PPHLN1

Summary

PPHLN1 (periphilin 1, HGNC:19369) is a protein-coding gene on chromosome 12q12, encoding Periphilin-1 (Q8NEY8). RNA-binding component of the HUSH complex, a multiprotein complex that mediates epigenetic repression of mobile genetic elements, such as retroviruses and transposable elements.

The protein encoded by this gene is one of the several proteins that become sequentially incorporated into the cornified cell envelope during the terminal differentiation of keratinocyte at the outer layers of epidermis. This protein interacts with periplakin, which is known as a precursor of the cornified cell envelope. The cellular localization pattern and insolubility of this protein suggest that it may play a role in epithelial differentiation and contribute to epidermal integrity and barrier formation. Multiple alternatively spliced transcript variants encoding distinct isoforms have been observed.

Source: NCBI Gene 51535 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 70 total
• Druggable target: yes
• MANE Select transcript: NM_201439

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19369
Approved symbol	PPHLN1
Name	periphilin 1
Location	12q12
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000134283
Ensembl biotype	protein_coding
OMIM	608150
Entrez	51535

Gene structure

Transcript identifiers

Ensembl transcripts: 64 — 54 protein_coding, 5 retained_intron, 2 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay, 1 TEC

ENST00000256678, ENST00000317560, ENST00000337898, ENST00000358314, ENST00000395568, ENST00000395580, ENST00000432191, ENST00000449194, ENST00000546750, ENST00000547440, ENST00000547696, ENST00000547847, ENST00000549190, ENST00000549774, ENST00000550535, ENST00000551406, ENST00000551658, ENST00000551723, ENST00000552202, ENST00000552429, ENST00000552761, ENST00000552794, ENST00000610488, ENST00000613154, ENST00000619544, ENST00000624028, ENST00000890819, ENST00000890820, ENST00000890821, ENST00000890822, ENST00000890823, ENST00000890824, ENST00000890825, ENST00000890826, ENST00000890827, ENST00000890828, ENST00000890829, ENST00000890830, ENST00000890831, ENST00000890832, ENST00000890833, ENST00000890834, ENST00000933367, ENST00000933368, ENST00000933369, ENST00000933370, ENST00000933371, ENST00000933372, ENST00000933373, ENST00000933374, ENST00000933375, ENST00000933376, ENST00000933377, ENST00000933378, ENST00000933379, ENST00000933380, ENST00000965397, ENST00000965398, ENST00000965399, ENST00000965400, ENST00000965401, ENST00000965402, ENST00000965403, ENST00000965404

RefSeq mRNA: 21 — MANE Select: NM_201439 NM_001143787, NM_001143788, NM_001143789, NM_001364822, NM_001364823, NM_001364824, NM_001364825, NM_001364826, NM_001364827, NM_001364828, NM_001364829, NM_001364830, NM_001364831, NM_001364832, NM_001364833, NM_001364834, NM_016488, NM_201438, NM_201439, NM_201440, NM_201515

CCDS: CCDS31777, CCDS41773, CCDS44860, CCDS44861, CCDS55817, CCDS8741, CCDS91684

Canonical transcript exons

ENST00000358314 — 10 exons

Exon	Start	End
ENSE00001217930	42398854	42398994
ENSE00002229578	42326167	42326229
ENSE00003517976	42374863	42375074
ENSE00003582419	42393570	42393689
ENSE00003604971	42387456	42387535
ENSE00003623458	42351885	42352049
ENSE00003648020	42355161	42355222
ENSE00003663741	42335883	42335974
ENSE00003683036	42384940	42384996
ENSE00003733724	42441315	42442181

Expression profiles

Bgee: expression breadth ubiquitous, 263 present calls, max score 99.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 57.7290 / max 800.2977, expressed in 1821 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
125106	55.7529	1820
125107	1.1186	734
125105	0.6661	391
125111	0.1670	43
125108	0.0244	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pancreatic ductal cell	CL:0002079	99.03	gold quality
oocyte	CL:0000023	98.95	gold quality
secondary oocyte	CL:0000655	98.85	gold quality
epithelial cell of pancreas	CL:0000083	98.68	gold quality
germinal epithelium of ovary	UBERON:0001304	96.93	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.57	gold quality
palpebral conjunctiva	UBERON:0001812	96.53	gold quality
oviduct epithelium	UBERON:0004804	96.49	gold quality
calcaneal tendon	UBERON:0003701	96.27	gold quality
adrenal tissue	UBERON:0018303	96.27	gold quality
Brodmann (1909) area 23	UBERON:0013554	95.99	gold quality
epithelium of nasopharynx	UBERON:0001951	95.79	gold quality
nasopharynx	UBERON:0001728	95.77	gold quality
eye	UBERON:0000970	95.74	gold quality
gingival epithelium	UBERON:0001949	95.69	gold quality
skin of hip	UBERON:0001554	95.66	gold quality
corpus epididymis	UBERON:0004359	95.61	gold quality
cauda epididymis	UBERON:0004360	95.54	gold quality
bone marrow	UBERON:0002371	95.49	gold quality
caput epididymis	UBERON:0004358	95.45	gold quality
kidney epithelium	UBERON:0004819	95.41	gold quality
sperm	CL:0000019	95.38	gold quality
monocyte	CL:0000576	95.24	gold quality
lymph node	UBERON:0000029	95.24	gold quality
endometrium	UBERON:0001295	95.16	gold quality
leukocyte	CL:0000738	95.13	gold quality
saphenous vein	UBERON:0007318	95.03	gold quality
layer of synovial tissue	UBERON:0007616	95.03	gold quality
penis	UBERON:0000989	95.00	gold quality
endothelial cell	CL:0000115	94.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	7.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

68 targeting PPHLN1, 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-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509
HSA-MIR-548C-5P	99.94	71.24	3488
HSA-MIR-548D-5P	99.94	71.23	3502
HSA-MIR-548H-5P	99.94	71.24	3488
HSA-MIR-548I	99.94	71.25	3481
HSA-MIR-548J-5P	99.94	71.14	3489
HSA-MIR-548O-5P	99.94	71.24	3488
HSA-MIR-548W	99.94	71.24	3488

Literature-anchored findings (GeneRIF, showing 7)

• periphilin is potentially involved in epithelial differentiation and contributes to epidermal integrity and barrier formation (PMID:12853457)
• CR (periphilin) retards S-phase progression by modifying expression of Cdc7 and other genes involved in progression of DNA replication (PMID:15474462)
• Data show that periphilin displays an overlapping expression pattern with synphilin-1 in cellular and animal models and in Lewy bodies of Parkinson’s disease (PD) patients, and support involvement of periphilin in PD. (PMID:19730898)
• analysis of FGFR2-PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma (PMID:25608663)
• this study identified the HUSH (human silencing hub) complex, comprising three poorly characterized proteins, TASOR, MPP8, and periphilin; this complex is absent from Drosophila but is conserved from fish to humans. (PMID:26022416)
• The haploid screen identified HUSH, an epigenetic heterochromatin repressor complex composed of three subunits, TASOR, MPP8 and Periphilin. (Review) (PMID:26853531)
• Periphilin self-association underpins epigenetic silencing by the HUSH complex. (PMID:32976585)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	pphln1	ENSDARG00000045692
mus_musculus	Pphln1	ENSMUSG00000036167
rattus_norvegicus	Pphln1	ENSRNOG00000022778
rattus_norvegicus		ENSRNOG00000084995

Protein

Protein identifiers

Periphilin-1 — Q8NEY8 (reviewed: Q8NEY8)

Alternative names: CDC7 expression repressor, Gastric cancer antigen Ga50

All UniProt accessions (10): B7Z8L1, Q8NEY8, F8VP48, F8VPY7, F8VRK2, F8VWU8, F8VXV7, F8W0Q9, F8W6A0, F8WF16

UniProt curated annotations — full annotation on UniProt →

Function. RNA-binding component of the HUSH complex, a multiprotein complex that mediates epigenetic repression of mobile genetic elements, such as retroviruses and transposable elements. The HUSH complex mainly represses LINE-1 (L1) retrotransposons that are still capable of transposition. The HUSH complex is recruited to genomic loci rich in H3K9me3 and is probably required to maintain transcriptional silencing by promoting recruitment of SETDB1, a histone methyltransferase that mediates further deposition of H3K9me3, as well as MORC2, a chromatin remodeler that compacts chromatin. The HUSH complex is also involved in the silencing of unintegrated retroviral DNA: some part of the retroviral DNA formed immediately after infection remains unintegrated in the host genome and is transcriptionally repressed. Within the HUSH complex, PPHLN1 acts as a mRNA-binding component, which specifically binds nascent transcripts of mobile genetic elements, enabling HUSH-dependent silencing of transcripts. Contributes to the maintenance of the HUSH complex at chromatin. As part of the HUSH2 complex, promotes epigenetic repression of interferon-stimulated genes. May be involved in epithelial differentiation by contributing to epidermal integrity and barrier formation.

Subunit / interactions. Homodimer. Component of the HUSH complex; composed of TASOR, PPHLN1 and MPHOSPH8. Component of the HUSH2 complex; composed of TASOR2, PPHLN1 and MPHOSPH8. Interacts with SIN3A and HDAC1. May interact with PPL.

Subcellular location. Nucleus. Cytoplasm. Chromosome.

Tissue specificity. Ubiquitous.

Post-translational modifications. Substrate of transglutaminase (in vitro).

Miscellaneous. May be due to intron retention. May be due to intron retention.

Isoforms (8)

UniProt ID	Names	Canonical?
Q8NEY8-1	1	yes
Q8NEY8-2	2, CR
Q8NEY8-3	3
Q8NEY8-5	5
Q8NEY8-6	6, CR-S
Q8NEY8-7	7
Q8NEY8-8	8
Q8NEY8-9	9

RefSeq proteins (21): NP_001137259, NP_001137260, NP_001137261, NP_001351751, NP_001351752, NP_001351753, NP_001351754, NP_001351755, NP_001351756, NP_001351757, NP_001351758, NP_001351759, NP_001351760, NP_001351761, NP_001351762, NP_001351763, NP_057572, NP_958846, NP_958847, NP_958848, NP_958923 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR028851	Pphln1	Family
IPR057603	Periphilin-1_C	Domain

Pfam: PF25234

UniProt features (57 total): modified residue 12, compositionally biased region 10, splice variant 10, cross-link 9, sequence conflict 5, region of interest 3, mutagenesis site 3, helix 2, chain 1, short sequence motif 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
6SWG	X-RAY DIFFRACTION	2.51

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NEY8-F1	56.89	0.16

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 (21): 110, 114, 133, 140, 161, 167, 197, 201, 205, 235, 240, 325, 109, 160, 180, 199, 227, 235, 240, 328 …

Mutagenesis-validated functional residues (3):

Position	Phenotype
319	in lli mutant; abolished mrna-binding and ability to silence mobile elements; when associated with a-326 and a-330.
326	in lli mutant; abolished mrna-binding and ability to silence mobile elements; when associated with a-319 and a-330.
330	in lli mutant; abolished mrna-binding and ability to silence mobile elements; when associated with a-319 and a-326.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9843970	Regulation of endogenous retroelements by the Human Silencing Hub (HUSH) complex

MSigDB gene sets: 171 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, chr12q12, GOBP_NEGATIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_NEGATIVE_REGULATION_OF_MULTICELLULAR_ORGANISMAL_PROCESS, MILI_PSEUDOPODIA_HAPTOTAXIS_UP, GOBP_PROTEIN_LOCALIZATION_TO_CHROMATIN, GOBP_PROTEIN_LOCALIZATION_TO_CHROMOSOME, GOBP_CYTOKINE_PRODUCTION, SCHAEFFER_PROSTATE_DEVELOPMENT_6HR_DN, SCHAEFFER_PROSTATE_DEVELOPMENT_AND_CANCER_BOX4_DN, CREB_Q2_01, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE

GO Biological Process (7): keratinization (GO:0031424), negative regulation of type I interferon production (GO:0032480), negative regulation of gene expression, epigenetic (GO:0045814), negative regulation of DNA-templated transcription (GO:0045892), protein localization to heterochromatin (GO:0097355), constitutive heterochromatin formation (GO:0140719), transposable element silencing by heterochromatin formation (GO:0141005)

GO Molecular Function (3): RNA binding (GO:0003723), mRNA binding (GO:0003729), protein binding (GO:0005515)

GO Cellular Component (9): chromatin (GO:0000785), nucleus (GO:0005634), nucleoplasm (GO:0005654), Golgi apparatus (GO:0005794), cytosol (GO:0005829), HUSH complex (GO:0140283), HUSH2 complex (GO:0140286), chromosome (GO:0005694), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Regulation of endogenous retroelements	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
intracellular membrane-bounded organelle	2
cytoplasm	2
chromatin silencing complex	2
keratinocyte differentiation	1
multicellular organismal process	1
negative regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
negative regulation of gene expression	1
epigenetic regulation of gene expression	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
negative regulation of RNA biosynthetic process	1
protein localization to chromatin	1
heterochromatin formation	1
transposable element silencing	1
constitutive heterochromatin formation	1
nucleic acid binding	1
RNA binding	1
binding	1
chromosome	1
nuclear lumen	1
endomembrane system	1
intracellular membraneless organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1430 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PPHLN1	TASOR	Q9UK61	993
PPHLN1	MPHOSPH8	Q99549	985
PPHLN1	PPL	O60437	869
PPHLN1	BICC1	Q9H694	739
PPHLN1	CASP5	P51878	667
PPHLN1	SETDB1	Q15047	650
PPHLN1	FGFR2	P18443	586
PPHLN1	TGM2	P21980	549
PPHLN1	AHCYL1	O43865	541
PPHLN1	MORC2	Q9Y6X9	526
PPHLN1	SHTN1	A0MZ66	515
PPHLN1	TACC3	Q9Y6A5	511
PPHLN1	RNF216	Q9NWF9	487
PPHLN1	CHAF1A	Q13111	445
PPHLN1	ZNF638	Q14966	440

IntAct

134 interactions, top by confidence:

A	B	Type	Score
P4HA3	FAM171A2	psi-mi:“MI:0914”(association)	0.640
SNRPA1	U2SURP	psi-mi:“MI:0914”(association)	0.640
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
DHX38	DHX16	psi-mi:“MI:0914”(association)	0.630
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
PPHLN1	CCDC57	psi-mi:“MI:0915”(physical association)	0.560
MTUS2	PPHLN1	psi-mi:“MI:0915”(physical association)	0.560
PPHLN1	TSGA10	psi-mi:“MI:0915”(physical association)	0.560
CCDC57	PPHLN1	psi-mi:“MI:0915”(physical association)	0.560
TSGA10	PPHLN1	psi-mi:“MI:0915”(physical association)	0.560
ZNF597	HCFC1	psi-mi:“MI:0914”(association)	0.530
KLHL40	CBX4	psi-mi:“MI:0914”(association)	0.530
ZC3H18	AQR	psi-mi:“MI:0914”(association)	0.530
ZFC3H1	HNRNPCL1	psi-mi:“MI:0914”(association)	0.530
EZH1	EPOP	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
SRSF3	CASC3	psi-mi:“MI:0914”(association)	0.530
CPSF6	DDX39A	psi-mi:“MI:0914”(association)	0.480
THRAP3	HNRNPC	psi-mi:“MI:0914”(association)	0.480
SNCAIP	PPHLN1	psi-mi:“MI:0403”(colocalization)	0.460
SNCAIP	PPHLN1	psi-mi:“MI:0915”(physical association)	0.460
CDK6	PPHLN1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
PPHLN1	FXR1	psi-mi:“MI:0915”(physical association)	0.370
PPHLN1	SHANK3	psi-mi:“MI:0915”(physical association)	0.370
VIM	PPHLN1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (197): PPHLN1 (Two-hybrid), TSGA10 (Two-hybrid), CCDC57 (Two-hybrid), PPHLN1 (Affinity Capture-RNA), PPHLN1 (Affinity Capture-RNA), PPHLN1 (Affinity Capture-RNA), PPHLN1 (Affinity Capture-MS), PPHLN1 (Affinity Capture-MS), PPHLN1 (Affinity Capture-MS), PPHLN1 (Affinity Capture-MS), PPHLN1 (Affinity Capture-MS), PPHLN1 (Biochemical Activity), PPHLN1 (Biochemical Activity), PPHLN1 (Affinity Capture-MS), PPHLN1 (Affinity Capture-MS)

ESM2 similar proteins: A0A1I8MUL8, A2AG58, A2AJT9, A6ZWC8, B3LKV0, B5VT41, B9UYK6, C1IWT1, C5IY45, C7GJ78, C8ZIQ5, E7KIY3, E7KVI3, E7M1C7, E7QAA9, E7QLB7, O14269, O23372, O94687, P0CO26, P0CO27, P11596, P30414, P30415, P33419, P97868, Q03063, Q08D57, Q18221, Q1LY77, Q23935, Q24669, Q3UC65, Q3YPH5, Q4R626, Q5LJZ2, Q5R840, Q5RAA7, Q5U2S0, Q66J90

Diamond homologs: Q8K2H1, Q8NEY8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PPHLN1	“form complex”	“HUSH epigenetic repressor complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 172 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	12	21.7×	3e-11
Transport of Mature Transcript to Cytoplasm	6	20.9×	2e-05
RNA Polymerase II Transcription Termination	9	18.1×	1e-07
Transport of Mature mRNA derived from an Intron-Containing Transcript	12	16.8×	6e-10
mRNA Splicing	15	15.1×	2e-11
Intrinsic Pathway for Apoptosis	5	13.4×	2e-03
Processing of Capped Intron-Containing Pre-mRNA	16	12.1×	3e-11
mRNA Polyadenylation	14	11.3×	2e-09

GO biological processes:

GO term	Partners	Fold	FDR
negative regulation of mRNA splicing, via spliceosome	5	25.7×	2e-04
regulation of alternative mRNA splicing, via spliceosome	11	18.0×	1e-08
mRNA stabilization	5	12.3×	5e-03
mRNA transport	6	10.6×	3e-03
mRNA splicing, via spliceosome	17	10.4×	5e-10
RNA splicing	15	8.9×	4e-08
regulation of RNA splicing	6	8.8×	5e-03
mRNA processing	13	6.9×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	43
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

4226 predictions. Top by Δscore:

Variant	Effect	Δscore
12:42313195:CTTG:C	acceptor_gain	1.0000
12:42313196:TTG:T	acceptor_gain	1.0000
12:42313197:TG:T	acceptor_gain	1.0000
12:42313198:GCTGT:G	acceptor_loss	1.0000
12:42313199:C:CA	acceptor_loss	1.0000
12:42313199:C:CC	acceptor_gain	1.0000
12:42313200:T:A	acceptor_loss	1.0000
12:42313201:G:C	acceptor_gain	1.0000
12:42313207:C:CT	acceptor_gain	1.0000
12:42313208:A:T	acceptor_gain	1.0000
12:42313684:TAATA:T	donor_loss	1.0000
12:42313685:AATAC:A	donor_loss	1.0000
12:42313686:ATAC:A	donor_loss	1.0000
12:42313687:TAC:T	donor_loss	1.0000
12:42313688:ACCTG:A	donor_loss	1.0000
12:42313689:C:G	donor_loss	1.0000
12:42313762:CTCA:C	acceptor_gain	1.0000
12:42313764:CA:C	acceptor_gain	1.0000
12:42313764:CACT:C	acceptor_gain	1.0000
12:42313766:C:CC	acceptor_gain	1.0000
12:42313767:T:C	acceptor_gain	1.0000
12:42313767:T:TC	acceptor_gain	1.0000
12:42313771:A:AC	acceptor_gain	1.0000
12:42313869:CATA:C	donor_gain	1.0000
12:42313870:ATACA:A	donor_loss	1.0000
12:42313871:TA:T	donor_loss	1.0000
12:42313872:A:AC	donor_gain	1.0000
12:42313872:ACA:A	donor_loss	1.0000
12:42313873:C:CA	donor_gain	1.0000
12:42313873:CA:C	donor_gain	1.0000

AlphaMissense

2395 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:42441339:T:C	F312L	1.000
12:42441341:C:A	F312L	1.000
12:42441341:C:G	F312L	1.000
12:42441361:T:A	L319Q	1.000
12:42441361:T:C	L319P	1.000
12:42398976:A:C	K297N	0.999
12:42398976:A:T	K297N	0.999
12:42398987:T:A	I301N	0.999
12:42398987:T:G	I301S	0.999
12:42441318:T:G	Y305D	0.999
12:42441322:G:C	R306P	0.999
12:42441325:A:C	Q307P	0.999
12:42441327:G:C	D308H	0.999
12:42441328:A:C	D308A	0.999
12:42441328:A:G	D308G	0.999
12:42441328:A:T	D308V	0.999
12:42441330:T:C	C309R	0.999
12:42441331:G:A	C309Y	0.999
12:42441340:T:C	F312S	0.999
12:42441340:T:G	F312C	0.999
12:42441348:G:A	V315M	0.999
12:42441348:G:C	V315L	0.999
12:42441348:G:T	V315L	0.999
12:42441349:T:A	V315E	0.999
12:42441352:T:A	V316E	0.999
12:42441358:T:C	M318T	0.999
12:42441358:T:G	M318R	0.999
12:42441359:G:A	M318I	0.999
12:42441359:G:C	M318I	0.999
12:42441359:G:T	M318I	0.999

dbSNP variants (sampled 300 via entrez): RS1000009284 (12:42394977 C>T), RS1000011390 (12:42353073 A>G), RS1000019213 (12:42355549 C>A,G,T), RS1000094174 (12:42439546 G>A,C), RS1000107478 (12:42341567 T>G), RS1000142038 (12:42367373 A>C), RS1000169074 (12:42347425 A>T), RS1000177171 (12:42359433 G>A), RS1000235143 (12:42376830 A>G), RS1000247997 (12:42401026 T>A), RS1000265291 (12:42445921 A>G,T), RS1000313102 (12:42394595 C>A,G,T), RS1000326009 (12:42445961 A>G), RS1000366567 (12:42359280 T>C), RS1000396093 (12:42406963 A>G,T)

Disease associations

OMIM: gene MIM:608150 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST005196_63	Coronary artery disease	2.000000e-06
GCST006627_51	Diastolic blood pressure	4.000000e-10
GCST010002_215	Refractive error	3.000000e-11
GCST010989_39	Body size at age 10	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0009819	comparative body size at age 10, self-reported

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067412 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.47	Kd	335.9	nM	CHEMBL3752910
6.47	ED50	335.9	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149916: Binding affinity to human PPHLN1 incubated for 45 mins by Kinobead based pull down assay	kd	0.3359	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation	2
Benzo(a)pyrene	increases methylation, affects methylation	2
Valproic Acid	affects expression, increases expression	2
Aflatoxin B1	decreases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
arsenite	affects binding, increases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
benzo(e)pyrene	decreases methylation	1
coumarin	affects phosphorylation	1
nivalenol	increases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
bisphenol S	decreases methylation	1
PCI 5002	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Air Pollutants	affects cotreatment, increases abundance, increases oxidation	1
Arbutin	increases expression	1
Arsenic	affects methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652958	Binding	Binding affinity to human PPHLN1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B3EC	Abcam HEK293T PPHLN1 KO	Transformed cell line	Female

Clinical trials (associated diseases)

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