PPFIA4

Summary

PPFIA4 (PPFI scaffold protein A4, HGNC:9248) is a protein-coding gene on chromosome 1q32.1, encoding Liprin-alpha-4 (O75335). May regulate the disassembly of focal adhesions.

PPFIA4, or liprin-alpha-4, belongs to the liprin-alpha gene family. See liprin-alpha-1 (LIP1, or PPFIA1; MIM 611054) for background on liprins.

Source: NCBI Gene 8497 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 115 total
• MANE Select transcript: NM_001304331

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9248
Approved symbol	PPFIA4
Name	PPFI scaffold protein A4
Location	1q32.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000143847
Ensembl biotype	protein_coding
OMIM	603145
Entrez	8497

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 9 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000272198, ENST00000295706, ENST00000367240, ENST00000447715, ENST00000486360, ENST00000594572, ENST00000594656, ENST00000597023, ENST00000599514, ENST00000599966, ENST00000600426, ENST00000600447, ENST00000601609, ENST00000688357, ENST00000692772, ENST00000951791

RefSeq mRNA: 10 — MANE Select: NM_001304331 NM_001304331, NM_001304332, NM_001393950, NM_001393951, NM_001393952, NM_001393953, NM_001393954, NM_001393955, NM_001393956, NM_001393957

CCDS: CCDS91145

Canonical transcript exons

ENST00000295706 — 30 exons

Exon	Start	End
ENSE00000962272	203055432	203055672
ENSE00000962273	203056120	203056155
ENSE00000962274	203056375	203056508
ENSE00000962276	203059178	203059271
ENSE00000962277	203059770	203059851
ENSE00000962279	203060970	203061032
ENSE00001075156	203061652	203061678
ENSE00001320480	203056784	203056950
ENSE00001357724	203075577	203075757
ENSE00001385058	203053753	203053961
ENSE00001443901	203076341	203078736
ENSE00001443906	203048583	203048714
ENSE00001443916	203038610	203039242
ENSE00002420372	203060217	203060417
ENSE00003459671	203067695	203067792
ENSE00003480717	203045841	203045987
ENSE00003510011	203048918	203048980
ENSE00003536731	203043397	203043498
ENSE00003556758	203071692	203071760
ENSE00003560385	203068453	203068628
ENSE00003564854	203063828	203064003
ENSE00003572175	203048227	203048310
ENSE00003581760	203044379	203044453
ENSE00003604098	203049676	203049767
ENSE00003659682	203051769	203051877
ENSE00003667904	203043931	203044095
ENSE00003669669	203045368	203045559
ENSE00003678334	203046248	203046382
ENSE00003688954	203044696	203044785
ENSE00003923052	203026491	203026629

Expression profiles

Bgee: expression breadth ubiquitous, 206 present calls, max score 99.33.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.4088 / max 825.3055, expressed in 939 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
7832	5.3826	936
7835	0.0224	6
7834	0.0038	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	99.33	gold quality
cerebellar cortex	UBERON:0002129	99.32	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.28	gold quality
cerebellum	UBERON:0002037	99.11	gold quality
cerebellar vermis	UBERON:0004720	97.93	gold quality
paraflocculus	UBERON:0005351	97.28	gold quality
right frontal lobe	UBERON:0002810	95.19	gold quality
primary visual cortex	UBERON:0002436	93.40	gold quality
Brodmann (1909) area 9	UBERON:0013540	92.10	gold quality
middle temporal gyrus	UBERON:0002771	91.86	gold quality
apex of heart	UBERON:0002098	91.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	91.57	gold quality
occipital lobe	UBERON:0002021	91.36	gold quality
frontal cortex	UBERON:0001870	91.01	gold quality
frontal lobe	UBERON:0016525	91.00	gold quality
cingulate cortex	UBERON:0003027	90.95	gold quality
anterior cingulate cortex	UBERON:0009835	90.88	gold quality
neocortex	UBERON:0001950	90.73	gold quality
prefrontal cortex	UBERON:0000451	90.54	gold quality
nucleus accumbens	UBERON:0001882	90.04	gold quality
cerebral cortex	UBERON:0000956	89.61	gold quality
amygdala	UBERON:0001876	89.36	gold quality
postcentral gyrus	UBERON:0002581	89.10	gold quality
Brodmann (1909) area 10	UBERON:0013541	88.78	gold quality
telencephalon	UBERON:0001893	88.67	gold quality
superior frontal gyrus	UBERON:0002661	88.61	gold quality
Brodmann (1909) area 46	UBERON:0006483	88.50	gold quality
gastrocnemius	UBERON:0001388	88.35	gold quality
parietal lobe	UBERON:0001872	88.31	gold quality
cortical plate	UBERON:0005343	88.11	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.21

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HIF1A

Literature-anchored findings (GeneRIF, showing 6)

• liprin-alpha4 is a hypoxia-induced gene potentially involved in cell-cell adhesion (PMID:20599943)
• presence of Liprin-alpha4 and nickel increased tyrosine phosphatase activity that reduced the global levels of tyrosine phosphorylation in the cell (PMID:21829649)
• The results identify PP1IFA4 loci associated with early onset atrial fibrillation in a Korean population. (PMID:28460022)
• Data show that liprin-alpha4 plays a pivotal role in inducing malignant phenotypes such as increased proliferation and invasion in pancreatic cancer, and that liprin-alpha4 could be a new effective therapeutic target for pancreatic cancer. (PMID:29187440)
• Hypoxia appears to up-regulate the expression of liprin-alpha4, which induces the expression of HIF1alpha. HIF1alpha contributes to increased proliferation and lower chemosensitivity. Therefore, inhibition of liprin-alpha4 or HIF1alpha led to reduced proliferation and increased chemosensitivity of SBC-5 cells. (PMID:30842147)
• PPFIA4 Promotes Proliferation, Migration and Glycolysis of Esophageal Cancer Cells. (PMID:38182152)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	ppfia4	ENSDARG00000053205
mus_musculus	Ppfia4	ENSMUSG00000026458
rattus_norvegicus	Ppfia4	ENSRNOG00000003494
drosophila_melanogaster	Liprin-alpha	FBGN0046704

Paralogs (5): PPFIBP1 (ENSG00000110841), PPFIA1 (ENSG00000131626), PPFIA2 (ENSG00000139220), PPFIBP2 (ENSG00000166387), PPFIA3 (ENSG00000177380)

Protein

Protein identifiers

Liprin-alpha-4 — O75335 (reviewed: O75335)

Alternative names: Protein tyrosine phosphatase receptor type f polypeptide-interacting protein alpha-4

All UniProt accessions (6): O75335, A0A8I5QJ45, A0A8J8YUZ5, B1APN9, M0QZB5, M0R219

UniProt curated annotations — full annotation on UniProt →

Function. May regulate the disassembly of focal adhesions. May localize receptor-like tyrosine phosphatases type 2A at specific sites on the plasma membrane, possibly regulating their interaction with the extracellular environment and their association with substrates.

Subunit / interactions. Forms homodimers and heterodimers with liprins-alpha and liprins-beta. Interacts with the second PTPase domain of PTPRD, PTPRF and PTPRS. Interacts with RIMS1 and RIMS2. Interacts with GIT1 and GIT2. Interacts with GRIP1. Interacts with KIF1A.

Subcellular location. Cytoplasm. Cell surface.

Tissue specificity. Expressed only in the heart, brain, and skeletal muscle.

Domain organisation. The N-terminal coiled coil regions mediate homodimerization preferentially and heterodimerization type alpha/alpha. The C-terminal, non-coiled coil regions mediate heterodimerization type alpha/beta and interaction with PTPRD, PTPRF and PTPRS.

Similarity. Belongs to the liprin family. Liprin-alpha subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
O75335-3	3	yes
O75335-1	1
O75335-2	2

RefSeq proteins (10): NP_001291260, NP_001291261, NP_001380879, NP_001380880, NP_001380881, NP_001380882, NP_001380883, NP_001380884, NP_001380885, NP_001380886 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001660	SAM	Domain
IPR013761	SAM/pointed_sf	Homologous_superfamily
IPR029515	Liprin	Family
IPR037620	LIP-1_SAM_1	Domain
IPR037621	LIP-1_SAM_2	Domain
IPR037622	LIP-1_SAM_3	Domain
IPR057892	LIP-1_CC2	Domain

Pfam: PF00536, PF07647, PF25526

UniProt features (18 total): domain 3, compositionally biased region 3, splice variant 3, modified residue 2, sequence conflict 2, region of interest 2, coiled-coil region 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75335-F1	66.68	0.25

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 (2): 640, 681

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-181429	Serotonin Neurotransmitter Release Cycle
R-HSA-181430	Norepinephrine Neurotransmitter Release Cycle
R-HSA-210500	Glutamate Neurotransmitter Release Cycle
R-HSA-212676	Dopamine Neurotransmitter Release Cycle
R-HSA-264642	Acetylcholine Neurotransmitter Release Cycle
R-HSA-388844	Receptor-type tyrosine-protein phosphatases
R-HSA-112310	Neurotransmitter release cycle
R-HSA-112315	Transmission across Chemical Synapses
R-HSA-112316	Neuronal System
R-HSA-6794362	Protein-protein interactions at synapses

MSigDB gene sets: 0 (showing top):

GO Biological Process (1): synapse organization (GO:0050808)

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

GO Cellular Component (8): cytosol (GO:0005829), cell surface (GO:0009986), synapse (GO:0045202), presynaptic active zone (GO:0048786), cytoplasm (GO:0005737), parallel fiber to Purkinje cell synapse (GO:0098688), presynapse (GO:0098793), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
Neurotransmitter release cycle	5
Neuronal System	2
Protein-protein interactions at synapses	1
Transmission across Chemical Synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
synapse	2
cell junction organization	1
binding	1
cytoplasm	1
cell junction	1
presynapse	1
intracellular anatomical structure	1
excitatory synapse	1

Protein interactions and networks

STRING

934 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPFIA4	KIF1A	Q12756	590
PPFIA4	RIMS2	Q9UQ26	499
PPFIA4	HIF1A	Q16665	483
PPFIA4	HS3ST1	O14792	469
PPFIA4	PPFIBP1	Q86W92	460
PPFIA4	PPFIBP2	Q8ND30	437
PPFIA4	GOLT1A	Q6ZVE7	404
PPFIA4	PTPRF	P10586	380
PPFIA4	RIMBP2	O15034	377
PPFIA4	ERC1	Q8IUD2	372
PPFIA4	ZNF654	Q8IZM8	366
PPFIA4	PTPRS	Q13332	355
PPFIA4	ZNF575	Q86XF7	354
PPFIA4	TSPOAP1	O95153	349
PPFIA4	ANKRD22	Q5VYY1	343

IntAct

5 interactions, top by confidence:

A	B	Type	Score
PPFIA4	PLCG1	psi-mi:“MI:0915”(physical association)	0.400
DNAJC5	PPFIA4	psi-mi:“MI:2364”(proximity)	0.270
PPFIA4	AGTPBP1	psi-mi:“MI:0915”(physical association)	0.000
AGTPBP1	PPFIA4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (15): ERC2 (Two-hybrid), GIT1 (Two-hybrid), GIT1 (Reconstituted Complex), ERC2 (Reconstituted Complex), DNAJC5 (FRET), GIT1 (Two-hybrid), PPFIA4 (Two-hybrid), PPFIA4 (Affinity Capture-MS), PPFIA4 (Affinity Capture-MS), NCOA2 (Two-hybrid), NCOA2 (Reconstituted Complex), PPFIA4 (Two-hybrid), LMNA (Cross-Linking-MS (XL-MS)), PPFIA4 (Affinity Capture-RNA), PPFIA4 (Two-hybrid)

ESM2 similar proteins: A0JNH6, A0JNT9, A1A5D9, A7YH32, A7YWC8, A9QT41, A9X1A5, B0KWC9, B1MTG4, B3EX63, E1U8D0, O75145, O75335, P55937, P58660, P59242, P60469, Q08378, Q2KJ21, Q2TAC2, Q3LUD3, Q3TMW1, Q3UHU5, Q3UMT1, Q4QRL3, Q5TZA2, Q60952, Q6DFL0, Q6NZW0, Q6PGZ0, Q6PHN1, Q6QZQ4, Q6ZP65, Q8BP01, Q8C7U1, Q8CHW5, Q8CJ40, Q8K2I2, Q8N137, Q8TF21

Diamond homologs: A9C3W3, O35711, O75145, O75334, O75335, P60469, Q13136, Q21049, Q5FWS6, Q674X7, Q69ZS8, Q86W92, Q8BSS9, Q8C8U0, Q8ND30, Q91Z79, Q91Z80, Q94071

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (0)

SpliceAI

5150 predictions. Top by Δscore:

Variant	Effect	Δscore
1:203043494:CACGG:C	donor_gain	1.0000
1:203043495:ACGG:A	donor_gain	1.0000
1:203043496:CGG:C	donor_gain	1.0000
1:203043497:GG:G	donor_gain	1.0000
1:203043497:GGG:G	donor_gain	1.0000
1:203043497:GGGTA:G	donor_loss	1.0000
1:203043498:GG:G	donor_gain	1.0000
1:203043499:G:GG	donor_gain	1.0000
1:203043499:GT:G	donor_loss	1.0000
1:203043500:T:G	donor_loss	1.0000
1:203043916:T:A	acceptor_gain	1.0000
1:203043927:CCAGC:C	acceptor_loss	1.0000
1:203043929:A:AG	acceptor_gain	1.0000
1:203043929:A:T	acceptor_loss	1.0000
1:203043929:AGCT:A	acceptor_gain	1.0000
1:203043930:G:GA	acceptor_gain	1.0000
1:203043930:GC:G	acceptor_gain	1.0000
1:203043930:GCT:G	acceptor_gain	1.0000
1:203043930:GCTG:G	acceptor_gain	1.0000
1:203043930:GCTGC:G	acceptor_gain	1.0000
1:203043932:T:A	acceptor_gain	1.0000
1:203044359:T:G	acceptor_gain	1.0000
1:203044369:C:G	acceptor_gain	1.0000
1:203044450:GCAG:G	donor_gain	1.0000
1:203044452:AGGTA:A	donor_loss	1.0000
1:203044453:GGTAA:G	donor_loss	1.0000
1:203044694:A:C	acceptor_loss	1.0000
1:203044695:G:A	acceptor_loss	1.0000
1:203044695:GGT:G	acceptor_gain	1.0000
1:203045358:A:AG	acceptor_gain	1.0000

AlphaMissense

7873 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:203043485:G:C	R108P	1.000
1:203043932:T:C	L113P	1.000
1:203043935:T:C	L114P	1.000
1:203043938:T:C	L115P	1.000
1:203043947:T:C	L118P	1.000
1:203043956:T:C	L121P	1.000
1:203044046:T:C	L151P	1.000
1:203044055:T:A	L154H	1.000
1:203044055:T:C	L154P	1.000
1:203044064:T:C	L157P	1.000
1:203044066:T:C	F158L	1.000
1:203044068:T:A	F158L	1.000
1:203044068:T:G	F158L	1.000
1:203044075:C:G	H161D	1.000
1:203044080:G:C	K162N	1.000
1:203044080:G:T	K162N	1.000
1:203044085:T:C	L164P	1.000
1:203048647:T:C	L434P	1.000
1:203048671:T:C	L442P	1.000
1:203048683:T:C	L446P	1.000
1:203059819:T:A	W829R	1.000
1:203059819:T:C	W829R	1.000
1:203059843:T:A	W837R	1.000
1:203059843:T:C	W837R	1.000
1:203059847:T:C	L838S	1.000
1:203060238:T:A	W847R	1.000
1:203060238:T:C	W847R	1.000
1:203060240:G:C	W847C	1.000
1:203060240:G:T	W847C	1.000
1:203060253:T:C	C852R	1.000

dbSNP variants (sampled 300 via entrez): RS1000119517 (1:203064898 T>G), RS1000123305 (1:203031501 C>T), RS1000185761 (1:203025729 A>G), RS1000212297 (1:203049831 C>G,T), RS1000238832 (1:203031771 C>T), RS1000341878 (1:203065341 G>A), RS1000361964 (1:203058757 C>T), RS1000369104 (1:203059086 G>A), RS1000507116 (1:203030832 C>T), RS1000520834 (1:203053482 G>A), RS1000523557 (1:203054435 C>G), RS1000651667 (1:203053731 T>C), RS1000706403 (1:203026078 A>G), RS1000793405 (1:203060716 G>A), RS1000865496 (1:203059403 G>A)

Disease associations

OMIM: gene MIM:603145 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST004352_1	Early onset atrial fibrillation	2.000000e-09
GCST004373_5	Atrial fibrillation	9.000000e-11
GCST006061_112	Atrial fibrillation	6.000000e-25
GCST006061_78	Atrial fibrillation	1.000000e-18
GCST006414_110	Atrial fibrillation	1.000000e-19
GCST007995_28	Asthma (childhood onset)	1.000000e-09
GCST009798_35	Asthma	8.000000e-12

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methylmercuric chloride	decreases expression	2
sodium arsenite	decreases expression	2
mercuric bromide	decreases expression, affects cotreatment	2
Ethanol	affects cotreatment, increases expression, decreases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Oxygen	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Silicon Dioxide	decreases expression, increases expression	2
Valproic Acid	decreases expression, increases methylation, affects cotreatment	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
Esketamine	increases expression	1
tungsten carbide	affects binding, increases expression	1
propionaldehyde	increases expression	1
sodium arsenate	increases abundance, increases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression	1
aflatoxin B2	decreases methylation	1
4-nonylphenol	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-tert-octylphenol	affects cotreatment, decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
dorsomorphin	decreases expression, affects cotreatment	1
bisphenol Z	increases expression	1
bisphenol S	decreases expression	1
(+)-JQ1 compound	increases expression	1

Clinical trials (associated diseases)

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