PSD4

Summary

PSD4 (pleckstrin and Sec7 domain containing 4, HGNC:19096) is a protein-coding gene on chromosome 2q14.1, encoding PH and SEC7 domain-containing protein 4 (Q8NDX1). Guanine nucleotide exchange factor for ARF6 and ARL14/ARF7.

Predicted to enable guanyl-nucleotide exchange factor activity and phospholipid binding activity. Predicted to be involved in regulation of ARF protein signal transduction. Located in ruffle membrane.

Source: NCBI Gene 23550 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 148 total
• MANE Select transcript: NM_012455

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19096
Approved symbol	PSD4
Name	pleckstrin and Sec7 domain containing 4
Location	2q14.1
Locus type	gene with protein product
Status	Approved
Aliases	TIC, EFA6B
Ensembl gene	ENSG00000125637
Ensembl biotype	protein_coding
OMIM	614442
Entrez	23550

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 7 protein_coding, 6 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000245796, ENST00000409378, ENST00000409656, ENST00000418251, ENST00000441564, ENST00000460725, ENST00000464559, ENST00000465592, ENST00000465917, ENST00000485525, ENST00000487574, ENST00000493329, ENST00000893513, ENST00000893514, ENST00000893515, ENST00000957718

RefSeq mRNA: 1 — MANE Select: NM_012455 NM_012455

CCDS: CCDS33276

Canonical transcript exons

ENST00000245796 — 17 exons

Exon	Start	End
ENSE00000856891	113201158	113209391
ENSE00001144814	113185877	113186255
ENSE00001799051	113185365	113185440
ENSE00001921144	113173971	113174054
ENSE00003469900	113197564	113197634
ENSE00003473877	113184957	113185073
ENSE00003486756	113197747	113197913
ENSE00003491221	113193592	113193650
ENSE00003534064	113192380	113192589
ENSE00003548498	113199083	113199226
ENSE00003558435	113193258	113193370
ENSE00003619895	113195727	113195770
ENSE00003623887	113182346	113183512
ENSE00003642357	113193048	113193128
ENSE00003652035	113198740	113198884
ENSE00003662962	113196147	113196307
ENSE00003668347	113193859	113193948

Expression profiles

Bgee: expression breadth ubiquitous, 223 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.1111 / max 254.6712, expressed in 1468 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
22136	12.7997	592
22134	6.0804	1141
22139	1.7359	612
22140	0.2877	140
22135	0.2074	115

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	97.60	gold quality
right lobe of liver	UBERON:0001114	94.58	gold quality
blood	UBERON:0000178	94.47	gold quality
spleen	UBERON:0002106	93.17	gold quality
right adrenal gland cortex	UBERON:0035827	91.89	gold quality
right adrenal gland	UBERON:0001233	91.88	gold quality
leukocyte	CL:0000738	91.73	gold quality
monocyte	CL:0000576	91.57	gold quality
mononuclear cell	CL:0000842	91.39	gold quality
lymph node	UBERON:0000029	91.39	gold quality
left adrenal gland cortex	UBERON:0035825	90.76	gold quality
left adrenal gland	UBERON:0001234	90.70	gold quality
tonsil	UBERON:0002372	90.67	gold quality
right lobe of thyroid gland	UBERON:0001119	90.63	gold quality
vermiform appendix	UBERON:0001154	90.10	gold quality
bone marrow cell	CL:0002092	90.05	gold quality
lower esophagus mucosa	UBERON:0035834	89.96	gold quality
left lobe of thyroid gland	UBERON:0001120	89.80	gold quality
small intestine Peyer’s patch	UBERON:0003454	89.54	gold quality
adrenal cortex	UBERON:0001235	89.33	gold quality
mucosa of transverse colon	UBERON:0004991	89.27	gold quality
thyroid gland	UBERON:0002046	88.93	gold quality
adrenal gland	UBERON:0002369	88.71	gold quality
saliva-secreting gland	UBERON:0001044	88.08	gold quality
minor salivary gland	UBERON:0001830	88.00	gold quality
body of pancreas	UBERON:0001150	87.66	gold quality
esophagus mucosa	UBERON:0002469	87.50	gold quality
small intestine	UBERON:0002108	87.44	gold quality
liver	UBERON:0002107	87.18	gold quality
body of stomach	UBERON:0001161	86.83	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.30
E-GEOD-110499	no	800.89

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GATA2

miRNA regulators (miRDB)

56 targeting PSD4, 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-8485	100.00	77.57	4731
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-22-3P	99.93	68.13	917
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-3614-5P	99.30	65.25	837
HSA-MIR-593-3P	99.22	67.28	1327
HSA-MIR-6510-5P	99.14	66.59	1081
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-3619-5P	99.00	68.87	2308

Literature-anchored findings (GeneRIF, showing 5)

• One of the cytohesin family of guanine nucleotide exchange factors, Tic may act on the ARF family of GTP-binding proteins. A PH domain with similar sequence and relative position to those in other cytohesins may allow association with phosphoinositides. (PMID:11050434)
• results identify EFA6B as a novel antagonist in breast cancer and they point to its regulatory and signaling pathways as rational therapeutic targets in aggressive forms of this disease (PMID:25115298)
• EFA6B regulates a stop signal for collective invasion in breast cancer. (PMID:33850160)
• TNF-alpha/NF-kappaB signaling epigenetically represses PSD4 transcription to promote alcohol-related hepatocellular carcinoma progression. (PMID:33932127)
• DDR1 promotes hepatocellular carcinoma metastasis through recruiting PSD4 to ARF6. (PMID:35140331)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
mus_musculus	Psd4	ENSMUSG00000026979
rattus_norvegicus	Psd4	ENSRNOG00000006079
drosophila_melanogaster	siz	FBGN0026179
drosophila_melanogaster	Sec71	FBGN0028538
drosophila_melanogaster	garz	FBGN0264560
caenorhabditis_elegans		WBGENE00007703
caenorhabditis_elegans		WBGENE00008685
caenorhabditis_elegans	agef-1	WBGENE00012386

Paralogs (15): CYTH3 (ENSG00000008256), PSD (ENSG00000059915), MON2 (ENSG00000061987), ARFGEF1 (ENSG00000066777), CYTH4 (ENSG00000100055), CYTH2 (ENSG00000105443), GBF1 (ENSG00000107862), CYTH1 (ENSG00000108669), IQSEC3 (ENSG00000120645), ARFGEF2 (ENSG00000124198), IQSEC2 (ENSG00000124313), IQSEC1 (ENSG00000144711), PSD2 (ENSG00000146005), PSD3 (ENSG00000156011), FBXO8 (ENSG00000164117)

Protein

Protein identifiers

PH and SEC7 domain-containing protein 4 — Q8NDX1 (reviewed: Q8NDX1)

Alternative names: Exchange factor for ADP-ribosylation factor guanine nucleotide factor 6 B, Pleckstrin homology and SEC7 domain-containing protein 4, Telomeric of interleukin-1 cluster protein

All UniProt accessions (3): B8ZZZ5, Q8NDX1, H7BZ06

UniProt curated annotations — full annotation on UniProt →

Function. Guanine nucleotide exchange factor for ARF6 and ARL14/ARF7. Through ARL14 activation, controls the movement of MHC class II-containing vesicles along the actin cytoskeleton in dendritic cells. Involved in membrane recycling. Interacts with several phosphatidylinositol phosphate species, including phosphatidylinositol 3,4-bisphosphate, phosphatidylinositol 3,5-bisphosphate and phosphatidylinositol 4,5-bisphosphate.

Subcellular location. Cell membrane. Cell projection. Ruffle membrane.

Tissue specificity. Widely expressed. Highest levels of expression are found in placenta, pancreas, spleen, thymus and peripheral blood.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NDX1-1	1	yes
Q8NDX1-2	2

RefSeq proteins (1): NP_036587* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000904	Sec7_dom	Domain
IPR001605	PH_dom-spectrin-type	Domain
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR023394	Sec7_C_sf	Homologous_superfamily
IPR035999	Sec7_dom_sf	Homologous_superfamily
IPR041681	PH_9	Domain

Pfam: PF01369, PF15410

UniProt features (43 total): compositionally biased region 11, modified residue 9, region of interest 7, sequence variant 5, sequence conflict 5, domain 2, splice variant 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NDX1-F1	55.88	0.22

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 (9): 131, 134, 143, 413, 448, 469, 491, 1019, 1022

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 162 (showing top): MODULE_45, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, LANG_MYB_FAMILY_TARGETS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_RUFFLE, MODULE_16, WEI_MYCN_TARGETS_WITH_E_BOX, RICKMAN_METASTASIS_DN, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, GATA3_01, ROZANOV_MMP14_TARGETS_UP, BLALOCK_ALZHEIMERS_DISEASE_UP, GATA6_01, GATA1_04, MODULE_88

GO Biological Process (1): regulation of ARF protein signal transduction (GO:0032012)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), phospholipid binding (GO:0005543), protein binding (GO:0005515), lipid binding (GO:0008289)

GO Cellular Component (4): membrane (GO:0016020), ruffle membrane (GO:0032587), plasma membrane (GO:0005886), cell projection (GO:0042995)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
binding	2
cellular anatomical structure	2
ARF protein signal transduction	1
regulation of small GTPase mediated signal transduction	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
lipid binding	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

618 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PSD4	ARL14	Q8N4G2	642
PSD4	ARF6	P26438	622
PSD4	NUMB	P49757	456
PSD4	AP3M1	Q9Y2T2	455
PSD4	NUMBL	Q9Y6R0	429
PSD4	ARFRP1	Q13795	421
PSD4	AGBL2	Q5U5Z8	415
PSD4	CHAMP1	Q96JM3	412
PSD4	GLYATL1	Q969I3	384
PSD4	RABIF	P47224	378
PSD4	ARF1	P10947	341
PSD4	DDX52	Q9Y2R4	341
PSD4	IL1F10	Q8WWZ1	337
PSD4	MRPL44	Q9H9J2	333
PSD4	ARL11	Q969Q4	329

IntAct

17 interactions, top by confidence:

A	B	Type	Score
PSD4	ARL14	psi-mi:“MI:0407”(direct interaction)	0.440
ARF6	PSD4	psi-mi:“MI:0407”(direct interaction)	0.440
	PSD4	psi-mi:“MI:0407”(direct interaction)	0.440
PSD4	TYMS	psi-mi:“MI:0914”(association)	0.350
PSD4	BCR	psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
SUPV3L1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAG	RPSA2	psi-mi:“MI:2364”(proximity)	0.270
DDX6	RPSA2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (26): PSD4 (Two-hybrid), PSD4 (Proximity Label-MS), PSD4 (Affinity Capture-MS), LDLRAP1 (Two-hybrid), PSD4 (Affinity Capture-RNA), BCR (Affinity Capture-MS), TYMS (Affinity Capture-MS), GULP1 (Affinity Capture-MS), THNSL1 (Affinity Capture-MS), GLB1 (Affinity Capture-MS), SNX17 (Affinity Capture-MS), EIF3M (Affinity Capture-MS), LDLRAP1 (Affinity Capture-MS), ACAD11 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS)

ESM2 similar proteins: A0A087WVF3, A0A087WXS9, A0A087X179, A0A087X1G2, A6NDS4, A6NER0, A6QPT6, B9A6J9, M3WHG5, O14771, O15482, O15553, O19110, O76081, P0C7X1, P0C7X3, P0C7X4, P35125, P48778, P48967, P79209, Q13670, Q15697, Q2TBC4, Q3T191, Q3UZD7, Q4R2Z8, Q5DRQ5, Q5SSQ6, Q5XFX8, Q69ZB3, Q6DHY5, Q6IPX1, Q6ZMN8, Q8BLR5, Q8BWA8, Q8IYF1, Q8IZP1, Q8JZW5, Q8N7G0

Diamond homologs: A0A0G2JUG7, A2A5R2, A5PKW4, D4A631, E1JIT7, F1MUS9, F4IXW2, F4JN05, F4JSZ5, F4K2K3, G3X9K3, G5EET6, O08967, O13690, O13817, O43739, O46382, P11075, P34512, P39993, P47102, P63034, P63035, P97694, P97696, Q10491, Q15438, Q2KI41, Q2PFD7, Q3TES0, Q42510, Q54KA7, Q5DTT2, Q5DU25, Q5E9G6, Q5JU85, Q6DFZ1, Q6DN90, Q6P1I6, Q76M68

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	121
Likely benign	10
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2432 predictions. Top by Δscore:

Variant	Effect	Δscore
2:113193367:G:GG	donor_gain	1.0000
2:113193850:T:TA	acceptor_gain	1.0000
2:113193853:CTACA:C	acceptor_loss	1.0000
2:113193854:TACAG:T	acceptor_loss	1.0000
2:113193855:ACAGA:A	acceptor_loss	1.0000
2:113193856:CAGA:C	acceptor_loss	1.0000
2:113193857:A:AG	acceptor_gain	1.0000
2:113193857:AG:A	acceptor_loss	1.0000
2:113193858:G:GG	acceptor_gain	1.0000
2:113195766:GCCGT:G	donor_gain	1.0000
2:113195769:GT:G	donor_gain	1.0000
2:113195771:G:GG	donor_gain	1.0000
2:113195775:G:GG	donor_gain	1.0000
2:113196142:TTCA:T	acceptor_loss	1.0000
2:113196143:TCAGG:T	acceptor_loss	1.0000
2:113196144:CA:C	acceptor_loss	1.0000
2:113196145:AG:A	acceptor_gain	1.0000
2:113196146:GG:G	acceptor_gain	1.0000
2:113196146:GGGAT:G	acceptor_gain	1.0000
2:113196303:GAAGA:G	donor_gain	1.0000
2:113196304:AAGA:A	donor_gain	1.0000
2:113196304:AAGAG:A	donor_loss	1.0000
2:113196305:AGA:A	donor_gain	1.0000
2:113196305:AGAG:A	donor_loss	1.0000
2:113196306:GA:G	donor_gain	1.0000
2:113196306:GAG:G	donor_gain	1.0000
2:113196307:AG:A	donor_loss	1.0000
2:113196308:G:GG	donor_gain	1.0000
2:113196309:TGAG:T	donor_loss	1.0000
2:113196310:GAGT:G	donor_loss	1.0000

AlphaMissense

6882 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:113197584:T:A	W803R	0.999
2:113197584:T:C	W803R	0.999
2:113198762:T:A	W883R	0.999
2:113198762:T:C	W883R	0.999
2:113193890:T:C	F708S	0.998
2:113197586:G:C	W803C	0.998
2:113197586:G:T	W803C	0.998
2:113201365:C:A	R1041S	0.998
2:113193308:G:C	R657P	0.997
2:113193625:T:C	L689P	0.997
2:113193628:T:C	L690P	0.997
2:113196279:A:C	K786N	0.997
2:113196279:A:T	K786N	0.997
2:113197868:T:C	F860S	0.997
2:113197874:T:C	L862P	0.997
2:113201302:A:C	S1020R	0.997
2:113201304:C:A	S1020R	0.997
2:113201304:C:G	S1020R	0.997
2:113201350:C:A	R1036S	0.997
2:113193302:G:C	R655P	0.996
2:113193640:T:C	L694P	0.996
2:113193889:T:C	F708L	0.996
2:113193891:C:A	F708L	0.996
2:113193891:C:G	F708L	0.996
2:113197865:T:A	V859D	0.996
2:113198790:C:A	A892D	0.996
2:113193902:T:C	L712P	0.995
2:113197829:C:A	A847D	0.995
2:113198840:T:C	F909L	0.995
2:113198842:C:A	F909L	0.995

dbSNP variants (sampled 300 via entrez): RS1000103257 (2:113190689 A>G), RS1000187401 (2:113197454 G>A,C), RS1000197740 (2:113199345 CG>C), RS1000347693 (2:113175115 G>A), RS1000377450 (2:113191496 T>C), RS1000629169 (2:113173722 G>A), RS1000677995 (2:113202319 C>A), RS1000709983 (2:113202646 G>A), RS1000728948 (2:113197084 T>C,G), RS1000780969 (2:113174929 C>T), RS1000845349 (2:113209433 G>C), RS1001130004 (2:113179574 C>G,T), RS1001140956 (2:113199076 C>A,G,T), RS1001153038 (2:113185516 C>A,T), RS1001190455 (2:113178134 C>T)

Disease associations

OMIM: gene MIM:614442 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST004531_1	Diastolic blood pressure	3.000000e-08
GCST004601_33	Red blood cell count	4.000000e-19
GCST004604_78	Hematocrit	8.000000e-20
GCST004615_4	Hemoglobin concentration	1.000000e-17
GCST005984_4	Glomerular filtration rate	2.000000e-15
GCST005985_5	Creatinine levels	5.000000e-14
GCST007344_107	Estimated glomerular filtration rate	8.000000e-15
GCST008058_83	Estimated glomerular filtration rate	3.000000e-22
GCST008060_38	Estimated glomerular filtration rate	1.000000e-11
GCST008064_1	Chronic kidney disease	2.000000e-10
GCST010083_142	Hemoglobin levels	7.000000e-30
GCST90002383_185	Hematocrit	2.000000e-35
GCST90002388_291	Lymphocyte count	1.000000e-19
GCST90002403_115	Red blood cell count	2.000000e-33
GCST90002407_62	White blood cell count	9.000000e-14

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0004305	erythrocyte count
EFO:0004348	hematocrit
EFO:0004509	hemoglobin measurement
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, affects methylation, decreases expression, increases expression	4
Acetaminophen	decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Particulate Matter	increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
ethyl-p-hydroxybenzoate	increases expression	1
quercitrin	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
ciglitazone	increases expression, affects binding	1
CGP 52608	affects binding, increases reaction	1
corosolic acid	increases expression	1
2-palmitoylglycerol	increases expression	1
abrine	decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Air Pollutants	increases abundance, increases expression	1
Caffeine	increases phosphorylation	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, increases expression	1
Nickel	increases expression	1
Phenobarbital	affects expression	1
Quercetin	increases expression	1
Silicon Dioxide	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Tretinoin	increases expression	1

Clinical trials (associated diseases)

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