PADI6

Summary

PADI6 (peptidyl arginine deiminase 6, HGNC:20449) is a protein-coding gene on chromosome 1p36.13, encoding Inactive protein-arginine deiminase type-6 (Q6TGC4). Structural constituent of cytoplasmic lattices, which plays a key role in early embryonic development.

This gene encodes a member of the peptidyl arginine deiminase family of enzymes, which catalyze the post-translational deimination of proteins by converting arginine residues into citrullines in the presence of calcium ions. The family members have distinct substrate specificities and tissue-specific expression patterns. This protein may play a role in cytoskeletal reorganization in the egg and in early embryo development.

Source: NCBI Gene 353238 — RefSeq curated summary.

At a glance

• Gene–disease (curated): preimplantation embryonic lethality 2 (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 116 total — 6 pathogenic, 10 likely-pathogenic
• Phenotypes (HPO): 3
• Druggable target: yes
• MANE Select transcript: NM_207421

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:20449
Approved symbol	PADI6
Name	peptidyl arginine deiminase 6
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000276747
Ensembl biotype	protein_coding
OMIM	610363
Entrez	353238

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000619609

RefSeq mRNA: 1 — MANE Select: NM_207421 NM_207421

CCDS: CCDS72715

Canonical transcript exons

ENST00000619609 — 16 exons

Exon	Start	End
ENSE00003712079	17401205	17401699
ENSE00003716662	17373056	17373233
ENSE00003721743	17388777	17388880
ENSE00003726671	17398686	17398847
ENSE00003730598	17381967	17382092
ENSE00003734363	17395540	17395663
ENSE00003734813	17397071	17397141
ENSE00003734908	17394951	17395107
ENSE00003736625	17372196	17372361
ENSE00003737453	17388381	17388559
ENSE00003739492	17393975	17394082
ENSE00003740425	17381047	17381164
ENSE00003741343	17375427	17375499
ENSE00003742860	17394300	17394454
ENSE00003744684	17392114	17392225
ENSE00003753264	17379920	17379987

Expression profiles

Bgee: expression breadth tissue_specific, 10 present calls, max score 81.43.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.43	gold quality
granulocyte	CL:0000094	71.83	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	56.24	gold quality
leukocyte	CL:0000738	50.80	gold quality
monocyte	CL:0000576	50.06	gold quality
blood	UBERON:0000178	47.30	gold quality
colonic epithelium	UBERON:0000397	45.63	gold quality
bone marrow cell	CL:0002092	44.45	gold quality
bone marrow	UBERON:0002371	42.04	gold quality
skeletal muscle tissue	UBERON:0001134	38.14	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
sural nerve	UBERON:0015488	35.79	gold quality
right ovary	UBERON:0002118	35.51	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
hindlimb stylopod muscle	UBERON:0004252	35.49	gold quality
muscle tissue	UBERON:0002385	34.56	gold quality
lymph node	UBERON:0000029	32.34	gold quality
vermiform appendix	UBERON:0001154	32.06	gold quality
mucosa of stomach	UBERON:0001199	31.91	gold quality
tonsil	UBERON:0002372	30.58	gold quality
liver	UBERON:0002107	30.16	gold quality
stromal cell of endometrium	CL:0002255	29.87	gold quality
ovary	UBERON:0000992	29.69	gold quality
prefrontal cortex	UBERON:0000451	29.35	gold quality
placenta	UBERON:0001987	29.13	gold quality
duodenum	UBERON:0002114	28.14	gold quality
left ovary	UBERON:0002119	27.84	gold quality
urinary bladder	UBERON:0001255	27.64	gold quality
spleen	UBERON:0002106	27.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-36552	yes	142.10
E-ANND-3	no	0.77

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TAL1

miRNA regulators (miRDB)

10 targeting PADI6, 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-486-3P	99.51	66.82	1901
HSA-MIR-367-5P	98.84	67.18	902
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-3187-5P	98.36	65.74	1776
HSA-MIR-1285-3P	97.72	67.02	1932
HSA-MIR-5189-5P	97.72	66.96	1814
HSA-MIR-612	97.26	65.95	1597
HSA-MIR-6860	97.21	66.31	1656
HSA-MIR-6508-3P	96.73	65.48	576

Literature-anchored findings (GeneRIF, showing 16)

• This study is the first description of the human PADI6 gene and encoded protein, and the first step towards a better understanding of the coordinated regulation of PADI gene expression. (PMID:15087120)
• Cloning, gene organization and expression of peptidylarginine deiminase type 6. (PMID:15625577)
• Crystallographic determination of 14-3-3-sigma binding sites in the human peptidylarginine deiminase type VI. (PMID:22634725)
• Mutations in PADI6 Cause Female Infertility Characterized by Early Embryonic Arrest (PMID:27545678)
• PADI6 gene loss causes very early embryonic lethality. (PMID:27730629)
• We now report 15 further pedigrees in which offspring had disturbance of imprinting, while their mothers had rare, predicted-deleterious variants in maternal effect genes, including NLRP2, NLRP7 and PADI6 (PMID:29574422)
• We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient (PMID:29693651)
• New biallelic mutations in PADI6 cause recurrent preimplantation embryonic arrest characterized by direct cleavage. (PMID:31664658)
• Loss-of-function maternal-effect mutations of PADI6 are associated with familial and sporadic Beckwith-Wiedemann syndrome with multi-locus imprinting disturbance. (PMID:32928291)
• Biallelic PADI6 variants cause multilocus imprinting disturbances and miscarriages in the same family. (PMID:33221824)
• Novel pathogenic variants in NLRP7, NLRP5, and PADI6 in patients with recurrent hydatidiform moles and reproductive failure. (PMID:33583041)
• Two novel mutations in PADI6 and TLE6 genes cause female infertility due to arrest in embryonic development. (PMID:34036456)
• Genetic Variation in PADI6-PADI4 on 1p36.13 Is Associated with Common Forms of Human Generalized Epilepsy. (PMID:34573423)
• Novel biallelic mutations in PADI6 in patients with early embryonic arrest. (PMID:34987164)
• Case report: human early embryonic arrest in a consanguineous Chinese family caused by a novel missense variant of PADI6. (PMID:37220902)
• Crystal structure of human peptidylarginine deiminase type VI (PAD6) provides insights into its inactivity. (PMID:38656308)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	padi2	ENSDARG00000044167
mus_musculus	Padi6	ENSMUSG00000040935
rattus_norvegicus	Padi6	ENSRNOG00000037079

Paralogs (4): PADI2 (ENSG00000117115), PADI3 (ENSG00000142619), PADI1 (ENSG00000142623), PADI4 (ENSG00000159339)

Protein

Protein identifiers

Inactive protein-arginine deiminase type-6 — Q6TGC4 (reviewed: Q6TGC4)

Alternative names: Peptidyl arginine deiminase-like protein, Peptidylarginine deiminase VI, Protein-arginine deiminase type VI, Protein-arginine deiminase type-6

All UniProt accessions (1): Q6TGC4

UniProt curated annotations — full annotation on UniProt →

Function. Structural constituent of cytoplasmic lattices, which plays a key role in early embryonic development. Cytoplasmic lattices consist in fibrous structures found in the cytoplasm of oocytes and preimplantation embryos. They are required to store maternal proteins critical for embryonic development, such as ribosomal proteins and proteins that control epigenetic reprogramming of the preimplantation embryo, and prevent their degradation or activation. In contrast to other members of the family, does not show protein-arginine deiminase activity due to its inability to bind Ca(2+).

Subunit / interactions. Homodimers. Associates with alpha-tubulin.

Subcellular location. Cytoplasm. Cytoplasmic vesicle. Secretory vesicle. Cortical granule. Nucleus.

Tissue specificity. Highly expressed in oocytes and weakly expressed in other somatic tissues.

Post-translational modifications. Phosphorylation at Ser-10, possibly by RSK-type kinases, and Ser-446 creates binding sites for 14-3-3 proteins.

Disease relevance. Oocyte/zygote/embryo maturation arrest 16 (OZEMA16) [MIM:617234] A rare cause of female primary infertility. In affected women, ovulation and fertilization proceed normally but embryos are arrested at early stages of development. Inheritance is autosomal recessive. The disease is caused by variants affecting the gene represented in this entry. PADI6 variants have been found in a spectrum of phenotypes characterized by aberrant methylation of multiple imprinted loci, a condition known as multi-locus imprinting defect or multi-locus imprinting disturbance (MLID). MLID-related phenotype spectrum ranges from intrauterine death to different types of imprinting disorders, including Beckwith-Wiedemann syndrome (BWS), Silver-Russell syndrome (SRS), and non-specific developmental and behavioral manifestations.

Similarity. Belongs to the protein arginine deiminase family.

RefSeq proteins (1): NP_997304* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004303	PAD	Family
IPR008972	Cupredoxin	Homologous_superfamily
IPR013530	PAD_C	Domain
IPR013732	PAD_N	Domain
IPR013733	Prot_Arg_deaminase_cen_dom	Domain
IPR036556	PAD_central_sf	Homologous_superfamily
IPR038685	PAD_N_sf	Homologous_superfamily

Pfam: PF03068, PF08526, PF08527

Enzyme classification (BRENDA):

• EC 3.5.3.15 — protein-arginine deiminase (BRENDA: 14 organisms, 435 substrates, 132 inhibitors, 239 Km, 204 kcat entries)

Substrate kinetics (BRENDA)

63 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
N-ALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.1–30	62
NALPHA-BENZOYL-L-ARGININE ETHYL ESTER	0.27–2.77	21
NALPHA-BENZOYL L-ARGININE ETHYL ESTER	0.44–1.7	20
[HISTONE H4]-L-ARG	0.088–0.35	17
BENZOYL-L-ARG	0.0029–33.6	6
ACETYL-L-ARG METHYL ESTER	1.19–66.3	5
BENZOYL-ARG ETHYL ESTER	0.33–0.78	4
BENZOYL-L-ARG ETHYL ESTER	0.35–7.5	4
N-ALPHA-BENZOYL-L-ARGININE AMIDE	0.16–17.5	4
AC-SER-GLY-ARG-GLY-ACETYL-LYS-GLY-GLY-ACETYL-LYS	0.15–1.07	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.15–0.59	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.22–1.95	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.21–0.64	3
AC-SER-GLY-ARG-GLY-LYS-GLY-GLY-LYS-GLY-LEU-GLY-L	0.48–3.27	3
ACETYL-L-ARG	0.91–11.3	3

UniProt features (95 total): strand 41, sequence variant 25, helix 19, sequence conflict 4, turn 3, modified residue 2, chain 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
4DAT	X-RAY DIFFRACTION	1.4
8QL0	X-RAY DIFFRACTION	1.68
4DAU	X-RAY DIFFRACTION	2
9FMN	X-RAY DIFFRACTION	2.44
9LPK	ELECTRON MICROSCOPY	3.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6TGC4-F1	85.88	0.56

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 (2): 10, 446

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-3247509	Chromatin modifying enzymes
R-HSA-9820841	M-decay: degradation of maternal mRNAs by maternally stored factors

MSigDB gene sets: 69 (showing top): GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOCC_SECRETORY_GRANULE, GOBP_SPINDLE_LOCALIZATION, GOBP_TRANSLATION, GOBP_POST_TRANSCRIPTIONAL_REGULATION_OF_GENE_EXPRESSION, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT, GOBP_REGULATION_OF_EMBRYONIC_DEVELOPMENT, GOBP_POSITIVE_REGULATION_OF_DEVELOPMENTAL_PROCESS, GOBP_CHROMATIN_REMODELING, GOBP_ORGANELLE_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_EMBRYONIC_DEVELOPMENT, GOBP_EPIGENETIC_REGULATION_OF_GENE_EXPRESSION, IVANOVA_HEMATOPOIESIS_STEM_CELL_LONG_TERM, GOCC_SECRETORY_VESICLE

GO Biological Process (8): in utero embryonic development (GO:0001701), cytoskeleton organization (GO:0007010), cytoplasm organization (GO:0007028), embryonic cleavage (GO:0040016), regulation of translation by machinery localization (GO:0043143), epigenetic programming in the zygotic pronuclei (GO:0044725), protein storage (GO:0140089), intracellular protein localization (GO:0008104)

GO Molecular Function (6): calcium ion binding (GO:0005509), tubulin binding (GO:0015631), identical protein binding (GO:0042802), structural constituent of cytoplasmic lattice (GO:0140094), protein-arginine deiminase activity (GO:0004668), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), cytoplasm (GO:0005737), intermediate filament cytoskeleton (GO:0045111), cortical granule (GO:0060473), cytoplasmic lattice (GO:0140095), cytoplasmic vesicle (GO:0031410), ooplasm (GO:1990917)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Chromatin organization	1
Maternal to zygotic transition (MZT)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
chordate embryonic development	1
organelle organization	1
cellular component organization	1
embryo development	1
cell division	1
translation	1
regulation of translation	1
intracellular protein localization	1
epigenetic programming of gene expression	1
nutrient storage	1
macromolecule localization	1
metal ion binding	1
cytoskeletal protein binding	1
protein binding	1
structural molecule activity	1
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoskeleton	1
secretory granule	1
intracellular membraneless organelle	1
ooplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

360 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PADI6	OOEP	A6NGQ2	965
PADI6	TLE6	Q9H808	950
PADI6	NLRP5	P59047	860
PADI6	KHDC3L	Q587J8	824
PADI6	NLRP2	Q9NX02	741
PADI6	ZBED3	Q96IU2	705
PADI6	ZAR1	Q86SH2	591
PADI6	NLRP7	Q8WX94	588
PADI6	ZP3	P21754	563
PADI6	PATL2	C9JE40	501
PADI6	BMP15	O95972	490
PADI6	FIGLA	Q6QHK4	465
PADI6	ELANE	P08246	447
PADI6	SLC45A2	Q9UMX9	441
PADI6	BTG4	Q9NY30	437

IntAct

18 interactions, top by confidence:

A	B	Type	Score
PADI6	DDIT4L	psi-mi:“MI:0915”(physical association)	0.560
PADI6	ZNF526	psi-mi:“MI:0915”(physical association)	0.560
KLHL2	PADI6	psi-mi:“MI:0915”(physical association)	0.560
SUV39H1	PADI6	psi-mi:“MI:0915”(physical association)	0.560
MTA3	KDM1A	psi-mi:“MI:0914”(association)	0.530
PADI6	NLRP7	psi-mi:“MI:0915”(physical association)	0.400
MN1	PADI6	psi-mi:“MI:0915”(physical association)	0.400
EBF2	LILRA5	psi-mi:“MI:0914”(association)	0.350
PADI6	PER1	psi-mi:“MI:0914”(association)	0.350
PADI6	ZNF526	psi-mi:“MI:0915”(physical association)	0.000
PADI6	KLHL2	psi-mi:“MI:0915”(physical association)	0.000
SUV39H1	PADI6	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (14): PADI6 (Two-hybrid), PADI6 (Two-hybrid), PADI6 (Two-hybrid), USP4 (Affinity Capture-MS), UHRF1 (Affinity Capture-MS), CAMKK1 (Affinity Capture-MS), KLHL28 (Affinity Capture-MS), PADI6 (Affinity Capture-MS), BRMS1 (Affinity Capture-MS), PER1 (Affinity Capture-MS), PADI6 (Affinity Capture-MS), APPBP2 (Affinity Capture-MS), DHPS (Affinity Capture-MS), PADI6 (Cross-Linking-MS (XL-MS))

ESM2 similar proteins: A0JPI4, A2CJ06, A6NMZ2, B7FF67, B7ZC32, F4I4P8, P11684, P34550, P80364, P86196, Q06A97, Q0P561, Q14D04, Q1LYL8, Q2VPS3, Q3HRN7, Q3HRN8, Q3HRP1, Q3HRP5, Q3MHP3, Q3UIR3, Q5PQS3, Q5SY68, Q5THR3, Q62082, Q6E240, Q6PBN2, Q6TGC4, Q75LU8, Q7FRS8, Q7Z3E5, Q8BMD7, Q8C9X1, Q8CCK0, Q8IGJ0, Q8LAS7, Q8SS49, Q8TDB6, Q91WD9, Q96M98

Diamond homologs: O02849, O88806, O88807, P20717, P70708, Q08642, Q6TGC4, Q8K3V4, Q9ULC6, Q9ULW8, Q9UM07, Q9Y2J8, Q9Z183, Q9Z184, Q9Z185

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	10
Uncertain significance	62
Likely benign	32
Benign	2

Top pathogenic / likely-pathogenic (16)

Variant ID	HGVS	Classification
1308679	NM_207421.4(PADI6):c.1043_1044dup (p.Asp349fs)	Pathogenic
1308683	NM_207421.4(PADI6):c.707dup (p.Leu237fs)	Pathogenic
1308687	NM_207421.4(PADI6):c.5dup (p.Ser3fs)	Pathogenic
1308688	NM_207421.4(PADI6):c.1996dup (p.Cys666fs)	Pathogenic
372229	NM_207421.4(PADI6):c.2009_2010del (p.Glu670fs)	Pathogenic
372231	NM_207421.4(PADI6):c.970C>T (p.Gln324Ter)	Pathogenic
1308676	NM_207421.4(PADI6):c.659C>A (p.Ala220Glu)	Likely pathogenic
1308677	NM_207421.4(PADI6):c.1054C>T (p.Arg352Cys)	Likely pathogenic
1308681	NM_207421.4(PADI6):c.1894C>A (p.Pro632Thr)	Likely pathogenic
2633287	NM_207421.4(PADI6):c.441dup (p.Trp148fs)	Likely pathogenic
3075995	NM_207421.4(PADI6):c.721C>T (p.Gln241Ter)	Likely pathogenic
3345192	NM_207421.4(PADI6):c.1493del (p.Lys498fs)	Likely pathogenic
3382509	NM_207421.4(PADI6):c.19C>T (p.Arg7Ter)	Likely pathogenic
372232	NM_207421.4(PADI6):c.1618G>A (p.Gly540Arg)	Likely pathogenic
3780079	NM_207421.4(PADI6):c.1494+1G>T	Likely pathogenic
4537398	NM_207421.4(PADI6):c.434dup (p.Lys146fs)	Likely pathogenic

SpliceAI

2391 predictions. Top by Δscore:

Variant	Effect	Δscore
1:17372358:GCGG:G	donor_gain	1.0000
1:17373042:ACC:A	acceptor_gain	1.0000
1:17373044:C:A	acceptor_gain	1.0000
1:17373045:G:A	acceptor_gain	1.0000
1:17373052:CCAGG:C	acceptor_loss	1.0000
1:17373055:G:GT	acceptor_loss	1.0000
1:17373055:GGT:G	acceptor_gain	1.0000
1:17373230:TAAGG:T	donor_gain	1.0000
1:17373231:AAGGT:A	donor_gain	1.0000
1:17373232:AGGTA:A	donor_gain	1.0000
1:17373233:GGT:G	donor_gain	1.0000
1:17373234:G:GG	donor_gain	1.0000
1:17373234:GT:G	donor_gain	1.0000
1:17373235:T:A	donor_loss	1.0000
1:17381146:A:T	donor_gain	1.0000
1:17381161:GAGG:G	donor_gain	1.0000
1:17381163:GG:G	donor_gain	1.0000
1:17381164:GG:G	donor_gain	1.0000
1:17381960:T:TA	acceptor_gain	1.0000
1:17381963:CCA:C	acceptor_loss	1.0000
1:17381964:CAGA:C	acceptor_loss	1.0000
1:17381965:A:AG	acceptor_gain	1.0000
1:17381965:A:C	acceptor_loss	1.0000
1:17381966:G:GC	acceptor_gain	1.0000
1:17381966:GA:G	acceptor_gain	1.0000
1:17381966:GAA:G	acceptor_gain	1.0000
1:17381966:GAAA:G	acceptor_gain	1.0000
1:17381966:GAAAT:G	acceptor_gain	1.0000
1:17382093:G:GG	donor_gain	1.0000
1:17388540:TGGAG:T	donor_gain	1.0000

AlphaMissense

4579 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:17401418:T:A	W689R	0.990
1:17401418:T:C	W689R	0.990
1:17381053:T:A	W148R	0.988
1:17381053:T:C	W148R	0.988
1:17401421:T:A	W690R	0.987
1:17401421:T:C	W690R	0.987
1:17395036:T:A	W475R	0.978
1:17395036:T:C	W475R	0.978
1:17401423:G:C	W690C	0.978
1:17401423:G:T	W690C	0.978
1:17375434:T:A	V101D	0.976
1:17401420:G:C	W689C	0.972
1:17401420:G:T	W689C	0.972
1:17381055:G:C	W148C	0.969
1:17381055:G:T	W148C	0.969
1:17388506:T:C	F269L	0.966
1:17388508:C:A	F269L	0.966
1:17388508:C:G	F269L	0.966
1:17382078:T:A	V222D	0.965
1:17395543:T:C	F500L	0.964
1:17395545:C:A	F500L	0.964
1:17395545:C:G	F500L	0.964
1:17388820:G:C	R301P	0.962
1:17373081:T:C	F48L	0.960
1:17373083:C:A	F48L	0.960
1:17373083:C:G	F48L	0.960
1:17375439:T:G	Y103D	0.960
1:17373210:A:C	S91R	0.957
1:17373212:C:A	S91R	0.957
1:17373212:C:G	S91R	0.957

dbSNP variants (sampled 300 via entrez): RS1000045574 (1:17384127 A>AGT), RS1000061073 (1:17398568 G>A,C), RS1000239789 (1:17375874 AGAACATT>A), RS1000285976 (1:17384972 A>T), RS1000290061 (1:17382495 A>G), RS1000294743 (1:17372738 C>T), RS1000320655 (1:17382274 G>C), RS1000523617 (1:17376579 T>C), RS1000593449 (1:17375684 C>T), RS1000713362 (1:17390999 C>A,T), RS1000835476 (1:17396569 C>T), RS1000876522 (1:17395189 G>A,C,T), RS1001065595 (1:17399541 G>A), RS1001096636 (1:17396446 C>A,T), RS1001098188 (1:17399773 C>T)

Disease associations

OMIM: gene MIM:610363 | disease phenotypes: MIM:617234

GenCC curated gene-disease

Disease	Classification	Inheritance
preimplantation embryonic lethality 2	Strong	Autosomal recessive

Mondo (3): oocyte/zygote/embryo maturation arrest 16 (MONDO:1010200), primary ovarian failure (MONDO:0005387), (MONDO:0014978)

Orphanet (1): NON RARE IN EUROPE: Primary ovarian failure (Orphanet:619)

HPO phenotypes

3 total (3 of 3 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000789	Infertility
HP:0032479	Preimplantation lethality

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000249_1	Basal cell carcinoma	4.000000e-12
GCST002331_3	Basal cell carcinoma	7.000000e-14
GCST002842_1	Basal cell carcinoma	8.000000e-17
GCST004599_241	Mean platelet volume	3.000000e-10

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3638347 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

4 measured of 6 human assays (6 total across all organisms); most potent 4 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-6-(dimethylamino)naphthalene-2-carboxamide	IC50	3500 nM	US-8969333: Therapeutic compositions and methods
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-oxo-1-[[4-[4-[5-(2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl)pentanoylamino]butanoylamino]phenyl]methylamino]pentan-2-yl]-6-(dimethylamino)naphthalene-2-carboxamide	IC50	3500 nM	US-8969333: Therapeutic compositions and methods
N-[(2S)-5-[(1-amino-2-chloroethylidene)amino]-1-(benzylamino)-1-oxopentan-2-yl]-3-phenylbenzamide	IC50	5000 nM	US-8969333: Therapeutic compositions and methods
N-[(2S)-1-amino-5-[(1-amino-2-chloroethylidene)amino]-1-oxopentan-2-yl]benzamide	IC50	12500 nM	US-8969333: Therapeutic compositions and methods

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.46	IC50	3500	nM	CHEMBL3682418
5.46	IC50	3500	nM	CHEMBL3682419
5.30	IC50	5000	nM	CHEMBL3682417

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation	2
aristolochic acid I	increases expression	1
bisphenol A	increases methylation, decreases methylation, affects cotreatment	1
aflatoxin B2	increases methylation	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Aflatoxin B1	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
CHEMBL3706281	Binding	Colorimetric Assay: The inhibition efficacy of PAD4 inhibitors were determined by colorimetric measurement of citrulline generated by PAD4 catalyzed citrullination of BAEE. 0.2 μg PAD4 was pre-incubated with inhibitors in 100 μl buffer cont	Therapeutic compositions and methods

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure
NCT00006156	Not specified	COMPLETED	Feasibility Study for Development of an Early Test for Ovarian Failure
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists