SERGEF

Summary

SERGEF (secretion regulating guanine nucleotide exchange factor, HGNC:17499) is a protein-coding gene on chromosome 11p15.1, encoding Secretion-regulating guanine nucleotide exchange factor (Q9UGK8). Probable guanine nucleotide exchange factor (GEF), which may be involved in the secretion process.

Predicted to enable guanyl-nucleotide exchange factor activity. Involved in negative regulation of protein secretion. Located in cytosol and nucleoplasm. Biomarker of atherosclerosis.

Source: NCBI Gene 26297 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 71 total
• MANE Select transcript: NM_012139

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17499
Approved symbol	SERGEF
Name	secretion regulating guanine nucleotide exchange factor
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	DelGEF, Gnefr
Ensembl gene	ENSG00000129158
Ensembl biotype	protein_coding
OMIM	606051
Entrez	26297

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 14 protein_coding, 8 protein_coding_CDS_not_defined, 6 nonsense_mediated_decay

ENST00000265965, ENST00000524589, ENST00000524716, ENST00000525168, ENST00000525422, ENST00000525920, ENST00000527494, ENST00000528200, ENST00000528369, ENST00000529151, ENST00000529440, ENST00000529728, ENST00000530613, ENST00000530925, ENST00000530951, ENST00000531299, ENST00000531926, ENST00000532212, ENST00000532265, ENST00000532389, ENST00000532546, ENST00000533241, ENST00000533328, ENST00000851625, ENST00000851626, ENST00000851627, ENST00000921620, ENST00000942383

RefSeq mRNA: 1 — MANE Select: NM_012139 NM_012139

CCDS: CCDS7828

Canonical transcript exons

ENST00000265965 — 11 exons

Exon	Start	End
ENSE00000886535	17959470	17959636
ENSE00001128900	18012951	18013047
ENSE00003529895	18000497	18000557
ENSE00003573571	17988597	17988755
ENSE00003589199	17878208	17878244
ENSE00003619667	17995796	17995909
ENSE00003626434	17992931	17992993
ENSE00003659577	17788048	17788413
ENSE00003661766	18007941	18008076
ENSE00003664068	18004441	18004535
ENSE00003689096	18006591	18006746

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 97.62.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 8.3778 / max 100.8958, expressed in 1776 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118882	4.7348	1701
118880	3.0536	1327
118883	0.2627	103
118881	0.1665	58
118884	0.1458	66
118875	0.0145	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	97.62	gold quality
anterior cingulate cortex	UBERON:0009835	97.58	gold quality
cingulate cortex	UBERON:0003027	97.47	gold quality
cerebellar hemisphere	UBERON:0002245	97.22	gold quality
cerebellar cortex	UBERON:0002129	97.15	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.14	gold quality
adenohypophysis	UBERON:0002196	96.60	gold quality
amygdala	UBERON:0001876	96.13	gold quality
prefrontal cortex	UBERON:0000451	95.79	gold quality
pituitary gland	UBERON:0000007	95.67	gold quality
cerebellum	UBERON:0002037	95.63	gold quality
nucleus accumbens	UBERON:0001882	95.60	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	95.13	gold quality
ascending aorta	UBERON:0001496	95.12	gold quality
caudate nucleus	UBERON:0001873	95.12	gold quality
thoracic aorta	UBERON:0001515	95.06	gold quality
right lobe of thyroid gland	UBERON:0001119	94.93	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.89	gold quality
left lobe of thyroid gland	UBERON:0001120	94.84	gold quality
aorta	UBERON:0000947	94.64	gold quality
popliteal artery	UBERON:0002250	94.45	gold quality
tibial artery	UBERON:0007610	94.45	gold quality
descending thoracic aorta	UBERON:0002345	94.33	gold quality
putamen	UBERON:0001874	94.27	gold quality
neocortex	UBERON:0001950	94.10	gold quality
thyroid gland	UBERON:0002046	94.03	gold quality
frontal cortex	UBERON:0001870	93.80	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.71	gold quality
left coronary artery	UBERON:0001626	93.64	gold quality
right coronary artery	UBERON:0001625	93.41	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.38
E-GEOD-75367	no	290.76

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 1)

• DelGEF binds to the human homologue of Sec5 and modulates secretion. (PMID:12459492)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	sergef	ENSDARG00000070986
mus_musculus	Sergef	ENSMUSG00000030839
rattus_norvegicus	Sergef	ENSRNOG00000011488
drosophila_melanogaster	ca	FBGN0000247
drosophila_melanogaster	Rcc1	FBGN0002638
drosophila_melanogaster	CG7420	FBGN0031344
caenorhabditis_elegans		WBGENE00004304

Paralogs (9): ALS2 (ENSG00000003393), HERC1 (ENSG00000103657), RCBTB1 (ENSG00000136144), RCBTB2 (ENSG00000136161), RPGR (ENSG00000156313), RCCD1 (ENSG00000166965), RCC2 (ENSG00000179051), RCC1 (ENSG00000180198), RCC1L (ENSG00000274523)

Protein

Protein identifiers

Secretion-regulating guanine nucleotide exchange factor — Q9UGK8 (reviewed: Q9UGK8)

Alternative names: Deafness locus-associated putative guanine nucleotide exchange factor, Guanine nucleotide exchange factor-related protein

All UniProt accessions (14): Q9UGK8, B4DFC0, E9PIU4, E9PIV0, E9PL52, E9PMV6, E9PR50, E9PS70, G3V1B4, H0YD20, H0YDC8, H0YE53, H0YEL8, H0YEV5

UniProt curated annotations — full annotation on UniProt →

Function. Probable guanine nucleotide exchange factor (GEF), which may be involved in the secretion process.

Subunit / interactions. Interacts with SEC5. The interaction occurs only in the presence of magnesium or manganese and is stimulated by dCTP or GTP.

Subcellular location. Cytoplasm. Nucleus.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UGK8-1	1, DelGEF1	yes
Q9UGK8-2	2, DelGEF2

RefSeq proteins (1): NP_036271* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000408	Reg_chr_condens	Repeat
IPR009091	RCC1/BLIP-II	Homologous_superfamily
IPR051625	Signaling_Regulatory_Domain	Family
IPR058923	RCC1-like_dom	Domain

Pfam: PF25390

UniProt features (15 total): repeat 7, splice variant 2, sequence variant 2, chain 1, modified residue 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UGK8-F1	84.61	0.72

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): 427

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 65 (showing top): MENSE_HYPOXIA_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_REGULATION_OF_PROTEIN_SECRETION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION, GOBP_NEGATIVE_REGULATION_OF_SECRETION, GOBP_SECRETION, GOBP_REGULATION_OF_TRANSPORT, MODULE_95, PARENT_MTOR_SIGNALING_UP, GOMF_GUANYL_NUCLEOTIDE_EXCHANGE_FACTOR_ACTIVITY, BLALOCK_ALZHEIMERS_DISEASE_DN, GOMF_NUCLEOSIDE_TRIPHOSPHATASE_REGULATOR_ACTIVITY, GOMF_ENZYME_REGULATOR_ACTIVITY

GO Biological Process (2): signal transduction (GO:0007165), negative regulation of protein secretion (GO:0050709)

GO Molecular Function (2): guanyl-nucleotide exchange factor activity (GO:0005085), protein binding (GO:0005515)

GO Cellular Component (4): nucleus (GO:0005634), 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
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein secretion	1
regulation of protein secretion	1
negative regulation of protein transport	1
negative regulation of secretion by cell	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

838 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SERGEF	DPH3	Q96FX2	968
SERGEF	EXOC2	Q96KP1	814
SERGEF	E9PNW1	E9PNW1	766
SERGEF	EEF2	P13639	666
SERGEF	RABIF	P47224	573
SERGEF	HEATR9	A2RTY3	572
SERGEF	DPH2	Q9BQC3	539
SERGEF	DPH1	Q9BZG8	530
SERGEF	VMA22	Q96NT0	513
SERGEF	EDNRA	P25101	512
SERGEF	TMEM19	Q96HH6	496
SERGEF	OTOG	Q6ZRI0	491
SERGEF	ZFC3H1	O60293	487
SERGEF	DPH7	Q9BTV6	473
SERGEF	RPS13	P19116	467

IntAct

31 interactions, top by confidence:

A	B	Type	Score
DPH3	SERGEF	psi-mi:“MI:0915”(physical association)	0.820
SERGEF	DPH3	psi-mi:“MI:0915”(physical association)	0.820
HGS	SERGEF	psi-mi:“MI:0915”(physical association)	0.560
FOXH1	SERGEF	psi-mi:“MI:0915”(physical association)	0.560
SPAG8	SERGEF	psi-mi:“MI:0915”(physical association)	0.560
PITX1	SERGEF	psi-mi:“MI:0915”(physical association)	0.560
DPH3	ATE1	psi-mi:“MI:0914”(association)	0.530
BLOC1S5	SNAPIN	psi-mi:“MI:0914”(association)	0.530
KDM1A	SERGEF	psi-mi:“MI:0915”(physical association)	0.510
SERGEF	PRMT6	psi-mi:“MI:0915”(physical association)	0.510
EXOC2	SERGEF	psi-mi:“MI:0915”(physical association)	0.400
NUDCD2	SERGEF	psi-mi:“MI:0915”(physical association)	0.400
PLXNB2	C2CD4B	psi-mi:“MI:0914”(association)	0.350
BFAR	PHYKPL	psi-mi:“MI:0914”(association)	0.350
HGS	SERGEF	psi-mi:“MI:0915”(physical association)	0.000
FOXH1	SERGEF	psi-mi:“MI:0915”(physical association)	0.000
SPAG8	SERGEF	psi-mi:“MI:0915”(physical association)	0.000
PITX1	SERGEF	psi-mi:“MI:0915”(physical association)	0.000
DPH3	SERGEF	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (20): SERGEF (Affinity Capture-MS), SERGEF (Two-hybrid), SPAG8 (Two-hybrid), DPH3 (Two-hybrid), FOXH1 (Two-hybrid), HGS (Two-hybrid), SERGEF (Affinity Capture-RNA), EXOC2 (Two-hybrid), EXOC2 (Reconstituted Complex), SERGEF (Affinity Capture-MS), SERGEF (Affinity Capture-MS), SERGEF (Affinity Capture-MS), SERGEF (Affinity Capture-MS), SERGEF (Co-fractionation), SERGEF (Co-fractionation)

ESM2 similar proteins: A0A0U1RPR8, A0A7N9VSG0, D3ZGQ5, D3ZHP7, O08644, O09127, O15197, O43542, O73875, O73878, O75676, P0C0K6, P0C0K7, P21709, P23800, P29317, P29322, P41243, P51839, P51840, P52785, P54753, P54754, P54760, P54761, P55203, P57078, P97343, Q1KL86, Q3U3Q1, Q4V7Q6, Q5RCY1, Q5ZJH6, Q60750, Q62270, Q63285, Q6PHR2, Q7ZZC8, Q80YD6, Q86SG6

Diamond homologs: A6NED2, D3ZGQ5, F1RD40, O75592, O95199, O95714, P0C5Y8, P18754, P23800, P25171, P25183, P58544, Q15034, Q15751, Q4R828, Q4U2R1, Q52KW8, Q5BIW4, Q5DX34, Q5GLZ8, Q5PQN1, Q5RCZ7, Q6NRS1, Q6NXM2, Q6NYE2, Q6PAV2, Q6ZPR6, Q7TPH6, Q7ZZC8, Q86SG6, Q8BK67, Q8BTU7, Q8IVU3, Q8K1R7, Q8K2J9, Q8NDN9, Q8SSY6, Q8TD19, Q8VE37, Q90XC2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	59
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

3896 predictions. Top by Δscore:

Variant	Effect	Δscore
11:17878203:CTTA:C	donor_loss	1.0000
11:17878205:TACCA:T	donor_loss	1.0000
11:17878206:A:AC	donor_gain	1.0000
11:17878206:ACCAA:A	donor_loss	1.0000
11:17878207:C:CA	donor_loss	1.0000
11:17878207:C:CC	donor_gain	1.0000
11:17995915:C:CT	acceptor_gain	1.0000
11:17995915:C:T	acceptor_gain	1.0000
11:17995916:A:T	acceptor_gain	1.0000
11:17995918:C:CT	acceptor_gain	1.0000
11:17995919:A:T	acceptor_gain	1.0000
11:17995922:A:AC	acceptor_gain	1.0000
11:17995922:A:C	acceptor_gain	1.0000
11:18004532:TTTT:T	acceptor_gain	1.0000
11:18006744:CAT:C	acceptor_gain	1.0000
11:18006747:C:CC	acceptor_gain	1.0000
11:18006748:T:C	acceptor_loss	1.0000
11:18012949:AC:A	donor_gain	1.0000
11:18012950:CC:C	donor_gain	1.0000
11:17878207:CCA:C	donor_gain	0.9900
11:17878207:CCAA:C	donor_gain	0.9900
11:17878244:CCTG:C	acceptor_loss	0.9900
11:17878245:C:CA	acceptor_loss	0.9900
11:17878245:C:CC	acceptor_gain	0.9900
11:17878246:T:A	acceptor_loss	0.9900
11:17992926:CCTA:C	donor_loss	0.9900
11:17992928:TAC:T	donor_loss	0.9900
11:17992929:ACCTG:A	donor_loss	0.9900
11:17992930:C:CA	donor_loss	0.9900
11:17992991:GACC:G	acceptor_loss	0.9900

AlphaMissense

2951 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:17995889:A:G	W177R	0.996
11:17995889:A:T	W177R	0.996
11:18004511:C:T	G126E	0.994
11:17788386:T:A	N359I	0.993
11:18006607:A:C	F112L	0.993
11:18006607:A:T	F112L	0.993
11:18006609:A:G	F112L	0.993
11:17988735:A:G	W236R	0.991
11:17988735:A:T	W236R	0.991
11:18008076:C:G	G21R	0.991
11:17788396:A:G	W356R	0.989
11:17788396:A:T	W356R	0.989
11:18006722:C:T	G74D	0.989
11:18008076:C:A	G21C	0.988
11:17959616:A:G	W289R	0.987
11:17959616:A:T	W289R	0.987
11:17995886:C:A	G178W	0.987
11:18008068:A:C	N23K	0.987
11:18008068:A:T	N23K	0.987
11:18008075:C:T	G21D	0.987
11:17788385:A:C	N359K	0.985
11:17788385:A:T	N359K	0.985
11:17878221:A:C	N345K	0.985
11:17878221:A:T	N345K	0.985
11:18006716:T:A	N76I	0.985
11:18008069:T:A	N23I	0.985
11:17788393:C:G	G357R	0.984
11:17988731:C:T	G237E	0.984
11:18007956:A:G	S61P	0.984
11:17995885:C:T	G178E	0.983

dbSNP variants (sampled 300 via entrez): RS1000009389 (11:17939362 A>G), RS1000015826 (11:17961336 G>A,T), RS1000021237 (11:18007844 C>G), RS1000035148 (11:17846607 G>A), RS1000040837 (11:17812504 G>A), RS1000042935 (11:17997221 T>C), RS1000057581 (11:17845188 G>A), RS1000068302 (11:17973555 G>A), RS1000082674 (11:17800890 G>A), RS1000087127 (11:17846961 C>A,G,T), RS1000087498 (11:17911930 T>C), RS1000090621 (11:17960994 C>T), RS1000092379 (11:17804926 A>C), RS1000101793 (11:17901410 A>G), RS1000144011 (11:17919109 T>G)

Disease associations

OMIM: gene MIM:606051 | 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
GCST005951_67	Body mass index	6.000000e-09
GCST005951_68	Body mass index	3.000000e-09
GCST007328_52	Alcohol consumption (drinks per week)	3.000000e-08
GCST012306_9	Bipolar disorder	2.000000e-07

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance	3
Benzo(a)pyrene	decreases expression, increases methylation	3
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	3
trichostatin A	affects cotreatment, decreases expression	2
Arsenic	affects methylation, affects cotreatment, decreases expression, increases abundance	2
Tetrachlorodibenzodioxin	increases expression	2
aristolochic acid I	decreases expression	1
dicrotophos	decreases expression	1
bisphenol A	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
dorsomorphin	decreases expression, affects cotreatment	1
(+)-JQ1 compound	decreases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	decreases expression	1
Vehicle Emissions	increases abundance, increases expression	1
Catechin	affects cotreatment, decreases expression	1
Estradiol	decreases expression	1
Formaldehyde	decreases expression	1
Hydrogen Peroxide	affects expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1
Silicon Dioxide	decreases expression	1
Tretinoin	increases expression	1
Valproic Acid	decreases methylation	1
Antirheumatic Agents	increases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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