PHETA2

Summary

PHETA2 (PH domain containing endocytic trafficking adaptor 2, HGNC:27161) is a protein-coding gene on chromosome 22q13.2, encoding Sesquipedalian-2 (Q6ICB4). Plays a role in endocytic trafficking.

Enables protein homodimerization activity. Involved in endosome organization; receptor recycling; and retrograde transport, endosome to Golgi. Located in cytoplasmic vesicle and trans-Golgi network.

Source: NCBI Gene 150368 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 40 total
• MANE Select transcript: NM_001002034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:27161
Approved symbol	PHETA2
Name	PH domain containing endocytic trafficking adaptor 2
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	DKFZp686J07229, SES2, IPIP27B
Ensembl gene	ENSG00000177096
Ensembl biotype	protein_coding
OMIM	614240
Entrez	150368

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 9 protein_coding

ENST00000321753, ENST00000419475, ENST00000904234, ENST00000904235, ENST00000923515, ENST00000923516, ENST00000923517, ENST00000963582, ENST00000963583

RefSeq mRNA: 1 — MANE Select: NM_001002034 NM_001002034

CCDS: CCDS33655

Canonical transcript exons

ENST00000321753 — 3 exons

Exon	Start	End
ENSE00001282280	42077280	42079438
ENSE00001364952	42075571	42075652
ENSE00001373525	42074248	42074341

Expression profiles

Bgee: expression breadth ubiquitous, 209 present calls, max score 86.66.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.2967 / max 34.5610, expressed in 1045 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192551	2.5544	991
192552	0.7423	453

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	86.66	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.47	gold quality
ileal mucosa	UBERON:0000331	85.19	gold quality
right coronary artery	UBERON:0001625	84.99	gold quality
body of pancreas	UBERON:0001150	84.81	gold quality
mucosa of stomach	UBERON:0001199	84.50	gold quality
descending thoracic aorta	UBERON:0002345	83.66	gold quality
body of stomach	UBERON:0001161	83.54	gold quality
left coronary artery	UBERON:0001626	83.52	gold quality
thoracic aorta	UBERON:0001515	83.40	gold quality
smooth muscle tissue	UBERON:0001135	83.30	gold quality
ascending aorta	UBERON:0001496	83.17	gold quality
lower esophagus muscularis layer	UBERON:0035833	83.12	gold quality
lower esophagus	UBERON:0013473	83.10	gold quality
left uterine tube	UBERON:0001303	82.94	gold quality
apex of heart	UBERON:0002098	82.89	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	82.86	gold quality
coronary artery	UBERON:0001621	82.71	gold quality
aorta	UBERON:0000947	82.51	gold quality
mucosa of transverse colon	UBERON:0004991	82.45	gold quality
popliteal artery	UBERON:0002250	82.03	gold quality
tibial artery	UBERON:0007610	82.03	gold quality
stomach	UBERON:0000945	81.49	gold quality
body of uterus	UBERON:0009853	81.35	gold quality
transverse colon	UBERON:0001157	81.33	gold quality
pancreas	UBERON:0001264	81.21	gold quality
muscle layer of sigmoid colon	UBERON:0035805	81.12	gold quality
tibialis anterior	UBERON:0001385	81.01	silver quality
endocervix	UBERON:0000458	80.86	gold quality
minor salivary gland	UBERON:0001830	80.62	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.49
E-MTAB-6142	no	41.69

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

40 targeting PHETA2, 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-4533	100.00	69.48	2758
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-205-5P	99.81	70.05	1557
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-378A-5P	99.65	66.33	1311
HSA-MIR-6861-3P	99.60	68.46	444
HSA-MIR-425-5P	99.59	67.67	900
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-2392	99.43	67.50	708
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-583	98.71	67.44	1791
HSA-MIR-4703-5P	98.53	70.13	1645
HSA-MIR-3942-5P	98.52	69.51	1517
HSA-MIR-4766-3P	98.48	67.94	1347
HSA-MIR-4768-3P	98.16	66.02	2330
HSA-MIR-4468	98.01	66.85	1187
HSA-MIR-3664-3P	97.85	67.62	1452
HSA-MIR-647	97.73	67.79	927
HSA-MIR-665	97.60	65.64	1781
HSA-MIR-3137	97.26	66.78	761
HSA-MIR-874-5P	96.93	63.92	1014

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	Pheta2	ENSMUSG00000049687
rattus_norvegicus	Pheta2	ENSRNOG00000042522

Paralogs (2): PLEKHJ1 (ENSG00000104886), PHETA1 (ENSG00000198324)

Protein

Protein identifiers

Sesquipedalian-2 — Q6ICB4 (reviewed: Q6ICB4)

Alternative names: 27 kDa inositol polyphosphate phosphatase interacting protein B, PH domain-containing endocytic trafficking adaptor 2

All UniProt accessions (2): Q6ICB4, B1AHR3

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 PHETA1. Interacts with OCRL and INPP5B.

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.

RefSeq proteins (1): NP_001002034* (*=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 (8 total): mutagenesis site 3, chain 1, domain 1, coiled-coil region 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ICB4-F1	76.70	0.44

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
224	loss of ocrl-binding.
228	loss of ocrl-binding.
234–235	loss of ocrl-binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 94 (showing top): GOBP_ENDOSOME_ORGANIZATION, GOBP_VESICLE_ORGANIZATION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOCC_TRANS_GOLGI_NETWORK, GOCC_COATED_VESICLE, GOBP_RECEPTOR_METABOLIC_PROCESS, GOBP_ENDOMEMBRANE_SYSTEM_ORGANIZATION, GOBP_RETROGRADE_TRANSPORT_ENDOSOME_TO_GOLGI, GOCC_CLATHRIN_COATED_VESICLE, GOBP_CYTOSOLIC_TRANSPORT, chr22q13, GOCC_RECYCLING_ENDOSOME, GOCC_ORGANELLE_SUBCOMPARTMENT, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY

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

224 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PHETA2	NAGA	P17050	527
PHETA2	SMDT1	Q9H4I9	450
PHETA2	WBP2NL	Q6ICG8	447
PHETA2	C10orf53	Q8N6V4	447
PHETA2	SEPTIN3	Q9UH03	447
PHETA2	NDUFA6	P56556	444
PHETA2	INPP5B	P32019	440
PHETA2	OCRL	Q01968	440
PHETA2	ERICH5	Q6P6B1	395
PHETA2	PRR18	Q8N4B5	393
PHETA2	ZSCAN29	Q8IWY8	380
PHETA2	SHISA8	B8ZZ34	370
PHETA2	CIMAP1D	Q3SX64	370
PHETA2	SFT2D1	Q8WV19	349
PHETA2	PACSIN2	Q9UNF0	331

IntAct

24 interactions, top by confidence:

A	B	Type	Score
PHETA2	OCRL	psi-mi:“MI:0915”(physical association)	0.770
OCRL	PHETA2	psi-mi:“MI:0915”(physical association)	0.770
PHETA2	PLEKHJ1	psi-mi:“MI:0915”(physical association)	0.740
PHETA2	CLVS2	psi-mi:“MI:0915”(physical association)	0.560
PHETA2	PHETA1	psi-mi:“MI:0915”(physical association)	0.560
CLVS2	PHETA2	psi-mi:“MI:0915”(physical association)	0.560
PHETA2	SEMG1	psi-mi:“MI:0914”(association)	0.530
GTSE1	HIP1	psi-mi:“MI:0914”(association)	0.350
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
PHETA2	NMT2	psi-mi:“MI:0914”(association)	0.350
PHETA2	INPP5B	psi-mi:“MI:0914”(association)	0.350
PHETA2	OCRL	psi-mi:“MI:0915”(physical association)	0.000
PHETA2	PHETA1	psi-mi:“MI:0915”(physical association)	0.000
PHETA2	PLEKHJ1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (25): FAM109B (Affinity Capture-MS), FAM109B (Affinity Capture-MS), PLEKHJ1 (Affinity Capture-MS), INPP5B (Affinity Capture-MS), OCRL (Affinity Capture-MS), SEMG1 (Affinity Capture-MS), NMT2 (Affinity Capture-MS), OCRL (Two-hybrid), FAM109B (Two-hybrid), FAM109B (Two-hybrid), FAM109B (Two-hybrid), FAM109A (Two-hybrid), FAM109B (Affinity Capture-MS), FAM109B (Negative Genetic), PLEKHJ1 (Affinity Capture-MS)

ESM2 similar proteins: A3R064, A7MBB8, B2RYG7, D3ZZN9, E1BDF2, O60496, O70469, O94989, O95153, P97465, P97680, P98077, Q13671, Q14B98, Q1RMU7, Q3MIN7, Q3UR97, Q3UYI5, Q494U1, Q4QQV2, Q58EX7, Q5EA84, Q5FWH6, Q6ICB4, Q6PGG2, Q6ZW31, Q7L591, Q7TNF8, Q8BH49, Q8BWA8, Q8IW93, Q8IYJ3, Q8N878, Q8NAG6, Q8NFA2, Q91WA6, Q921Q7, Q92502, Q969H4, Q969T3

Diamond homologs: A2CEA7, A7KAN4, B6RSP1, D3ZL52, I1S8Q3, O08967, O14827, O43739, P0CN90, P0CN91, P27671, P28818, P42331, P60669, P63034, P63035, P70392, P97696, Q13972, Q14B98, Q1RMU7, Q1ZXL0, Q2U0C3, Q5U2Z7, Q5ZLT5, Q6ICB4, Q6P0G8, Q6P4L6, Q76MY7, Q7Z5H3, Q801R7, Q80YW0, Q86IV4, Q8BH49, Q8BIK4, Q8BL80, Q8BUL6, Q8BYW1, Q8C4V1, Q8N264

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	38
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

380 predictions. Top by Δscore:

Variant	Effect	Δscore
22:42077278:A:AG	acceptor_gain	1.0000
22:42077279:G:GA	acceptor_gain	1.0000
22:42074578:G:GT	donor_gain	0.9900
22:42075640:G:GG	donor_gain	0.9900
22:42077270:T:TA	acceptor_gain	0.9900
22:42077275:CACAG:C	acceptor_loss	0.9900
22:42077277:C:G	acceptor_gain	0.9900
22:42077277:CAG:C	acceptor_loss	0.9900
22:42077278:AGT:A	acceptor_loss	0.9900
22:42077279:G:GT	acceptor_loss	0.9900
22:42077279:GT:G	acceptor_gain	0.9900
22:42077279:GTT:G	acceptor_gain	0.9900
22:42077279:GTTC:G	acceptor_gain	0.9900
22:42077279:GTTCC:G	acceptor_gain	0.9900
22:42074339:G:GT	donor_gain	0.9800
22:42074457:G:GT	donor_gain	0.9800
22:42075652:GGTA:G	donor_loss	0.9800
22:42075653:G:GT	donor_loss	0.9800
22:42075654:TAA:T	donor_loss	0.9800
22:42075655:A:AG	donor_loss	0.9800
22:42074339:GAGG:G	donor_loss	0.9700
22:42074341:GGTGA:G	donor_loss	0.9700
22:42075639:A:AG	donor_gain	0.9700
22:42077276:A:AG	acceptor_gain	0.9700
22:42074339:G:T	donor_gain	0.9600
22:42075649:GCTG:G	donor_gain	0.9500
22:42075656:AG:A	donor_loss	0.9500
22:42074344:G:GT	donor_loss	0.9400
22:42075653:G:GG	donor_gain	0.9400
22:42076188:C:G	donor_gain	0.9400

AlphaMissense

1674 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:42077552:T:C	F87L	0.995
22:42077554:T:A	F87L	0.995
22:42077554:T:G	F87L	0.995
22:42077629:G:C	W112C	0.995
22:42077629:G:T	W112C	0.995
22:42077627:T:A	W112R	0.994
22:42077627:T:C	W112R	0.994
22:42077445:T:C	L51P	0.993
22:42077450:T:C	F53L	0.993
22:42077452:C:A	F53L	0.993
22:42077452:C:G	F53L	0.993
22:42077553:T:C	F87S	0.993
22:42077437:G:C	K48N	0.992
22:42077437:G:T	K48N	0.992
22:42077451:T:C	F53S	0.992
22:42077564:T:C	F91L	0.991
22:42077566:T:A	F91L	0.991
22:42077566:T:G	F91L	0.991
22:42077654:T:C	F121L	0.991
22:42077656:T:A	F121L	0.991
22:42077656:T:G	F121L	0.991
22:42077426:T:C	F45L	0.990
22:42077428:T:A	F45L	0.990
22:42077428:T:G	F45L	0.990
22:42077443:C:A	N50K	0.989
22:42077443:C:G	N50K	0.989
22:42077546:T:C	F85L	0.989
22:42077548:T:A	F85L	0.989
22:42077548:T:G	F85L	0.989
22:42077559:T:A	I89N	0.989

dbSNP variants (sampled 300 via entrez): RS1000215125 (22:42076912 A>G), RS1000227213 (22:42073809 G>A), RS1000656075 (22:42078630 G>A), RS1001370721 (22:42077060 T>C), RS1002317807 (22:42075507 G>A,C), RS1002987560 (22:42078474 G>A), RS1003450532 (22:42072479 C>A), RS1003592860 (22:42074610 G>C), RS1003805175 (22:42078768 T>A,C), RS1004158160 (22:42079400 G>C), RS1005781567 (22:42074619 T>C), RS1005814284 (22:42075726 T>C), RS1006179803 (22:42079365 T>C), RS1006370230 (22:42073324 G>A), RS1006401466 (22:42074383 G>C)

Disease associations

OMIM: gene MIM:614240 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001585_27	Breast size	5.000000e-07
GCST002539_95	Schizophrenia	2.000000e-09
GCST004364_23	Intelligence	3.000000e-10
GCST004364_5	Intelligence	3.000000e-10
GCST004521_160	Autism spectrum disorder or schizophrenia	3.000000e-08
GCST004521_244	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST005142_47	Cognitive ability	4.000000e-09
GCST006803_13	Schizophrenia	2.000000e-14
GCST010002_83	Refractive error	2.000000e-27

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1807493	PHETA2, SMDT1		0.00	0

CTD chemical–gene interactions

17 total (human), top 17 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	2
(+)-JQ1 compound	decreases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
GSK-J4	decreases expression	1
bisphenol A	increases expression	1
zinc chromate	decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
Atrazine	increases expression	1
Cadmium	increases abundance, increases expression	1
Estradiol	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Triclosan	increases expression	1
Valproic Acid	decreases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Okadaic Acid	decreases expression	1

Clinical trials (associated diseases)

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