PLEKHD1

Summary

PLEKHD1 (pleckstrin homology and coiled-coil domain containing D1, HGNC:20148) is a protein-coding gene on chromosome 14q24.1, encoding Pleckstrin homology domain-containing family D member 1 (A6NEE1).

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 101 total
• MANE Select transcript: NM_001161498

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20148
Approved symbol	PLEKHD1
Name	pleckstrin homology and coiled-coil domain containing D1
Location	14q24.1
Locus type	gene with protein product
Status	Approved
Aliases	UPF0639
Ensembl gene	ENSG00000175985
Ensembl biotype	protein_coding
Entrez	400224

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000322564, ENST00000556123, ENST00000923232

RefSeq mRNA: 1 — MANE Select: NM_001161498 NM_001161498

CCDS: CCDS53903

Canonical transcript exons

ENST00000322564 — 13 exons

Exon	Start	End
ENSE00001243777	69527783	69527932
ENSE00001243782	69527188	69527332
ENSE00001243789	69526697	69526829
ENSE00001243797	69525944	69526122
ENSE00001243803	69524229	69524322
ENSE00001243820	69522283	69522377
ENSE00001488082	69528250	69531551
ENSE00001549614	69501734	69501825
ENSE00001563219	69502827	69502879
ENSE00001601779	69500115	69500208
ENSE00001623688	69500871	69500947
ENSE00001689851	69500577	69500666
ENSE00001721640	69484728	69485114

Expression profiles

Bgee: expression breadth broad, 81 present calls, max score 76.97.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1290 / max 55.3459, expressed in 35 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
140345	0.0815	21
140346	0.0474	12

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	76.97	gold quality
cerebellum	UBERON:0002037	76.72	gold quality
cerebellar cortex	UBERON:0002129	76.68	gold quality
cerebellar hemisphere	UBERON:0002245	76.62	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	71.55	gold quality
primary visual cortex	UBERON:0002436	64.95	gold quality
right lobe of thyroid gland	UBERON:0001119	64.47	gold quality
left lobe of thyroid gland	UBERON:0001120	63.74	gold quality
thyroid gland	UBERON:0002046	63.58	gold quality
metanephros cortex	UBERON:0010533	62.87	gold quality
prefrontal cortex	UBERON:0000451	61.93	gold quality
superior frontal gyrus	UBERON:0002661	61.14	gold quality
skin of leg	UBERON:0001511	60.97	gold quality
frontal cortex	UBERON:0001870	60.50	gold quality
cortex of kidney	UBERON:0001225	60.43	gold quality
zone of skin	UBERON:0000014	59.54	gold quality
adult mammalian kidney	UBERON:0000082	58.41	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	58.32	gold quality
kidney	UBERON:0002113	58.25	gold quality
right frontal lobe	UBERON:0002810	58.16	gold quality
Brodmann (1909) area 9	UBERON:0013540	58.12	gold quality
skin of abdomen	UBERON:0001416	57.90	gold quality
bone marrow cell	CL:0002092	57.31	silver quality
cerebral cortex	UBERON:0000956	57.27	gold quality
anterior cingulate cortex	UBERON:0009835	56.79	gold quality
ventricular zone	UBERON:0003053	54.45	silver quality
lymph node	UBERON:0000029	53.56	gold quality
brain	UBERON:0000955	53.10	gold quality
granulocyte	CL:0000094	51.24	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	50.97	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	4.63
E-ANND-3	yes	3.70
E-MTAB-4850	no	30.08
E-ENAD-27	no	3.87

Regulation

Is transcription factor: no

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	plekhd1	ENSDARG00000091349
mus_musculus	Plekhd1	ENSMUSG00000066438
rattus_norvegicus	Plekhd1	ENSRNOG00000038297
caenorhabditis_elegans		WBGENE00009292

Paralogs (2): DEF6 (ENSG00000023892), SWAP70 (ENSG00000133789)

Protein

Protein identifiers

Pleckstrin homology domain-containing family D member 1 — A6NEE1 (reviewed: A6NEE1)

All UniProt accessions (1): A6NEE1

UniProt curated annotations — full annotation on UniProt →

Similarity. Belongs to the PLEKHD1 family.

RefSeq proteins (1): NP_001154970* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001849	PH_domain	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily

Pfam: PF00169

UniProt features (4 total): chain 1, domain 1, coiled-coil region 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-A6NEE1-F1	82.29	0.47

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): 503

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 12 (showing top): chr14q24, PANGAS_TUMOR_SUPPRESSION_BY_SMAD1_AND_SMAD5_DN, GSE14699_NAIVE_VS_DELETIONAL_TOLERANCE_CD8_TCELL_DN, RYBP_TARGET_GENES, SIX1_TARGET_GENES, GSE13306_TREG_VS_TCONV_SPLEEN_UP, HARALAMBIEVA_PBMC_M_M_R_II_AGE_11_22YO_VACCINATED_VS_UNVACCINATED_7YR_UP, GSE7460_CTRL_VS_TGFB_TREATED_ACT_TCONV_DN, GSE7460_CTRL_VS_TGFB_TREATED_ACT_FOXP3_HET_TCONV_DN, GSE5542_UNTREATED_VS_IFNG_TREATED_EPITHELIAL_CELLS_24H_UP, GSE28737_WT_VS_BCL6_KO_FOLLICULAR_BCELL_UP, GSE43863_TH1_VS_LY6C_INT_CXCR5POS_EFFECTOR_CD4_TCELL_DN

GO Biological Process (0):

GO Molecular Function (0):

GO Cellular Component (0):

Protein interactions and networks

STRING

280 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PLEKHD1	SLC39A9	Q9NUM3	620
PLEKHD1	A0A087WYV9	A0A087WYV9	570
PLEKHD1	KLHDC10	Q6PID8	569
PLEKHD1	ZSWIM5	Q9P217	526
PLEKHD1	SLC10A1	Q14973	473
PLEKHD1	LRRC3B	Q96PB8	446
PLEKHD1	ZNF404	Q494X3	414
PLEKHD1	FLACC1	Q96Q35	404
PLEKHD1	SPATA18	Q8TC71	397
PLEKHD1	POU2AF2	Q8IXP5	392
PLEKHD1	POU2AF3	A8K830	386
PLEKHD1	ATP6AP1L	Q52LC2	378
PLEKHD1	KLHDC7A	Q5VTJ3	378
PLEKHD1	SUSD6	Q92537	376
PLEKHD1	CCDC177	Q9NQR7	376

IntAct

3 interactions, top by confidence:

A	B	Type	Score
PLEKHD1	RSL1D1	psi-mi:“MI:0915”(physical association)	0.400
SYK	PLEKHD1	psi-mi:“MI:0914”(association)	0.350

BioGRID (6): PLEKHD1 (Synthetic Lethality), RSL1D1 (Proximity Label-MS), PLEKHD1 (Affinity Capture-MS), PLEKHD1 (Affinity Capture-MS), TMED5 (Cross-Linking-MS (XL-MS)), PLEKHD1 (Affinity Capture-MS)

ESM2 similar proteins: A0JMK8, A0JMQ7, A0JNT9, A0JP75, A1A600, A2A6T1, A2AUM9, A2BGP7, A6NEE1, A6NI79, A6QNP9, B1WBU8, B2RPU2, B8JK76, B9V5F5, D3YV10, G9G127, P0CB05, P0CF95, P60853, Q32PN7, Q3UP38, Q499E4, Q5JU67, Q5SPX1, Q5U3A8, Q5U4W1, Q5XIA0, Q61043, Q6DIS8, Q6GLX3, Q6P402, Q6PA69, Q6PGZ0, Q6ZP65, Q6ZQ12, Q7TMK6, Q80YT7, Q8BIJ7, Q8BMK0

Diamond homologs: A6NEE1, B1WBU8, B2RPU2, O45420

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	93
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

2054 predictions. Top by Δscore:

Variant	Effect	Δscore
14:69500664:CATG:C	donor_loss	1.0000
14:69500666:TG:T	donor_loss	1.0000
14:69500667:G:GG	donor_gain	1.0000
14:69500669:G:GT	donor_loss	1.0000
14:69500671:G:GG	donor_gain	1.0000
14:69501801:GC:G	donor_gain	1.0000
14:69501802:C:G	donor_gain	1.0000
14:69501807:G:GT	donor_gain	1.0000
14:69501808:A:T	donor_gain	1.0000
14:69501815:G:GT	donor_gain	1.0000
14:69501815:GGA:G	donor_gain	1.0000
14:69501816:GAG:G	donor_gain	1.0000
14:69502875:GAGAG:G	donor_gain	1.0000
14:69502877:GAG:G	donor_gain	1.0000
14:69502879:GGTA:G	donor_loss	1.0000
14:69502880:G:A	donor_loss	1.0000
14:69502881:T:G	donor_loss	1.0000
14:69522271:T:TA	acceptor_gain	1.0000
14:69522272:G:A	acceptor_gain	1.0000
14:69522281:AG:A	acceptor_gain	1.0000
14:69522282:GG:G	acceptor_gain	1.0000
14:69522282:GGA:G	acceptor_gain	1.0000
14:69522364:G:GT	donor_gain	1.0000
14:69522375:G:GT	donor_gain	1.0000
14:69524318:TGGAG:T	donor_loss	1.0000
14:69524320:G:GT	donor_gain	1.0000
14:69524321:AG:A	donor_loss	1.0000
14:69524322:GGTG:G	donor_loss	1.0000
14:69524323:G:A	donor_loss	1.0000
14:69524324:T:G	donor_loss	1.0000

AlphaMissense

3350 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
14:69485076:G:C	K37N	1.000
14:69485076:G:T	K37N	1.000
14:69485104:T:A	W47R	1.000
14:69485104:T:C	W47R	1.000
14:69500141:T:C	L59P	1.000
14:69500200:C:G	H79D	1.000
14:69500204:C:A	P80H	1.000
14:69500916:T:A	W127R	1.000
14:69500916:T:C	W127R	1.000
14:69527327:T:C	L399P	1.000
14:69485069:T:C	L35P	0.999
14:69485106:G:C	W47C	0.999
14:69485106:G:T	W47C	0.999
14:69500116:T:C	F51L	0.999
14:69500117:T:C	F51S	0.999
14:69500118:T:A	F51L	0.999
14:69500118:T:G	F51L	0.999
14:69500129:A:T	K55I	0.999
14:69500130:A:C	K55N	0.999
14:69500130:A:T	K55N	0.999
14:69500137:T:C	F58L	0.999
14:69500139:T:A	F58L	0.999
14:69500139:T:G	F58L	0.999
14:69500141:T:A	L59Q	0.999
14:69500141:T:G	L59R	0.999
14:69500144:T:C	L60P	0.999
14:69500146:T:G	Y61D	0.999
14:69500149:T:G	Y62D	0.999
14:69500203:C:T	P80S	0.999
14:69500204:C:G	P80R	0.999

dbSNP variants (sampled 300 via entrez): RS1000099135 (14:69506819 T>G), RS1000132715 (14:69523746 A>C,G), RS1000147144 (14:69519121 T>C), RS1000225094 (14:69483510 T>G), RS1000246410 (14:69484491 A>G), RS1000289871 (14:69525207 C>A), RS1000336501 (14:69528971 C>T), RS1000347263 (14:69490286 A>G), RS1000422055 (14:69489029 A>G), RS1000503651 (14:69511524 G>T), RS1000506623 (14:69471023 C>T), RS1000538946 (14:69467254 T>C), RS1000554490 (14:69506491 C>T), RS1000591022 (14:69511503 T>A), RS1000656192 (14:69505097 T>G)

Disease associations

OMIM: gene `` | 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
GCST004362_2	Plasma estrone levels in resected estrogen-receptor positive breast cancer	2.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007970	estrone measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

4 total (human), top 4 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation	1
sodium arsenite	increases expression	1
Benzo(a)pyrene	increases methylation, decreases methylation	1
Malathion	decreases expression	1

Clinical trials (associated diseases)

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