PHETA1

Summary

PHETA1 (PH domain containing endocytic trafficking adaptor 1, HGNC:26509) is a protein-coding gene on chromosome 12q24.12, encoding Sesquipedalian-1 (Q8N4B1). Plays a role in endocytic trafficking.

This gene encodes a protein that localizes to the endosome and interacts with the enzyme, inositol polyphosphate 5-phosphatase OCRL-1. Alternate splicing results in multiple transcript variants.

Source: NCBI Gene 144717 — RefSeq curated summary.

At a glance

• GWAS associations: 10
• Clinical variants (ClinVar): 54 total
• MANE Select transcript: NM_144671

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26509
Approved symbol	PHETA1
Name	PH domain containing endocytic trafficking adaptor 1
Location	12q24.12
Locus type	gene with protein product
Status	Approved
Aliases	FLJ32356, SES1, IPIP27A
Ensembl gene	ENSG00000198324
Ensembl biotype	protein_coding
OMIM	614239
Entrez	144717

Gene structure

Transcript identifiers

Ensembl transcripts: 20 — 20 protein_coding

ENST00000361483, ENST00000547710, ENST00000547838, ENST00000548163, ENST00000549321, ENST00000683047, ENST00000890591, ENST00000890592, ENST00000890593, ENST00000890594, ENST00000913600, ENST00000913601, ENST00000913602, ENST00000913603, ENST00000913604, ENST00000971134, ENST00000971135, ENST00000971136, ENST00000971137, ENST00000971138

RefSeq mRNA: 3 — MANE Select: NM_144671 NM_001177996, NM_001177997, NM_144671

CCDS: CCDS53833, CCDS9152

Canonical transcript exons

ENST00000683047 — 3 exons

Exon	Start	End
ENSE00001319694	111366113	111366257
ENSE00001722947	111368912	111369095
ENSE00003919457	111360679	111363463

Expression profiles

Bgee: expression breadth ubiquitous, 237 present calls, max score 96.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 5.3664 / max 98.2244, expressed in 1681 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
133287	3.6266	1590
133288	1.6088	873
133286	0.1311	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	96.46	silver quality
apex of heart	UBERON:0002098	91.29	gold quality
kidney epithelium	UBERON:0004819	90.00	gold quality
nasal cavity epithelium	UBERON:0005384	89.84	silver quality
pylorus	UBERON:0001166	89.44	gold quality
upper arm skin	UBERON:0004263	89.13	silver quality
vena cava	UBERON:0004087	88.59	gold quality
cardia of stomach	UBERON:0001162	87.76	gold quality
lower esophagus mucosa	UBERON:0035834	86.80	gold quality
buccal mucosa cell	CL:0002336	86.70	silver quality
mucosa of transverse colon	UBERON:0004991	86.46	gold quality
body of pancreas	UBERON:0001150	86.29	gold quality
cerebellar vermis	UBERON:0004720	85.98	silver quality
body of stomach	UBERON:0001161	85.64	gold quality
lateral globus pallidus	UBERON:0002476	85.11	silver quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.04	silver quality
duodenum	UBERON:0002114	84.83	gold quality
body of tongue	UBERON:0011876	84.81	silver quality
cardiac ventricle	UBERON:0002082	84.76	gold quality
heart left ventricle	UBERON:0002084	84.75	gold quality
parotid gland	UBERON:0001831	84.67	silver quality
stomach	UBERON:0000945	84.01	gold quality
pharyngeal mucosa	UBERON:0000355	83.74	gold quality
spleen	UBERON:0002106	83.73	gold quality
skin of leg	UBERON:0001511	83.71	gold quality
fundus of stomach	UBERON:0001160	83.64	gold quality
tendon of biceps brachii	UBERON:0008188	83.42	silver quality
heart right ventricle	UBERON:0002080	83.33	silver quality
adrenal cortex	UBERON:0001235	83.24	gold quality
small intestine	UBERON:0002108	83.23	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.87

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting PHETA1, 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-450A-1-3P	100.00	69.33	1837
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-4641	99.28	66.64	744
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-1245B-5P	98.88	66.55	576
HSA-MIR-3142	98.88	66.09	529
HSA-MIR-5006-5P	98.79	66.92	1246
HSA-MIR-7113-3P	98.75	65.71	1120
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-6826-3P	98.19	66.32	1153
HSA-MIR-6773-3P	98.17	65.51	1213
HSA-MIR-744-3P	97.99	67.76	637
HSA-MIR-4469	97.93	65.81	1319
HSA-MIR-3664-3P	97.85	67.62	1452

Literature-anchored findings (GeneRIF, showing 3)

• Two closely related endocytic proteins, Ses1 and Ses2, which interact with OCRL, were identified. The interaction is mediated by a short amino acid motif similar to that used by the rab-5 effector APPL1. (PMID:20133602)
• Two novel OCRL1-binding proteins, termed inositol polyphosphate phosphatase interacting protein of 27 kDa (IPIP27)A and B (also known as Ses1 and 2), that also bind the related 5-phosphatase Inpp5b, were identified. (PMID:21233288)
• Deficiency in the endocytic adaptor proteins PHETA1/2 impairs renal and craniofacial development. (PMID:32152089)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pheta2	ENSDARG00000110325
mus_musculus	Pheta1	ENSMUSG00000044134
rattus_norvegicus	Pheta1	ENSRNOG00000028206

Paralogs (2): PLEKHJ1 (ENSG00000104886), PHETA2 (ENSG00000177096)

Protein

Protein identifiers

Sesquipedalian-1 — Q8N4B1 (reviewed: Q8N4B1)

Alternative names: 27 kDa inositol polyphosphate phosphatase-interacting protein A, PH domain-containing endocytic trafficking adaptor 1

All UniProt accessions (3): Q8N4B1, F8VZK7, F8W0V2

UniProt curated annotations — full annotation on UniProt →

Function. Plays a role in endocytic trafficking. Required for receptor recycling from endosomes, both to the trans-Golgi network and the plasma membrane.

Subunit / interactions. Forms homodimers and heterodimers with PHETA2. Interacts with OCRL and INPP5B. Interaction with OCRL may be important for endosomal morphology and function.

Subcellular location. Early endosome. Recycling endosome. Golgi apparatus. trans-Golgi network. Cytoplasmic vesicle. Clathrin-coated vesicle.

Domain organisation. The F&H motif, an approximately 12-13 amino-acid sequence centered around Phe and His residues, is essential for binding to OCRL and INPP5B.

Miscellaneous. Was named after ‘sesquipedalian’, an unnecessarily long description of a simple thing.

Similarity. Belongs to the sesquipedalian family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q8N4B1-1	1	yes
Q8N4B1-2	2
Q8N4B1-3	3
Q8N4B1-4	4

RefSeq proteins (3): NP_001171467, NP_001171468, NP_653272* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR045188	Boi1/Boi2-like	Family

Pfam: PF00169

UniProt features (17 total): splice variant 5, mutagenesis site 3, region of interest 2, chain 1, domain 1, helix 1, turn 1, short sequence motif 1, compositionally biased region 1, modified residue 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3QIS	X-RAY DIFFRACTION	2.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8N4B1-F1	76.59	0.42

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): 213

Mutagenesis-validated functional residues (3):

Position	Phenotype
224	loss of ocrl-binding. drastically reduces membrane targeting.
228	loss of ocrl-binding.
234–235	loss of ocrl-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 73 (showing top): GOBP_ENDOSOME_ORGANIZATION, GOBP_VESICLE_ORGANIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, GOCC_COATED_VESICLE, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, GOBP_RECEPTOR_METABOLIC_PROCESS, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, SANSOM_APC_TARGETS_DN, TGTTTAC_MIR30A5P_MIR30C_MIR30D_MIR30B_MIR30E5P, GOBP_RETROGRADE_TRANSPORT_ENDOSOME_TO_GOLGI, GOCC_CLATHRIN_COATED_VESICLE, GOBP_CYTOSOLIC_TRANSPORT, GOCC_RECYCLING_ENDOSOME, GOCC_ORGANELLE_SUBCOMPARTMENT

GO Biological Process (3): receptor recycling (GO:0001881), endosome organization (GO:0007032), retrograde transport, endosome to Golgi (GO:0042147)

GO Molecular Function (2): protein homodimerization activity (GO:0042803), protein binding (GO:0005515)

GO Cellular Component (8): early endosome (GO:0005769), trans-Golgi network (GO:0005802), cytosol (GO:0005829), clathrin-coated vesicle (GO:0030136), recycling endosome (GO:0055037), endosome (GO:0005768), Golgi apparatus (GO:0005794), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
endosome	2
endomembrane system	2
endocytosis	1
receptor metabolic process	1
endomembrane system organization	1
vesicle organization	1
intercellular transport	1
endosomal transport	1
cytosolic transport	1
identical protein binding	1
protein dimerization activity	1
binding	1
Golgi apparatus subcompartment	1
cellular anatomical structure	1
coated vesicle	1
cytoplasmic vesicle	1
intracellular membrane-bounded organelle	1
intracellular vesicle	1

Protein interactions and networks

STRING

374 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHETA1	CUX2	O14529	833
PHETA1	INPP5B	P32019	715
PHETA1	TSPEAR	Q8WU66	665
PHETA1	F8VP50	F8VP50	609
PHETA1	OCRL	Q01968	609
PHETA1	PACSIN2	Q9UNF0	592
PHETA1	SLC4A4	Q9Y6R1	580
PHETA1	ABCA13	Q86UQ4	548
PHETA1	ZNF684	Q5T5D7	543
PHETA1	CCDC17	Q96LX7	541
PHETA1	HYDIN	Q4G0P3	535
PHETA1	GORAB	Q5T7V8	533
PHETA1	ASPM	Q8IZT6	509
PHETA1	MT-ND1	P03886	491
PHETA1	KRTAP19-7	Q3SYF9	474

IntAct

18 interactions, top by confidence:

A	B	Type	Score
OCRL	PHETA1	psi-mi:“MI:0915”(physical association)	0.710
PLEKHJ1	PHETA1	psi-mi:“MI:0915”(physical association)	0.660
GPX7	GAK	psi-mi:“MI:0914”(association)	0.640
PLEKHJ1	OCRL	psi-mi:“MI:0914”(association)	0.530
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
OCRL	ERC2	psi-mi:“MI:0914”(association)	0.350
OCRL	MYO1C	psi-mi:“MI:0914”(association)	0.350
PHETA1	INPP5B	psi-mi:“MI:0914”(association)	0.350
OCRL	LTF	psi-mi:“MI:0914”(association)	0.350
OCRL	G6PD	psi-mi:“MI:0914”(association)	0.350
PLEKHJ1	AP3B1	psi-mi:“MI:0914”(association)	0.350
PHETA1	CTNND1	psi-mi:“MI:0914”(association)	0.350
PHETA2	INPP5B	psi-mi:“MI:0914”(association)	0.350
PLEKHJ1	DENND4B	psi-mi:“MI:0914”(association)	0.350
RNPS1	WWP2	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): FAM109A (Affinity Capture-MS), PLEKHJ1 (Affinity Capture-MS), INPP5B (Affinity Capture-MS), CARD9 (Affinity Capture-MS), OCRL (Affinity Capture-MS), FAM109A (Affinity Capture-MS), SPG7 (Affinity Capture-MS), FAM109A (Affinity Capture-MS), FAM109A (Two-hybrid), FAM109A (Two-hybrid), FAM109A (Two-hybrid), FAM109A (Two-hybrid), FAM109A (Two-hybrid), FAM109A (Two-hybrid), FAM109A (Two-hybrid)

ESM2 similar proteins: A2AB59, A3R064, B2RYG7, D3ZL52, D3ZZN9, O09039, O95382, Q03160, Q0P5E6, Q0V987, Q13425, Q14451, Q14B98, Q1RMU7, Q28626, Q2M3V2, Q2TBQ9, Q4ACU6, Q4LDD4, Q5R8E2, Q60806, Q61193, Q61234, Q61235, Q6ICB4, Q6NY19, Q6P597, Q6PGG2, Q6ZUM4, Q6ZW31, Q8BH49, Q8BLS7, Q8C6B2, Q8N4B1, Q8R5G7, Q8TE68, Q8WWN8, Q969H4, Q96P48, Q99704

Diamond homologs: A1CFB3, A1CYS1, A2QNQ5, A7A179, A7ERM5, A7KAK6, A7KAN4, A7TF84, C4B4E5, I1S8Q3, P0CN90, P0CN91, P64866, P9WN06, P9WN07, Q06321, Q0CKU4, Q0UY53, Q2U0C3, Q4WID6, Q54IL5, Q5A950, Q5B4C9, Q5RC33, Q6BN88, Q6C8M8, Q6CUV2, Q751Z4, Q7S1I0, Q8C115, Q8CI52, Q8IVE3, Q8IYS0, Q8N4B1, Q8NJS1, Q9M8Z7, Q9XIG1, Q9Y751, Q00IB7, Q08001

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	51
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

62 predictions. Top by Δscore:

Variant	Effect	Δscore
12:111363040:CAG:C	donor_gain	0.7900
12:111363039:A:AC	donor_gain	0.7800
12:111363040:C:CC	donor_gain	0.7800
12:111363070:C:CT	donor_gain	0.7700
12:111363039:ACAG:A	donor_gain	0.7200
12:111363040:CAGC:C	donor_gain	0.7200
12:111361560:C:CC	acceptor_gain	0.7000
12:111363071:C:CT	donor_gain	0.6700
12:111361559:A:AC	acceptor_gain	0.5100
12:111361566:T:A	acceptor_gain	0.5100
12:111363577:CG:C	donor_gain	0.4900
12:111363575:G:T	donor_gain	0.4800
12:111361558:CA:C	acceptor_gain	0.4600
12:111363037:G:T	donor_gain	0.4500
12:111363551:C:A	donor_gain	0.4500
12:111363024:C:CT	donor_gain	0.4400
12:111363696:ATC:A	donor_gain	0.4300
12:111362554:AGGG:A	donor_gain	0.4100
12:111363041:A:C	donor_gain	0.4100
12:111363550:T:TA	donor_gain	0.4000
12:111361545:G:GA	acceptor_gain	0.3900
12:111361546:A:AA	acceptor_gain	0.3900
12:111363132:T:TA	donor_gain	0.3900
12:111361547:T:A	acceptor_gain	0.3800
12:111361541:CCT:C	acceptor_gain	0.3700
12:111363698:C:A	donor_gain	0.3700
12:111361529:C:CG	acceptor_gain	0.3400
12:111361542:CT:C	acceptor_gain	0.3400
12:111363264:CGG:C	donor_gain	0.3400
12:111362667:C:CA	donor_gain	0.3200

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000042756 (12:111367561 T>C), RS1000054453 (12:111361678 T>G), RS1000057229 (12:111361983 G>A,C), RS1000490786 (12:111361622 C>G), RS1000862982 (12:111360823 G>C), RS1001034939 (12:111367967 G>A), RS1001356418 (12:111367460 C>T), RS1001373997 (12:111362366 C>T), RS1001388940 (12:111367172 C>T), RS1001446912 (12:111366165 C>T), RS1002286137 (12:111366535 A>C), RS1002296485 (12:111360996 G>A), RS1002345331 (12:111361383 G>A,C), RS1002410905 (12:111361097 G>A,C), RS1002968469 (12:111369420 A>T)

Disease associations

OMIM: gene MIM:614239 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST004603_114	Platelet count	4.000000e-126
GCST005951_75	Body mass index	2.000000e-11
GCST006190_12	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	8.000000e-13
GCST006190_82	Diastolic blood pressure x smoking status (ever vs never) interaction (2df test)	1.000000e-26
GCST006192_56	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	2.000000e-19
GCST006192_83	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	5.000000e-08
GCST006193_45	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	6.000000e-12
GCST006193_83	Diastolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-23
GCST006195_34	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-07
GCST006195_75	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	1.000000e-16

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004309	platelet count
EFO:0004340	body mass index
EFO:0006336	diastolic blood pressure
EFO:0006527	smoking status measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	2
aristolochic acid I	increases expression	1
dicrotophos	increases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	decreases expression	1
abrine	decreases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
licochalcone B	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Rosiglitazone	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	increases expression	1
Vehicle Emissions	decreases expression, decreases reaction	1
Cisplatin	affects cotreatment, increases expression	1
Diazinon	increases methylation	1
Smoke	decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Okadaic Acid	increases expression	1
Particulate Matter	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

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