1-like

All UniProt accessions (3): Q8WU79, A0A087WV97, X6RCC3

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activating protein that acts on ARF1. Can also activate ARF6 (in vitro). May play a role in clathrin-dependent retrograde transport from early endosomes to the trans-Golgi network.

Subunit / interactions. Interacts with ARF1. Interacts with PICALM and clathrin heavy chains.

Subcellular location. Cytoplasm.

Isoforms (3)

UniProt ID	Names	Canonical?
Q8WU79-1	1	yes
Q8WU79-2	2
Q8WU79-3	3

RefSeq proteins (4): NP_001185907, NP_001185908, NP_001185909, NP_073570* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001164	ArfGAP_dom	Domain
IPR037278	ARFGAP/RecO	Homologous_superfamily
IPR038508	ArfGAP_dom_sf	Homologous_superfamily
IPR051718	ARF_GTPase-activating	Family

Pfam: PF01412

UniProt features (32 total): modified residue 6, helix 6, turn 5, region of interest 4, strand 3, splice variant 2, compositionally biased region 2, chain 1, domain 1, sequence variant 1, zinc finger region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2IQJ	X-RAY DIFFRACTION	1.9

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WU79-F1	63.37	0.29

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): 219, 223, 225, 231, 240, 127

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 246 (showing top): GCACCTT_MIR18A_MIR18B, YAATNRNNNYNATT_UNKNOWN, MYOGENIN_Q6, ZHAN_MULTIPLE_MYELOMA_PR_DN, GCANCTGNY_MYOD_Q6, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, MORI_IMMATURE_B_LYMPHOCYTE_UP, CACCAGC_MIR138, CAGCTG_AP4_Q5, EFC_Q6, WANG_LMO4_TARGETS_DN, chr1p34, CREIGHTON_ENDOCRINE_THERAPY_RESISTANCE_5, GGCKCATGS_UNKNOWN, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN

GO Biological Process (0):

GO Molecular Function (4): GTPase activator activity (GO:0005096), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (3): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
transition metal ion binding	1
binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

690 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SMAP2	STX2	P32856	745
SMAP2	PICALM	Q13492	527
SMAP2	SH3YL1	Q96HL8	525
SMAP2	ZFP69B	Q9UJL9	507
SMAP2	APPL2	Q8NEU8	489
SMAP2	ZFP69	Q49AA0	446
SMAP2	TMF1	P82094	438
SMAP2	RAI14	Q9P0K7	430
SMAP2	C2orf42	Q9NWW7	428
SMAP2	GOPC	Q9HD26	393
SMAP2	DOC2B	Q14184	376
SMAP2	ZDHHC23	Q8IYP9	373
SMAP2	GOLGA3	Q08378	370
SMAP2	PICK1	Q9NRD5	366
SMAP2	VPS54	Q9P1Q0	327
SMAP2	TMCO2	Q7Z6W1	327

IntAct

96 interactions, top by confidence:

A	B	Type	Score
SMAP2	DAZAP2	psi-mi:“MI:0915”(physical association)	0.720
MAGED1	SMAP2	psi-mi:“MI:0915”(physical association)	0.720
SMAP2	MAGED1	psi-mi:“MI:0915”(physical association)	0.720
DAZAP2	SMAP2	psi-mi:“MI:0915”(physical association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
SMAP2	DAB1	psi-mi:“MI:0915”(physical association)	0.560
C1orf94	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
SMAP2	FAM168A	psi-mi:“MI:0915”(physical association)	0.560
FAM168A	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
DAB1	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
SMAP2	C1orf94	psi-mi:“MI:0915”(physical association)	0.560
BHLHE40	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
CRX	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
SMAP1	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
SMAP2	TENT5B	psi-mi:“MI:0915”(physical association)	0.560
KRTAP6-2	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
MSX2	SMAP2	psi-mi:“MI:0915”(physical association)	0.560
CLINT1	PIK3C2A	psi-mi:“MI:0914”(association)	0.530
BAG2	HGS	psi-mi:“MI:0914”(association)	0.530
CELF5	CASC3	psi-mi:“MI:0914”(association)	0.530
MFSD4A	HIP1R	psi-mi:“MI:0914”(association)	0.530
SLC25A11	POTEI	psi-mi:“MI:0914”(association)	0.530

BioGRID (230): SMAP2 (Two-hybrid), SMAP2 (Two-hybrid), SMAP2 (Two-hybrid), SMAP2 (Two-hybrid), C1orf94 (Two-hybrid), SMAP2 (Affinity Capture-MS), SMAP2 (Affinity Capture-MS), SMAP2 (Co-fractionation), SMAP2 (Proximity Label-MS), SMAP2 (Proximity Label-MS), SMAP2 (Proximity Label-MS), DAZAP2 (Two-hybrid), SMAP2 (Affinity Capture-MS), SMAP2 (Affinity Capture-MS), SMAP2 (Affinity Capture-MS)

ESM2 similar proteins: A7Z035, O08719, O14964, O55012, O60641, O75061, O75553, O88339, O88797, O95208, P47160, P52594, P70429, P78813, P97318, P98078, P98082, Q05140, Q0V8S0, Q13492, Q14677, Q27974, Q2TA45, Q4KLH5, Q5EA00, Q5F413, Q5R896, Q61548, Q67YI9, Q6CHN0, Q7M6Y3, Q7TN29, Q80TZ3, Q80VP1, Q8CHU3, Q8CJH2, Q8IYB5, Q8K2K6, Q8L860, Q8WU79

Diamond homologs: A1L520, A1Z7A6, A4RF61, B1V8A0, L7XCU0, O35179, O35180, O35964, O43150, O74345, O75689, O80925, O82171, O94601, O97902, P10569, P35197, P38682, P40529, Q04412, Q09531, Q0WQQ1, Q10165, Q10367, Q17R07, Q1AAU6, Q28CM8, Q2KJA1, Q3MID3, Q4KLN7, Q4R4C9, Q5EA00, Q5F413, Q5R787, Q5RAT7, Q5U464, Q5VTM2, Q5XHY7, Q62419, Q62420

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 94 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
Golgi Associated Vesicle Biogenesis	6	18.8×	2e-04
Clathrin-mediated endocytosis	10	13.3×	1e-06
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	12.1×	8e-03

GO biological processes:

GO term	Partners	Fold	FDR
axonogenesis	6	11.9×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

2846 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:40374202:T:A	C28S	1.000
1:40374202:T:C	C28R	1.000
1:40374203:G:A	C28Y	1.000
1:40374203:G:C	C28S	1.000
1:40374203:G:T	C28F	1.000
1:40374204:T:G	C28W	1.000
1:40374211:T:A	C31S	1.000
1:40374211:T:C	C31R	1.000
1:40374212:G:A	C31Y	1.000
1:40374212:G:C	C31S	1.000
1:40374212:G:T	C31F	1.000
1:40374213:C:G	C31W	1.000
1:40406744:T:A	W38R	1.000
1:40406744:T:C	W38R	1.000
1:40406745:G:C	W38S	1.000
1:40406746:G:C	W38C	1.000
1:40406746:G:T	W38C	1.000
1:40406747:G:C	A39P	1.000
1:40406748:C:A	A39D	1.000
1:40406750:T:C	S40P	1.000
1:40406751:C:A	S40Y	1.000
1:40406751:C:T	S40F	1.000
1:40406753:T:A	W41R	1.000
1:40406753:T:C	W41R	1.000
1:40406758:C:A	N42K	1.000
1:40406758:C:G	N42K	1.000
1:40406762:G:C	G44R	1.000
1:40406763:G:A	G44D	1.000
1:40406763:G:T	G44V	1.000
1:40406769:T:C	F46S	1.000

dbSNP variants (sampled 300 via entrez): RS1000077675 (1:40359447 G>T), RS1000082050 (1:40387601 A>C,G), RS1000129785 (1:40359249 C>T), RS1000138720 (1:40403231 C>T), RS1000169290 (1:40385624 T>C,G), RS1000267416 (1:40385051 G>A), RS1000346251 (1:40422464 A>G), RS1000375307 (1:40373852 C>CT), RS1000491789 (1:40377824 C>T), RS1000537829 (1:40408046 A>G), RS1000556324 (1:40383651 G>A,T), RS1000634222 (1:40357271 A>G,T), RS1000713113 (1:40420565 A>G), RS1000726746 (1:40376557 T>C), RS1000777832 (1:40421995 G>A)

Disease associations

OMIM: gene MIM:616916 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST004485_25	Survival in pancreatic cancer	4.000000e-06
GCST90002395_302	Mean platelet volume	8.000000e-19
GCST90002401_16	Platelet distribution width	9.000000e-11
GCST90002402_543	Platelet count	2.000000e-10

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0000638	overall survival
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
Valproic Acid	affects expression, increases expression	3
Tetrachlorodibenzodioxin	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	increases expression	1
tibolone	increases expression	1
di-n-butylphosphoric acid	affects expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Norethindrone Acetate	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Aspirin	affects response to substance	1
Vehicle Emissions	decreases reaction, increases expression	1
Cisplatin	increases expression	1
Drugs, Chinese Herbal	decreases expression	1
Estradiol	increases expression, affects cotreatment	1
Methylcholanthrene	affects binding, increases reaction	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	increases expression	1
Testosterone	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1
Urethane	increases expression	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0237	Capan-1	Cancer cell line	Male
CVCL_0A59	Capan1M9	Cancer cell line	Male
CVCL_S022	Capan-1 SimpleCell O-GalNAc	Cancer cell line	Male

Clinical trials (associated diseases)

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