SRGAP2C

Summary

SRGAP2C (SLIT-ROBO Rho GTPase activating protein 2C, HGNC:30584) is a protein-coding gene on chromosome 1p11.2, encoding SLIT-ROBO Rho GTPase-activating protein 2C (P0DJJ0). Human-specific protein that acts as a key modifier of cortical connectivity in the human brain.

This locus encodes a member of the SLIT-ROBO Rho GTPase activating protein family. This human-specific locus resulted from segmental duplication of the SLIT-ROBO Rho GTPase activating protein 2B locus. The encoded protein lacks the GTPase activating protein domain compared to proteins encoded by SLIT-ROBO Rho GTPase activating protein 2, and acts antagonistically to these proteins in cortical neuron development.

Source: NCBI Gene 653464 — RefSeq curated summary.

At a glance

• MANE Select transcript: NM_001329984

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30584
Approved symbol	SRGAP2C
Name	SLIT-ROBO Rho GTPase activating protein 2C
Location	1p11.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000171943
Ensembl biotype	protein_coding
OMIM	614704
Entrez	653464

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 4 protein_coding, 3 protein_coding_CDS_not_defined

ENST00000304465, ENST00000367123, ENST00000412759, ENST00000613462, ENST00000617209, ENST00000918137, ENST00000951839

RefSeq mRNA: 2 — MANE Select: NM_001329984 NM_001271872, NM_001329984

CCDS: CCDS81364

Canonical transcript exons

ENST00000367123 — 10 exons

Exon	Start	End
ENSE00001669237	121184975	121185124
ENSE00001748861	121186905	121187513
ENSE00002307331	121365293	121365355
ENSE00003344537	121387634	121392874
ENSE00003590215	121382701	121382925
ENSE00003713101	121386506	121386607
ENSE00003713963	121284803	121284995
ENSE00003729841	121373971	121374186
ENSE00003745469	121324478	121324640
ENSE00003750377	121374826	121374954

Expression profiles

Bgee: expression breadth ubiquitous, 141 present calls, max score 92.05.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 2.8330 / max 54.2742, expressed in 1404 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
201651	2.8330	1404

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	92.05	gold quality
cerebellum	UBERON:0002037	90.56	gold quality
cerebellar cortex	UBERON:0002129	90.52	gold quality
corpus callosum	UBERON:0002336	90.49	gold quality
cerebellar hemisphere	UBERON:0002245	90.41	gold quality
cortical plate	UBERON:0005343	89.58	gold quality
right hemisphere of cerebellum	UBERON:0014890	88.92	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.07	gold quality
ganglionic eminence	UBERON:0004023	87.02	gold quality
embryo	UBERON:0000922	87.01	gold quality
adrenal tissue	UBERON:0018303	86.11	gold quality
nerve	UBERON:0001021	83.92	gold quality
tibial nerve	UBERON:0001323	83.92	gold quality
skin of leg	UBERON:0001511	82.91	gold quality
zone of skin	UBERON:0000014	82.90	gold quality
skin of abdomen	UBERON:0001416	82.71	gold quality
Ammon’s horn	UBERON:0001954	82.38	gold quality
substantia nigra	UBERON:0002038	82.26	gold quality
stromal cell of endometrium	CL:0002255	82.23	gold quality
sural nerve	UBERON:0015488	81.80	gold quality
monocyte	CL:0000576	81.70	gold quality
calcaneal tendon	UBERON:0003701	81.37	gold quality
leukocyte	CL:0000738	81.22	gold quality
temporal lobe	UBERON:0001871	80.98	gold quality
primary visual cortex	UBERON:0002436	80.92	gold quality
amygdala	UBERON:0001876	80.87	gold quality
superior frontal gyrus	UBERON:0002661	80.82	gold quality
islet of Langerhans	UBERON:0000006	80.36	gold quality
brain	UBERON:0000955	80.35	gold quality
prefrontal cortex	UBERON:0000451	80.01	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-119	yes	32.59
E-HCAD-35	yes	32.47
E-HCAD-25	yes	17.67
E-HCAD-10	yes	15.36
E-ANND-3	yes	6.99

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

72 targeting SRGAP2C, 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-4673	100.00	66.64	1490
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-145-5P	99.92	71.13	1836
HSA-MIR-5195-3P	99.92	70.92	1877
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-4799-5P	99.82	70.60	2663
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-4255	99.72	67.70	1541
HSA-MIR-12129	99.72	67.45	1311
HSA-MIR-12124	99.68	69.17	2700
HSA-MIR-4804-3P	99.65	67.78	866
HSA-MIR-5695	99.41	67.48	1047

Literature-anchored findings (GeneRIF, showing 1)

• A human-specific modifier of cortical connectivity and circuit function. (PMID:34707291)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	srgap2	ENSDARG00000032161
mus_musculus	Srgap2	ENSMUSG00000026425
rattus_norvegicus	Srgap2	ENSRNOG00000006733
caenorhabditis_elegans		WBGENE00006406

Paralogs (5): ARHGAP4 (ENSG00000089820), SRGAP3 (ENSG00000196220), SRGAP2B (ENSG00000196369), SRGAP1 (ENSG00000196935), SRGAP2 (ENSG00000266028)

Protein

Protein identifiers

SLIT-ROBO Rho GTPase-activating protein 2C — P0DJJ0 (reviewed: P0DJJ0)

Alternative names: SLIT-ROBO Rho GTPase activating protein 2 pseudogene 1

All UniProt accessions (2): P0DJJ0, A0A087X0L1

UniProt curated annotations — full annotation on UniProt →

Function. Human-specific protein that acts as a key modifier of cortical connectivity in the human brain. Acts by inhibiting the functions of ancestral paralog SRGAP2/SRGAP2A, a postsynaptic protein that regulates excitatory and inhibitory synapse maturation and density in cortical pyramidal neurons. SRGAP2C is unstable but is able to heterodimerize with SRGAP2/SRGAP2A, thereby reducing SRGAP2/SRGAP2A levels through proteasome-dependent degradation. Inhibition of SRGAP2/SRGAP2A by SRGAP2C leads to an increase in synaptic density and protracted synaptic maturation of both excitatory and inhibitory synapses. Modifies cortical circuit connectivity by increasing the number of local and long-range cortical inputs received by layer 2/3 pyramidal neurons. Also able to increase the probability of sensory-evoked responses by layer 2/3 pyramidal neurons.

Subunit / interactions. Homodimer. Interacts (via F-BAR domain) with SRGAP2/SRGAP2A (via F-BAR domain); formation of the heterodimer inhibits SRGAP2/SRGAP2A function.

Tissue specificity. Ubiquitously expressed with higher expression in cerebellum. Probably expressed in fetal and adult neurons (at protein level).

Domain organisation. SRGAP2C is truncated at its C-terminus compared to SRGAP2/SRGAP2A. It only contains an extended F-BAR domain that lacks the last C-terminal 49 amino acids of SRGAP2/SRGAP2A, which are replaced with seven unique C-terminal amino acids. In addition, SRGAP2C acquired a series of unique nonsynonymous base pair mutations selectively targeting five arginine residues compared to SRGAP2B. This truncation and these specific arginine mutations reduce solubility of SRGAP2C and increase its ability to heterodimerize with SRGAP2/SRGAP2A to form an insoluble complex.

Miscellaneous. This is one of the 3 duplications of the ancestral gene SRGAP2/SRGAP2A which has undergone human-specific segmental gene duplications. The appearance of SRGAP2C in the human genome is estimated to 2,4 million years and corresponds to the beginning of neocortex expansion in human evolution. The emergence of SRGAP2C at the birth of the Homo lineage probably contributed to the evolution of specific structural and functional features of cortical circuits in the human cortex. Expression of SRGAP2C in mouse cortical pyramidal neurons leads to the emergence of human-specific traits of synaptic development, characterized by increases in the density of both excitatory and inhibitory synapses received by layer 2/3 pyramidal neurons and neotenic features of excitatory and inhibitory synaptic development. Mice humanized for SRGAP2C expression in all cortical pyramidal neurons show a shift in the fraction of layer 2/3 pyramidal neurons activated by sensory stimulation and an enhanced ability to learn a cortex-dependent sensory-discrimination task.

RefSeq proteins (2): NP_001258801, NP_001316913* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001060	FCH_dom	Domain
IPR027267	AH/BAR_dom_sf	Homologous_superfamily
IPR031160	F_BAR_dom	Domain
IPR051627	SLIT-ROBO_RhoGAP	Family

Pfam: PF00611

UniProt features (11 total): mutagenesis site 5, chain 1, domain 1, sequence conflict 1, region of interest 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P0DJJ0-F1	87.99	0.74

Functional residue map

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

Mutagenesis-validated functional residues (5):

Position	Phenotype
73	does not improve solubility; when associated with r-108, r-205, r-235 and r-250.
108	does not improve solubility; when associated with r-73, r-205, r-235 and r-250.
205	does not improve solubility; when associated with r-73, r-108, r-235 and r-250.
235	does not improve solubility; when associated with r-73, r-108, r-205 and r-250.
250	does not improve solubility; when associated with r-73, r-108, r-205 and r-235.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 126 (showing top): GOBP_DENDRITE_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_DENDRITIC_SPINE_DEVELOPMENT, GOBP_SYNAPSE_ASSEMBLY, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_CELL_JUNCTION_ASSEMBLY, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_FOREBRAIN_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_FOREBRAIN_CELL_MIGRATION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_CELL_JUNCTION_ORGANIZATION, chr1p11, GOBP_TELENCEPHALON_GLIAL_CELL_MIGRATION, GOBP_REGULATION_OF_SYNAPSE_ASSEMBLY

GO Biological Process (10): nervous system development (GO:0007399), extension of a leading process involved in cell motility in cerebral cortex radial glia guided migration (GO:0021816), cerebral cortex development (GO:0021987), negative regulation of cell migration (GO:0030336), negative regulation of filopodium assembly (GO:0051490), regulation of synapse assembly (GO:0051963), negative regulation of dendritic spine development (GO:0061000), excitatory synapse assembly (GO:1904861), inhibitory synapse assembly (GO:1904862), positive regulation of neuron migration (GO:2001224)

GO Molecular Function (3): GTPase activator activity (GO:0005096), protein homodimerization activity (GO:0042803), protein heterodimerization activity (GO:0046982)

GO Cellular Component (2): dendritic spine (GO:0043197), glutamatergic synapse (GO:0098978)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
synapse assembly	3
protein dimerization activity	2
system development	1
modulation of microtubule cytoskeleton involved in cerebral cortex radial glia guided migration	1
pseudopodium assembly	1
pallium development	1
anatomical structure development	1
cell migration	1
regulation of cell migration	1
negative regulation of cell motility	1
filopodium assembly	1
regulation of filopodium assembly	1
negative regulation of plasma membrane bounded cell projection assembly	1
regulation of synapse organization	1
regulation of cell junction assembly	1
negative regulation of developmental process	1
dendritic spine development	1
regulation of dendritic spine development	1
neuron migration	1
positive regulation of cell migration	1
regulation of neuron migration	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
identical protein binding	1
dendrite	1
neuron spine	1
postsynapse	1
synapse	1

Protein interactions and networks

STRING

312 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SRGAP2C	ARHGAP11B	Q3KRB8	720
SRGAP2C	FAM72B	Q86X60	652
SRGAP2C	NOTCH2NLA	Q7Z3S9	541
SRGAP2C	A0A1B0GVM2	A0A1B0GVM2	525
SRGAP2C	FAM72C	H0Y354	518
SRGAP2C	NOTCH2NLB	P0DPK3	516
SRGAP2C	BOLA2	Q9H3K6	502
SRGAP2C	FAM72D	Q6L9T8	459
SRGAP2C	FAM86B2	P0C5J1	431
SRGAP2C	GTF2IRD2B	Q6EKJ0	418
SRGAP2C	GTF2IRD2	Q86UP8	417
SRGAP2C	TSACC	Q96A04	385
SRGAP2C	ARHGAP11A	Q6P4F7	371
SRGAP2C	ARHGEF35	A5YM69	366
SRGAP2C	MCPH1	Q8NEM0	358

IntAct

3 interactions, top by confidence:

A	B	Type	Score
SRGAP2	SRGAP2C	psi-mi:“MI:0915”(physical association)	0.400
SRGAP2C	SRGAP2C	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (13): SRGAP2C (Affinity Capture-MS), SRGAP2 (Cross-Linking-MS (XL-MS)), SRGAP2C (Co-fractionation), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS), SRGAP2C (Proximity Label-MS)

ESM2 similar proteins: A1XBS5, B0S6J3, D4A208, O35180, O35964, O43295, O75044, P0DJJ0, P0DMP2, P25343, Q08DK5, Q15057, Q1LU86, Q1RMK1, Q2VR06, Q32LM0, Q3SZG6, Q3V2J0, Q5AFE4, Q5FVC7, Q5PPJ9, Q5PPZ5, Q5R8P5, Q5ZIR1, Q5ZJ81, Q5ZK62, Q62419, Q62421, Q68FW8, Q6AYE2, Q6GN09, Q6IVG4, Q6ZQK5, Q6ZTR7, Q7Z6B7, Q812A2, Q8AXU9, Q8BP22, Q8I190, Q8I1C0

Diamond homologs: A0JNB0, A1A5H8, A1Y2K1, A7A261, B0S6J3, B1V8A0, D4A208, F1LM93, F1LXF1, F1RDG9, O35413, O43295, O75044, O94875, P00523, P00525, P05480, P06241, P07947, P09324, P09769, P0DJJ0, P0DMP2, P10936, P11274, P12931, P13115, P13116, P13406, P14084, P14085, P15054, P15882, P19706, P27446, P27447, P30337, P32793, P39688, P42686

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3098 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:121284881:T:C	L49P	0.995
1:121382878:T:C	F337L	0.993
1:121382880:C:A	F337L	0.993
1:121382880:C:G	F337L	0.993
1:121386567:T:C	L373P	0.992
1:121382732:T:C	L288P	0.990
1:121324512:T:A	W99R	0.989
1:121324512:T:C	W99R	0.989
1:121382902:T:C	F345L	0.989
1:121382904:T:A	F345L	0.989
1:121382904:T:G	F345L	0.989
1:121387712:T:C	F413L	0.989
1:121387714:C:A	F413L	0.989
1:121387714:C:G	F413L	0.989
1:121382744:T:C	L292P	0.988
1:121387820:T:C	F449L	0.988
1:121387822:T:A	F449L	0.988
1:121387822:T:G	F449L	0.988
1:121284904:G:C	A57P	0.985
1:121284925:T:C	S64P	0.985
1:121284889:T:C	F52L	0.984
1:121284891:C:A	F52L	0.984
1:121284891:C:G	F52L	0.984
1:121387789:G:C	K438N	0.984
1:121387789:G:T	K438N	0.984
1:121284869:T:C	L45P	0.983
1:121284935:T:C	L67P	0.983
1:121382896:T:C	F343L	0.981
1:121382898:T:A	F343L	0.981
1:121382898:T:G	F343L	0.981

dbSNP variants (sampled 300 via entrez): RS1040707 (1:121200198 A>G), RS1046102 (1:121391515 A>G,T), RS1046103 (1:121391531 T>C), RS1048832 (1:121389148 G>A,T), RS1048833 (1:121389093 C>A,T), RS1055121 (1:121376968 G>A), RS1055124 (1:121377057 T>C), RS1060483 (1:121390518 C>G,T), RS1062231 (1:121389972 T>C), RS10706592 (1:121205906 TAA>T,TA,TAAA), RS10717526 (1:121209556 TC>T), RS10736939 (1:121210607 T>A), RS10751781 (1:121267321 A>G), RS10794690 (1:121229224 C>A,T), RS10903166 (1:121368178 C>A,G,T)

Disease associations

OMIM: gene MIM:614704 | 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

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
Valproic Acid	increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
aristolochic acid I	decreases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
methacrylaldehyde	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Acrolein	affects cotreatment, decreases expression, increases abundance	1
Air Pollutants	affects cotreatment, decreases expression, increases abundance	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Dietary Carbohydrates	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Methyl Methanesulfonate	increases expression	1
Ozone	decreases expression, increases abundance, affects cotreatment	1
Sodium Dodecyl Sulfate	decreases expression	1
Dronabinol	increases expression	1
S-Nitrosoglutathione	decreases expression	1
Volatile Organic Compounds	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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