PADI3

Summary

PADI3 (peptidyl arginine deiminase 3, HGNC:18337) is a protein-coding gene on chromosome 1p36.13, encoding Protein-arginine deiminase type-3 (Q9ULW8). Catalyzes the deimination of arginine residues of proteins.

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. The type III enzyme modulates hair structural proteins, such as filaggrin in the hair follicle and trichohyalin in the inner root sheath, during hair follicle formation. Together with the type I enzyme, this enzyme may also play a role in terminal differentiation of the epidermis. This gene exists in a cluster with four other paralogous genes.

Source: NCBI Gene 51702 — RefSeq curated summary.

At a glance

• Gene–disease (curated): uncombable hair syndrome 1 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 164 total — 5 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_016233

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18337
Approved symbol	PADI3
Name	peptidyl arginine deiminase 3
Location	1p36.13
Locus type	gene with protein product
Status	Approved
Aliases	PDI3
Ensembl gene	ENSG00000142619
Ensembl biotype	protein_coding
OMIM	606755
Entrez	51702

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000375460

RefSeq mRNA: 1 — MANE Select: NM_016233 NM_016233

CCDS: CCDS179

Canonical transcript exons

ENST00000375460 — 16 exons

Exon	Start	End
ENSE00000955336	17259578	17259758
ENSE00000955342	17270879	17270982
ENSE00000955349	17280671	17280796
ENSE00001162330	17280350	17280429
ENSE00001162335	17276774	17276876
ENSE00001162342	17276519	17276663
ENSE00001162351	17274635	17274786
ENSE00001162367	17271067	17271178
ENSE00001162376	17270233	17270411
ENSE00001162383	17267837	17267962
ENSE00001162391	17266719	17266836
ENSE00001162396	17265659	17265720
ENSE00001162404	17262133	17262205
ENSE00001467155	17282846	17284233
ENSE00001467168	17249098	17249229
ENSE00001613238	17273340	17273447

Expression profiles

Bgee: expression breadth broad, 43 present calls, max score 91.96.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.4975 / max 67.9565, expressed in 125 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
990	0.4975	125

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	91.96	gold quality
esophagus mucosa	UBERON:0002469	78.46	gold quality
urinary bladder	UBERON:0001255	77.20	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	75.01	silver quality
olfactory segment of nasal mucosa	UBERON:0005386	58.79	gold quality
esophagus	UBERON:0001043	55.87	gold quality
vagina	UBERON:0000996	55.46	gold quality
tonsil	UBERON:0002372	49.96	gold quality
skin of abdomen	UBERON:0001416	49.59	gold quality
gall bladder	UBERON:0002110	49.19	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	47.50	silver quality
zone of skin	UBERON:0000014	47.20	gold quality
prostate gland	UBERON:0002367	45.35	gold quality
skin of leg	UBERON:0001511	45.28	gold quality
islet of Langerhans	UBERON:0000006	44.86	gold quality
ectocervix	UBERON:0012249	42.70	gold quality
mucosa of transverse colon	UBERON:0004991	40.42	silver quality
saliva-secreting gland	UBERON:0001044	39.72	gold quality
uterine cervix	UBERON:0000002	39.66	gold quality
stromal cell of endometrium	CL:0002255	39.35	gold quality
minor salivary gland	UBERON:0001830	39.34	gold quality
skeletal muscle tissue	UBERON:0001134	39.19	gold quality
bone marrow cell	CL:0002092	38.36	gold quality
bone marrow	UBERON:0002371	37.75	gold quality
rectum	UBERON:0001052	37.29	silver quality
colonic epithelium	UBERON:0000397	37.20	gold quality
duodenum	UBERON:0002114	36.77	gold quality
granulocyte	CL:0000094	36.66	gold quality
muscle tissue	UBERON:0002385	36.60	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, JUN, SP1, SP3

miRNA regulators (miRDB)

54 targeting PADI3, 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-3667-3P	99.99	67.17	1636
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-12130	99.75	65.47	452
HSA-MIR-1976	99.74	65.48	1127
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-3158-5P	99.65	67.51	1763
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-4753-5P	99.54	68.51	1356
HSA-MIR-6832-3P	99.52	70.44	1726
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-223-5P	99.24	68.82	1206
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-6815-3P	99.13	68.98	1530
HSA-MIR-328-5P	99.08	64.65	1000
HSA-MIR-10524-5P	99.05	66.08	963
HSA-MIR-29B-1-5P	98.86	68.35	1364
HSA-MIR-331-3P	98.76	64.91	793
HSA-MIR-589-5P	98.72	66.96	927
HSA-MIR-6885-5P	98.71	64.33	902
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-4646-3P	98.65	66.98	693
HSA-MIR-6887-5P	98.56	68.49	1295
HSA-MIR-6795-5P	98.52	68.51	1277
HSA-MIR-1248	98.47	67.54	1314

Literature-anchored findings (GeneRIF, showing 18)

• peptidylarginine deiminase types 1 and 3 loci map to chromosomal band 1p36.13 (PMID:15150696)
• PAD1 and 3 are able to modify filaggrin (PMID:15675958)
• PAD3 is co-located with filaggrin within the filamentous matrix of the deeper corneocytes where the protein is deiminated. (PMID:16091842)
• PADI3 expression is driven by Sp1/Sp3 and NF-Y binding to the promoter region (PMID:16671893)
• cytoplasmic S100A3 within the cuticular layer is mostly co-localized with the type III isoform of peptidylarginine deiminase (PAD3) (PMID:18083705)
• Peptidylarginine deiminase Intergenic Enhancer is a strong enhancer of the PADI3 promoter in Ca2+-differentiated epidermal keratinocytes, and requires bound (PMID:18923650)
• These results reveal the molecular bases of the expression specificity of PADI1 and PADI3 during keratinocyte differentiation through a long-range enhancer and support a model of PADI gene regulation depending on c-Jun-JunD competition. (PMID:18952102)
• Crystals of PAD3 obtained using polyethylene glycol 400 as a precipitant diffracted to 2.95 A resolution using synchrotron radiation (PMID:22684066)
• The prevalence and extent of ILD was markedly higher among RA patients with anti-PAD3/4 cross-reactive antibodies, even after accounting for relevant confounders, particularly among ever smokers. (PMID:24901704)
• We identified the presence of PADI3 mRNA expression in synovial tissue and PADI2 and PADI4 mRNA expressions in fibroblast-like synoviocytes from patients with rheumatoid arthritis. (PMID:26255191)
• Identify acefylline as an activator of peptidylarginine deiminase 1 and 3 in the epidermis, resulting in filaggrin deimination. (PMID:26616205)
• The two enzymes PADI3 and TGM3, responsible for posttranslational protein modifications, and their target structural protein TCHH are all involved in hair shaft formation. (PMID:27866708)
• Mutations in PADI3, which encodes a protein that is essential to proper hair-shaft formation, were associated with Central Centrifugal Cicatricial Alopecia. (PMID:30763140)
• Peptidylarginine Deiminase Isozyme-Specific PAD2, PAD3 and PAD4 Inhibitors Differentially Modulate Extracellular Vesicle Signatures and Cell Invasion in Two Glioblastoma Multiforme Cell Lines. (PMID:32098295)
• Peptidylarginine Deiminase Inhibitor Application, Using Cl-Amidine, PAD2, PAD3 and PAD4 Isozyme-Specific Inhibitors in Pancreatic Cancer Cells, Reveals Roles for PAD2 and PAD3 in Cancer Invasion and Modulation of Extracellular Vesicle Signatures. (PMID:33573274)
• Citrullination of pyruvate kinase M2 by PADI1 and PADI3 regulates glycolysis and cancer cell proliferation. (PMID:33741961)
• Structures of human peptidylarginine deiminase type III provide insights into substrate recognition and inhibitor design. (PMID:33971157)
• PADI3 inhibits epithelial-mesenchymal transition by targeting CKS1-induced signal transduction in colon cancer. (PMID:39206995)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	padi2	ENSDARG00000044167
mus_musculus	Padi3	ENSMUSG00000025328
rattus_norvegicus	Padi3	ENSRNOG00000006950

Paralogs (4): PADI2 (ENSG00000117115), PADI1 (ENSG00000142623), PADI4 (ENSG00000159339), PADI6 (ENSG00000276747)

Protein

Protein identifiers

Protein-arginine deiminase type-3 — Q9ULW8 (reviewed: Q9ULW8)

Alternative names: Peptidylarginine deiminase III, Protein-arginine deiminase type III

All UniProt accessions (1): Q9ULW8

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the deimination of arginine residues of proteins.

Subcellular location. Cytoplasm.

Tissue specificity. Hair follicles, and epidermis at very low levels.

Disease relevance. Uncombable hair syndrome 1 (UHS1) [MIM:191480] A form of uncombable hair syndrome, a condition characterized by scalp hair that is impossible to comb due to the haphazard arrangement of the hair bundles. A characteristic morphologic feature is a triangular to reniform to heart shape on cross-sections, and a groove, canal or flattening along the entire length of the hair. Most individuals are affected early in childhood and the hair takes on a spun-glass appearance with the hair becoming dry, curly, glossy, lighter in color, and progressively uncombable. The hair growth rate can range from slow to normal, and the condition improves with age. UHS1 inheritance is autosomal dominant. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the protein arginine deiminase family.

RefSeq proteins (1): NP_057317* (*=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

Catalyzed reactions (Rhea), 1 shown:

• L-arginyl-[protein] + H2O = L-citrullyl-[protein] + NH4(+) (RHEA:18089)

UniProt features (83 total): strand 52, helix 16, sequence variant 8, turn 5, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
7D5V	X-RAY DIFFRACTION	2.1
7D8N	X-RAY DIFFRACTION	2.75
6CE1	X-RAY DIFFRACTION	2.8
7D4Y	X-RAY DIFFRACTION	2.96
7DAN	X-RAY DIFFRACTION	3.1
7D5R	X-RAY DIFFRACTION	3.15
7D56	X-RAY DIFFRACTION	3.17

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9ULW8-F1	93.67	0.84

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-3247509	Chromatin modifying enzymes

MSigDB gene sets: 104 (showing top): GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_UP, MARTINEZ_RB1_TARGETS_DN, BACH2_01, JAZAG_TGFB1_SIGNALING_VIA_SMAD4_UP, TGANTCA_AP1_C, MODULE_397, NAKAMURA_METASTASIS, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_CARBON_NITROGEN_BUT_NOT_PEPTIDE_BONDS_IN_LINEAR_AMIDINES, NAKAMURA_METASTASIS_MODEL_UP, GSE13887_HEALTHY_VS_LUPUS_RESTING_CD4_TCELL_UP, GOMF_HYDROLASE_ACTIVITY_ACTING_ON_CARBON_NITROGEN_BUT_NOT_PEPTIDE_BONDS, chr1p36, RICKMAN_HEAD_AND_NECK_CANCER_E, BHAT_ESR1_TARGETS_NOT_VIA_AKT1_UP

GO Biological Process (0):

GO Molecular Function (5): protein-arginine deiminase activity (GO:0004668), calcium ion binding (GO:0005509), identical protein binding (GO:0042802), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (4): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Chromatin organization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
hydrolase activity, acting on carbon-nitrogen (but not peptide) bonds, in linear amidines	1
metal ion binding	1
protein binding	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

376 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
PADI3	TCHH	Q07283	880
PADI3	FLG2	Q5D862	846
PADI3	FLG	P20930	839
PADI3	S100A3	P33764	705
PADI3	SPARC	P09486	491
PADI3	ELANE	P08246	470
PADI3	PRTN3	P15637	457
PADI3	MPO	P05164	431
PADI3	H3C1	P02295	397
PADI3	H3C14	Q71DI3	396
PADI3	H3-4	Q16695	396
PADI3	H3-7	Q5TEC6	396
PADI3	H3-5	Q6NXT2	395
PADI3	H3-3A	P06351	394
PADI3	TGM3	Q08188	381

IntAct

62 interactions, top by confidence:

A	B	Type	Score
OAZ3	AZIN1	psi-mi:“MI:0914”(association)	0.800
SMARCD1	ARID1A	psi-mi:“MI:0914”(association)	0.790
KIF3A	KIF3C	psi-mi:“MI:0914”(association)	0.730
PADI3	PADI3	psi-mi:“MI:0915”(physical association)	0.670
ANXA9	PPL	psi-mi:“MI:0914”(association)	0.660
RAB11B	SH3BP5	psi-mi:“MI:0914”(association)	0.640
INCA1	PADI3	psi-mi:“MI:0915”(physical association)	0.560
REL	PADI3	psi-mi:“MI:0915”(physical association)	0.560
PADI3	ATP5PB	psi-mi:“MI:0915”(physical association)	0.560
PADI3	MAPK3	psi-mi:“MI:0915”(physical association)	0.560
DNALI1	PADI3	psi-mi:“MI:0915”(physical association)	0.560
KLF11	PADI3	psi-mi:“MI:0915”(physical association)	0.560
NUP58	PADI3	psi-mi:“MI:0915”(physical association)	0.560
MRPL38	DUSP14	psi-mi:“MI:0914”(association)	0.530
FBXL4	DUSP14	psi-mi:“MI:0914”(association)	0.530
CPLX3	CIAO1	psi-mi:“MI:0914”(association)	0.530

BioGRID (56): PADI3 (Two-hybrid), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI4 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI1 (Affinity Capture-MS), NFKB1 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS), PADI3 (Affinity Capture-MS)

ESM2 similar proteins: A6NC97, A8MVJ9, F4IRQ5, F4ISV6, F4IY62, G5ECQ8, O02849, O15091, O64967, O88806, P10759, P17532, P20717, P23109, P53215, P70708, Q05B50, Q08642, Q0EAB8, Q2HZ26, Q3V1D3, Q4R366, Q54E29, Q5K651, Q5M965, Q6BKD4, Q6CW75, Q6CY84, Q6DDV1, Q6FPX3, Q75DJ3, Q7SDM8, Q86VD1, Q8C5W4, Q8CGU9, Q8CGV2, Q8IVG5, Q8IWU9, Q8L627, Q9CY52

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

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	1
Uncertain significance	121
Likely benign	15
Benign	9

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
374869	NM_016233.2(PADI3):c.1813C>A (p.Pro605Thr)	Pathogenic
4277967	NM_016233.2(PADI3):c.274-2A>G	Pathogenic
599197	NM_016233.2(PADI3):c.832-2A>G	Pathogenic
599198	NM_016233.2(PADI3):c.1955G>A (p.Arg652Lys)	Pathogenic
599199	NM_016233.2(PADI3):c.628C>T (p.Arg210Trp)	Pathogenic
3602987	NM_016233.2(PADI3):c.505C>T (p.Gln169Ter)	Likely pathogenic

SpliceAI

2527 predictions. Top by Δscore:

Variant	Effect	Δscore
1:17249228:GG:G	donor_gain	1.0000
1:17249229:GG:G	donor_gain	1.0000
1:17259754:GCCAT:G	donor_gain	1.0000
1:17265653:TTGCA:T	acceptor_loss	1.0000
1:17265654:TGCA:T	acceptor_loss	1.0000
1:17265655:GCAG:G	acceptor_loss	1.0000
1:17265656:CA:C	acceptor_loss	1.0000
1:17265657:A:AC	acceptor_loss	1.0000
1:17265657:A:AG	acceptor_gain	1.0000
1:17265658:G:GG	acceptor_gain	1.0000
1:17265658:GA:G	acceptor_gain	1.0000
1:17265658:GAC:G	acceptor_gain	1.0000
1:17265658:GACAT:G	acceptor_gain	1.0000
1:17265719:AGG:A	donor_loss	1.0000
1:17265722:T:A	donor_loss	1.0000
1:17266711:ATT:A	acceptor_gain	1.0000
1:17266713:T:TA	acceptor_gain	1.0000
1:17266833:CAAG:C	donor_loss	1.0000
1:17266834:AAG:A	donor_loss	1.0000
1:17266837:G:GC	donor_loss	1.0000
1:17266838:T:G	donor_loss	1.0000
1:17267826:T:TA	acceptor_gain	1.0000
1:17267832:CACAG:C	acceptor_loss	1.0000
1:17267835:A:AC	acceptor_loss	1.0000
1:17267835:A:AG	acceptor_gain	1.0000
1:17267836:G:GC	acceptor_gain	1.0000
1:17267836:GA:G	acceptor_gain	1.0000
1:17267836:GAC:G	acceptor_gain	1.0000
1:17267836:GACC:G	acceptor_gain	1.0000
1:17267836:GACCT:G	acceptor_gain	1.0000

AlphaMissense

4410 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:17274716:A:C	S413R	0.998
1:17274718:C:A	S413R	0.998
1:17274718:C:G	S413R	0.998
1:17276604:T:A	W465R	0.997
1:17276604:T:C	W465R	0.997
1:17271170:T:A	W347R	0.990
1:17271170:T:C	W347R	0.990
1:17276777:T:C	F486L	0.989
1:17276779:C:A	F486L	0.989
1:17276779:C:G	F486L	0.989
1:17276608:T:C	L466S	0.988
1:17276644:T:A	V478D	0.988
1:17280752:T:C	F573L	0.988
1:17280754:C:A	F573L	0.988
1:17280754:C:G	F573L	0.988
1:17270933:T:A	W296R	0.987
1:17270933:T:C	W296R	0.987
1:17274708:T:C	L410P	0.987
1:17280690:G:C	R552P	0.987
1:17282972:T:C	F630L	0.987
1:17282974:C:A	F630L	0.987
1:17282974:C:G	F630L	0.987
1:17283059:T:A	W659R	0.987
1:17283059:T:C	W659R	0.987
1:17262134:T:A	V92D	0.985
1:17274706:C:A	N409K	0.983
1:17274706:C:G	N409K	0.983
1:17259735:A:C	S84R	0.982
1:17259737:C:A	S84R	0.982
1:17259737:C:G	S84R	0.982

dbSNP variants (sampled 300 via entrez): RS1000092798 (1:17281403 C>T), RS1000440688 (1:17265155 T>C,G), RS1000447365 (1:17258964 G>A,T), RS1000463327 (1:17276950 GA>G), RS1000471890 (1:17264869 G>A), RS1000605503 (1:17254474 G>A), RS1000608238 (1:17258908 G>C), RS1000675329 (1:17253344 G>A,T), RS1000738284 (1:17276173 A>G,T), RS1000782002 (1:17260214 G>A), RS1000810154 (1:17259930 T>C), RS1001021374 (1:17254695 G>A), RS1001064360 (1:17270730 C>A), RS1001198948 (1:17281785 C>T), RS1001225045 (1:17281527 C>G,T)

Disease associations

OMIM: gene MIM:606755 | disease phenotypes: MIM:191480, MIM:618352

GenCC curated gene-disease

Disease	Classification	Inheritance
uncombable hair syndrome 1	Strong	Autosomal recessive
uncombable hair syndrome	Supportive	Autosomal recessive

Mondo (3): uncombable hair syndrome 1 (MONDO:0020736), central centrifugal cicatricial alopecia (MONDO:0022113), uncombable hair syndrome (MONDO:0008621)

Orphanet (1): Uncombable hair syndrome (Orphanet:1410)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001595	Abnormal hair morphology
HP:0002208	Coarse hair
HP:0002224	Woolly hair
HP:0002232	Patchy alopecia
HP:0002235	Pili canaliculi
HP:0002552	Trichodysplasia
HP:0011359	Dry hair
HP:0011364	White hair
HP:0011463	Childhood onset
HP:0030056	Uncombable hair

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001784_18	Pulmonary function (smoking interaction)	4.000000e-07
GCST002655_13	IgA nephropathy	2.000000e-06
GCST006988_200	Blond vs. brown/black hair color	2.000000e-11
GCST006988_211	Blond vs. brown/black hair color	5.000000e-12
GCST008151_28	Waist circumference	4.000000e-06
GCST008160_73	Waist circumference	4.000000e-06

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003892	pulmonary function measurement
EFO:0004314	forced expiratory volume
EFO:0003924	hair color

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536939	Uncombable hair syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1909488 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 43,337 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL11417	STREPTONIGRIN	2	43,337

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — 3.5.3.15 Peptidyl arginine deiminases (PADI)

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
streptonigrin	Inhibition	6.37	pIC50

ChEMBL bioactivities

13 potent at pChembl≥5 of 21 total, top 13 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.89	IC50	130	nM	CHEMBL57818
6.77	IC50	170	nM	CHEMBL60908
6.41	IC50	390	nM	CHEMBL3113470
6.37	IC50	430	nM	STREPTONIGRIN
6.16	IC50	690	nM	CHEMBL1910971
6.15	IC50	710	nM	CHEMBL58150
5.36	IC50	4400	nM	CHEMBL1714002
5.27	IC50	5400	nM	CHEMBL4468883
5.25	IC50	5600	nM	CHEMBL4473416
5.24	IC50	5800	nM	CHEMBL4464539
5.22	IC50	6000	nM	CHEMBL1910972
5.21	IC50	6200	nM	CHEMBL5715918
5.14	IC50	7300	nM	CHEMBL4449566

PubChem BioAssay actives

12 with measured affinity, of 117 total; 12 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
7-amino-2-pyridin-2-ylquinoline-5,8-dione	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.1300	uM
7-aminoquinoline-5,8-dione	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.1700	uM
7-amino-6-bromoquinoline-5,8-dione	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.3900	uM
5-amino-6-(7-amino-6-methoxy-5,8-dioxoquinolin-2-yl)-4-(2-hydroxy-3,4-dimethoxyphenyl)-3-methylpyridine-2-carboxylic acid	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.4300	uM
2-[[(2S)-1-amino-5-[(1-amino-2-chloroethylidene)amino]-1-oxopentan-2-yl]carbamoyl]benzoic acid;2,2,2-trifluoroacetic acid	627374: Irreversible inhibition of PAD3 assessed as hydrolysis of benzoyl-L-arginine ethyl ester preincubated for 15 mins measured after 15 mins by fluorometric analysis	ic50	0.6900	uM
6-(7-amino-5,8-dioxoquinolin-2-yl)pyridine-2-carboxylic acid	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	0.7100	uM
7-bromo-6-methoxyquinoline-5,8-dione	1069620: Inhibition of recombinant wild-type PAD3 (unknown origin) using N-alpha-Benzoyl-L-arginine amide as substrate preincubated for 15 mins followed by substrate addition measured after 15 mins by COLDER assay	ic50	4.4000	uM
2-chloro-N’-[3-[5-(3-phenylphenyl)-1H-imidazol-2-yl]propyl]ethanimidamide	1632995: Inhibition of recombinant human 6His-tagged PAD3 expressed in Escherichia coli BL21-DE3 pLysS assessed as reduction in residual activity preincubated for 15 mins followed by addition of N-benzoylated arginine ethyl ester hydrochloride measured after 15 mins by colder assay	ic50	5.4000	uM
(E)-4-[(1-amino-2-chloroethylidene)amino]-N-[(3-phenylphenyl)methyl]but-2-enamide	1632995: Inhibition of recombinant human 6His-tagged PAD3 expressed in Escherichia coli BL21-DE3 pLysS assessed as reduction in residual activity preincubated for 15 mins followed by addition of N-benzoylated arginine ethyl ester hydrochloride measured after 15 mins by colder assay	ic50	5.6000	uM
4-[(1-amino-2-chloroethylidene)amino]-N-[(3-phenylphenyl)methyl]butanamide	1632995: Inhibition of recombinant human 6His-tagged PAD3 expressed in Escherichia coli BL21-DE3 pLysS assessed as reduction in residual activity preincubated for 15 mins followed by addition of N-benzoylated arginine ethyl ester hydrochloride measured after 15 mins by colder assay	ic50	5.8000	uM
N-[(2S)-1-amino-5-[(1-amino-2-chloroethylidene)amino]-1-oxopentan-2-yl]benzamide;2,2,2-trifluoroacetic acid	627374: Irreversible inhibition of PAD3 assessed as hydrolysis of benzoyl-L-arginine ethyl ester preincubated for 15 mins measured after 15 mins by fluorometric analysis	ic50	6.0000	uM
2-chloro-N’-[3-[5-chloro-4-(3-phenylphenyl)-1H-imidazol-2-yl]propyl]ethanimidamide	1632995: Inhibition of recombinant human 6His-tagged PAD3 expressed in Escherichia coli BL21-DE3 pLysS assessed as reduction in residual activity preincubated for 15 mins followed by addition of N-benzoylated arginine ethyl ester hydrochloride measured after 15 mins by colder assay	ic50	7.3000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Estradiol	increases reaction, affects cotreatment, increases expression	4
Benzo(a)pyrene	decreases expression, increases expression, increases methylation	3
Valproic Acid	affects expression, increases expression, increases methylation	3
sodium arsenite	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Cadmium Chloride	decreases expression, increases abundance	2
Particulate Matter	increases expression, decreases expression, increases abundance	2
propionaldehyde	increases expression	1
pentanal	increases expression	1
yessotoxin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Temozolomide	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cadmium	decreases expression, increases abundance	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Cisplatin	affects cotreatment, increases expression	1
Diethylhexyl Phthalate	decreases expression	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Nickel	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Silicon Dioxide	increases expression	1
Smoke	increases expression	1
Tetrachlorodibenzodioxin	affects cotreatment, increases expression	1
Tobacco Smoke Pollution	increases expression	1
Aflatoxin B1	increases methylation	1

ChEMBL screening assays

27 unique, capped per target: 27 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1913982	Binding	Irreversible inhibition of PAD3 assessed as residual activity at 1 mM measured after 20 hrs by colorimetric assay in presence of 2 mM benzoyl-L-arginine ethyl ester	The development of N-α-(2-carboxyl)benzoyl-N(5)-(2-fluoro-1-iminoethyl)-l-ornithine amide (o-F-amidine) and N-α-(2-carboxyl)benzoyl-N(5)-(2-chloro-1-iminoethyl)-l-ornithine amide (o-Cl-amidine) as second generation protein arginine deiminase (PAD) inhibitors. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03521687	PHASE4	COMPLETED	Apremilast in the Treatment of Central Centrifugal Cicatricial Alopecia (CCCA)
NCT04207931	PHASE4	RECRUITING	Treatment Results for Patients With Central Centrifugal Cicatricial Alopecia (CCCA): a Multicenter Prospective Study
NCT06998433	PHASE4	NOT_YET_RECRUITING	Effect of Platelet-Rich Plasma Versus Placebo in the Treatment of Central Centrifugal Cicatricial Alopecia
NCT07487948	PHASE2	RECRUITING	Safety and Biomarker Responses of Delgocitinib (JAK1,2,3/TYK2 Inhibitor) in Central Centrifugal Cicatricial Alopecia and Lichen Planopilaris
NCT07508488	PHASE2	RECRUITING	Deucravacitinib in the Treatment of Cicatricial Alopecias
NCT03346668	EARLY_PHASE1	COMPLETED	Role of Neurogenic Inflammation and Topical 6% Gabapentin Therapy in Symptomatic Scarring Alopecia
NCT03491267	EARLY_PHASE1	COMPLETED	Study to Determine Effect of Gentle Wounding to Stimulate Hair Follicle Neogenesis
NCT05416320	EARLY_PHASE1	WITHDRAWN	Calcipotriol as a Novel Treatment for Central Centrifugal Cicatricial Alopecia (CCCA)
NCT05416333	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Azelaic Acid as a Novel Treatment for Central Centrifugal Cicatricial Alopecia (CCCA)
NCT03044782	Not specified	COMPLETED	Barriers to Care and QOL for CCCA Patients
NCT04342091	Not specified	COMPLETED	Follicular Revival in Fibrosing Alopecia: Evaluating Use of Micro-needling
NCT04764331	Not specified	RECRUITING	A Pilot Study of Revian Red All LED Cap as a Novel Treatment for Central Centrifugal Cicatricial Alopecia
NCT05759338	Not specified	COMPLETED	A Study of Revian Red All LED Cap as a Novel Treatment for Central Centrifugal Cicatricial Alopecia