PLEKHF1

Summary

PLEKHF1 (pleckstrin homology and FYVE domain containing 1, HGNC:20764) is a protein-coding gene on chromosome 19q12, encoding Pleckstrin homology domain-containing family F member 1 (Q96S99). May induce apoptosis through the lysosomal-mitochondrial pathway.

Enables phosphatidylinositol-3-phosphate binding activity; phosphatidylinositol-4-phosphate binding activity; and phosphatidylinositol-5-phosphate binding activity. Involved in endosome organization; positive regulation of autophagy; and protein localization to plasma membrane. Located in endosome and lysosome.

Source: NCBI Gene 79156 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 62 total
• MANE Select transcript: NM_024310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20764
Approved symbol	PLEKHF1
Name	pleckstrin homology and FYVE domain containing 1
Location	19q12
Locus type	gene with protein product
Status	Approved
Aliases	APPD, MGC4090, PHAFIN1, ZFYVE15
Ensembl gene	ENSG00000166289
Ensembl biotype	protein_coding
OMIM	615200
Entrez	79156

Gene structure

Transcript identifiers

Ensembl transcripts: 16 — 16 protein_coding

ENST00000436066, ENST00000586888, ENST00000588833, ENST00000592810, ENST00000875188, ENST00000875189, ENST00000875190, ENST00000875191, ENST00000875192, ENST00000914502, ENST00000914503, ENST00000943377, ENST00000943378, ENST00000943379, ENST00000943380, ENST00000943381

RefSeq mRNA: 1 — MANE Select: NM_024310 NM_024310

CCDS: CCDS12417

Canonical transcript exons

ENST00000436066 — 2 exons

Exon	Start	End
ENSE00002208132	29673824	29675477
ENSE00002252305	29665461	29665505

Expression profiles

Bgee: expression breadth ubiquitous, 228 present calls, max score 95.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.5119 / max 72.4574, expressed in 1359 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
175006	5.1967	1347
175007	0.3152	168

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
hindlimb stylopod muscle	UBERON:0004252	95.51	gold quality
granulocyte	CL:0000094	94.35	gold quality
gastrocnemius	UBERON:0001388	93.92	gold quality
muscle of leg	UBERON:0001383	93.25	gold quality
diaphragm	UBERON:0001103	92.66	gold quality
apex of heart	UBERON:0002098	92.18	gold quality
muscle organ	UBERON:0001630	92.04	gold quality
lower esophagus mucosa	UBERON:0035834	89.45	gold quality
body of tongue	UBERON:0011876	89.41	gold quality
vastus lateralis	UBERON:0001379	89.38	gold quality
quadriceps femoris	UBERON:0001377	89.32	gold quality
skeletal muscle tissue	UBERON:0001134	88.56	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	88.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	87.81	gold quality
heart left ventricle	UBERON:0002084	87.73	gold quality
cardiac ventricle	UBERON:0002082	87.58	gold quality
triceps brachii	UBERON:0001509	87.56	gold quality
right atrium auricular region	UBERON:0006631	87.03	gold quality
tibial nerve	UBERON:0001323	86.99	gold quality
parotid gland	UBERON:0001831	86.65	silver quality
cardiac atrium	UBERON:0002081	86.60	gold quality
muscle tissue	UBERON:0002385	86.58	gold quality
vena cava	UBERON:0004087	86.54	gold quality
gluteal muscle	UBERON:0002000	86.45	silver quality
tongue	UBERON:0001723	86.00	gold quality
biceps brachii	UBERON:0001507	85.70	gold quality
descending thoracic aorta	UBERON:0002345	85.40	gold quality
mucosa of stomach	UBERON:0001199	85.39	gold quality
heart	UBERON:0000948	85.29	gold quality
deltoid	UBERON:0001476	85.22	silver quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-3929	yes	137.70
E-ANND-3	yes	7.09

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

42 targeting PLEKHF1, 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-4795-3P	100.00	74.62	4024
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-8080	99.82	67.52	1342
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4786-3P	99.36	68.35	1390
HSA-MIR-5787	99.22	67.86	2628
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-939-3P	98.97	65.07	2347
HSA-MIR-5000-3P	98.79	65.63	1251
HSA-MIR-198	98.70	67.32	920
HSA-MIR-6810-5P	98.29	66.21	975
HSA-MIR-3155A	98.16	66.09	965

Literature-anchored findings (GeneRIF, showing 1)

• The results suggest that in addition to its role in endosome transport, phafin1 is also involved in lysosomal targeting and autophagosome formation. (PMID:22115783)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	plekhf1	ENSDARG00000102435
mus_musculus	Plekhf1	ENSMUSG00000074170
rattus_norvegicus	Plekhf1	ENSRNOG00000027724
drosophila_melanogaster	CG6051	FBGN0039492
drosophila_melanogaster	CG31064	FBGN0051064
caenorhabditis_elegans		WBGENE00003084

Paralogs (13): RUFY3 (ENSG00000018189), ZFYVE16 (ENSG00000039319), SNX29 (ENSG00000048471), ZFYVE26 (ENSG00000072121), RUNDC3B (ENSG00000105784), RUNDC3A (ENSG00000108309), PLEKHM2 (ENSG00000116786), ZFYVE28 (ENSG00000159733), ZFYVE1 (ENSG00000165861), ZFYVE19 (ENSG00000166140), PLEKHF2 (ENSG00000175895), RUFY1 (ENSG00000176783), RUFY2 (ENSG00000204130)

Protein

Protein identifiers

Pleckstrin homology domain-containing family F member 1 — Q96S99 (reviewed: Q96S99)

Alternative names: Lysosome-associated apoptosis-inducing protein containing PH and FYVE domains, PH and FYVE domain-containing protein 1, Phafin-1, Zinc finger FYVE domain-containing protein 15

All UniProt accessions (3): Q96S99, K7EIX0, K7ELB8

UniProt curated annotations — full annotation on UniProt →

Function. May induce apoptosis through the lysosomal-mitochondrial pathway. Translocates to the lysosome initiating the permeabilization of lysosomal membrane (LMP) and resulting in the release of CTSD and CTSL to the cytoplasm. Triggers the caspase-independent apoptosis by altering mitochondrial membrane permeabilization (MMP) resulting in the release of PDCD8.

Subcellular location. Nucleus. Cytoplasm. Perinuclear region. Lysosome.

Tissue specificity. Highly expressed in heart and skeletal muscle. Weakly expressed in brain, thymus, spleen, kidney, liver, small intestine, placenta and lung.

Domain organisation. PH and FYVE-type zinc finger domains are required for lysosomal location.

RefSeq proteins (1): NP_077286* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000306	Znf_FYVE	Domain
IPR001849	PH_domain	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR037871	PH_Phafin	Domain
IPR042762	PKHF1_FYVE	Domain
IPR051765	PH_domain-containing_F	Family

Pfam: PF00169, PF01363

UniProt features (16 total): binding site 8, sequence conflict 3, chain 1, domain 1, zinc finger region 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96S99-F1	86.05	0.66

Functional residue map

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

Ligand- & substrate-binding residues (8): 186; 204; 207; 158; 161; 175; 178; 183

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 186 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_LYSOSOMAL_TRANSPORT, GOBP_ENDOSOME_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOBP_VESICLE_ORGANIZATION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_REGULATION_OF_CATABOLIC_PROCESS, GOBP_POSITIVE_REGULATION_OF_CATABOLIC_PROCESS, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_LOCALIZATION_WITHIN_MEMBRANE

GO Biological Process (6): apoptotic process (GO:0006915), endosome organization (GO:0007032), endosome to lysosome transport (GO:0008333), positive regulation of autophagy (GO:0010508), vesicle organization (GO:0016050), protein localization to plasma membrane (GO:0072659)

GO Molecular Function (7): zinc ion binding (GO:0008270), phosphatidylinositol-5-phosphate binding (GO:0010314), phosphatidylinositol-3-phosphate binding (GO:0032266), phosphatidylinositol binding (GO:0035091), phosphatidylinositol-4-phosphate binding (GO:0070273), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (8): nucleus (GO:0005634), lysosome (GO:0005764), lysosomal membrane (GO:0005765), early endosome (GO:0005769), endosome membrane (GO:0010008), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), endosome (GO:0005768)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
anion binding	3
phosphatidylinositol phosphate binding	3
endosome	2
cellular anatomical structure	2
programmed cell death	1
apoptotic signaling pathway	1
execution phase of apoptosis	1
endomembrane system organization	1
vesicle organization	1
lysosomal transport	1
intercellular transport	1
vesicle-mediated transport	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
organelle organization	1
protein localization to membrane	1
protein localization to cell periphery	1
transition metal ion binding	1
binding	1
cation binding	1
intracellular membrane-bounded organelle	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
cytoplasm	1
intracellular anatomical structure	1
endomembrane system	1
cytoplasmic vesicle	1

Protein interactions and networks

STRING

636 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEKHF1	GGCT	O75223	840
PLEKHF1	TRIM11	Q96F44	768
PLEKHF1	PYCR1	P32322	666
PLEKHF1	FPR2	P25090	653
PLEKHF1	STK17A	Q9UEE5	588
PLEKHF1	CYCS	P00001	564
PLEKHF1	TP53	P04637	548
PLEKHF1	MT-ATP6	P00846	523
PLEKHF1	TNFRSF10B	O14763	445
PLEKHF1	SRC	P12931	438
PLEKHF1	DAPK2	Q9UIK4	429
PLEKHF1	STK17B	O94768	428
PLEKHF1	PSEN2	P49810	424
PLEKHF1	C19orf12	Q9NSK7	418
PLEKHF1	DAPK3	O43293	408

IntAct

22 interactions, top by confidence:

A	B	Type	Score
PLEKHF1	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.560
CAVIN2	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.560
NPM2	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.560
L3MBTL3	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.560
TNFAIP8	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.560
PLEKHF1	CHIC2	psi-mi:“MI:0915”(physical association)	0.560
PLEKHF1	POTEI	psi-mi:“MI:0915”(physical association)	0.400
TNNT1	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.370
KIFBP	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.370
PLEKHF1	CAVIN2	psi-mi:“MI:0915”(physical association)	0.000
PLEKHF1	L3MBTL3	psi-mi:“MI:0915”(physical association)	0.000
PLEKHF1	NPM2	psi-mi:“MI:0915”(physical association)	0.000
CHIC2	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.000
TNFAIP8	PLEKHF1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): L3MBTL3 (Two-hybrid), PLEKHF1 (Two-hybrid), PLEKHF1 (Two-hybrid), PLEKHF1 (Two-hybrid), PLEKHF1 (Two-hybrid), PLEKHF1 (Two-hybrid), SDPR (Two-hybrid), L3MBTL3 (Two-hybrid), PLEKHF1 (Proximity Label-MS), POTEI (Affinity Capture-MS), PLEKHF1 (Proximity Label-MS), PPIB (Co-fractionation), VAMP7 (Co-fractionation)

ESM2 similar proteins: A0FI79, A1A5B6, A5PJU7, A5PKD8, A8MQ27, D3ZL52, D7PF45, F1SAM7, I3L5V6, O15524, O35716, O60346, O76050, P60827, Q03160, Q08DG4, Q0MW30, Q14451, Q1RMW5, Q2MJR0, Q3UPE3, Q60806, Q6P6N5, Q6SZW1, Q6UKI2, Q6WVG3, Q6ZT52, Q8BNW9, Q8CHE4, Q8N119, Q8N2R8, Q8N4B1, Q8TF61, Q96BM1, Q96CD0, Q96E14, Q96S99, Q9BR09, Q9BYB0, Q9D0S4

Diamond homologs: A0A0D1E015, A0JMD2, A1CEK1, A1DFP5, A2QWA2, A3LX75, A4QTV1, B0G126, B0WAQ0, B3MT31, B3P851, B4G2G5, B4IC49, B4JHI7, B4K982, B4M140, B4NFJ7, B4PRU6, D2H5P6, D3ZVP7, D4A8G9, E1BLZ4, O13821, O14964, O76902, O95405, O96838, P0CS26, P0CS27, P34657, P34756, P40343, Q05B78, Q0CJV3, Q0P4S0, Q0U4Z8, Q0V8S0, Q0WUR5, Q15075, Q17AN2

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	50
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

304 predictions. Top by Δscore:

Variant	Effect	Δscore
19:29673821:CAGCC:C	acceptor_loss	1.0000
19:29673822:A:AG	acceptor_gain	1.0000
19:29673822:A:C	acceptor_loss	1.0000
19:29673822:AGCC:A	acceptor_gain	1.0000
19:29673823:G:GG	acceptor_gain	1.0000
19:29673823:GC:G	acceptor_gain	1.0000
19:29673823:GCC:G	acceptor_gain	1.0000
19:29673823:GCCG:G	acceptor_gain	1.0000
19:29673823:GCCGC:G	acceptor_gain	1.0000
19:29673818:CTGCA:C	acceptor_gain	0.9900
19:29673819:T:A	acceptor_gain	0.9900
19:29673819:TGCA:T	acceptor_gain	0.9900
19:29673820:GCAG:G	acceptor_gain	0.9900
19:29673821:CAGC:C	acceptor_gain	0.9900
19:29673822:AGCCG:A	acceptor_gain	0.9900
19:29673823:G:C	acceptor_gain	0.9900
19:29665503:AAGGT:A	donor_loss	0.9800
19:29665504:AGGT:A	donor_loss	0.9800
19:29665505:GGTG:G	donor_loss	0.9800
19:29665506:G:A	donor_loss	0.9800
19:29665507:T:A	donor_loss	0.9800
19:29673809:T:A	acceptor_gain	0.9700
19:29665502:GAAG:G	donor_gain	0.9600
19:29665506:G:GG	donor_gain	0.9400
19:29665508:GAGTC:G	donor_loss	0.9300
19:29666875:C:A	acceptor_gain	0.9300
19:29665677:G:T	donor_gain	0.9000
19:29665779:GAT:G	donor_gain	0.9000
19:29666498:G:GT	donor_gain	0.8900
19:29666739:G:GT	donor_gain	0.8600

AlphaMissense

1823 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:29673971:A:C	K44N	1.000
19:29673971:A:T	K44N	1.000
19:29674203:T:A	W122R	1.000
19:29674203:T:C	W122R	1.000
19:29674335:T:C	F166L	1.000
19:29674337:C:A	F166L	1.000
19:29674337:C:G	F166L	1.000
19:29673903:T:C	F22L	0.999
19:29673905:C:A	F22L	0.999
19:29673905:C:G	F22L	0.999
19:29674018:A:C	D60A	0.999
19:29674018:A:T	D60V	0.999
19:29674137:T:A	W100R	0.999
19:29674137:T:C	W100R	0.999
19:29674164:T:C	F109L	0.999
19:29674166:T:A	F109L	0.999
19:29674166:T:G	F109L	0.999
19:29674205:G:C	W122C	0.999
19:29674205:G:T	W122C	0.999
19:29674284:T:A	W149R	0.999
19:29674284:T:C	W149R	0.999
19:29674311:T:A	C158S	0.999
19:29674311:T:C	C158R	0.999
19:29674312:G:A	C158Y	0.999
19:29674312:G:C	C158S	0.999
19:29674313:C:G	C158W	0.999
19:29674336:T:C	F166S	0.999
19:29674336:T:G	F166C	0.999
19:29674356:C:G	H173D	0.999
19:29674358:C:A	H173Q	0.999

dbSNP variants (sampled 300 via entrez): RS1000132452 (19:29667566 T>C), RS1000208156 (19:29667785 C>T), RS1000241116 (19:29672773 G>C), RS1000413053 (19:29673318 T>A,C), RS1000482462 (19:29673949 T>A,G), RS1000516170 (19:29674258 C>G,T), RS1000658646 (19:29668177 C>A,G), RS1000796416 (19:29668482 G>A), RS1000863756 (19:29667130 C>T), RS1001259626 (19:29673641 G>A), RS1001766734 (19:29668219 C>T), RS1001945639 (19:29668489 G>A), RS1002157993 (19:29675222 G>A), RS1002415995 (19:29669842 C>T), RS1002680000 (19:29665428 G>A,C,T)

Disease associations

OMIM: gene MIM:615200 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST005951_21	Body mass index	4.000000e-09

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

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, increases expression	4
bisphenol A	increases expression, affects cotreatment, decreases expression	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
Estradiol	affects cotreatment, affects binding, decreases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	affects expression, increases expression	2
Arsenic	increases abundance, increases expression, affects expression	2
Cisplatin	increases expression, increases reaction, decreases expression	2
Valproic Acid	increases methylation, increases expression	2
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
bisphenol F	affects cotreatment, increases expression	1
2,4,6-tribromophenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, increases activity, increases expression	1
sodium arsenate	increases abundance, increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, increases reaction	1
afimoxifene	decreases expression, decreases reaction	1
cobaltous chloride	increases expression	1
butyraldehyde	increases expression	1
tetrabromobisphenol A	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	increases expression	1
1,1-bis(4-hydroxyphenyl)-2-phenylbut-1-ene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
pentabrominated diphenyl ether 100	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1

Clinical trials (associated diseases)

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