SPRR3

Summary

SPRR3 (small proline rich protein 3, HGNC:11268) is a protein-coding gene on chromosome 1q21.3, encoding Small proline-rich protein 3 (Q9UBC9). Cross-linked envelope protein of keratinocytes.

Predicted to enable structural molecule activity. Predicted to be involved in keratinocyte differentiation and wound healing. Located in Golgi apparatus and perinuclear region of cytoplasm.

Source: NCBI Gene 6707 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 38 total
• Druggable target: yes
• MANE Select transcript: NM_001097589

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11268
Approved symbol	SPRR3
Name	small proline rich protein 3
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000163209
Ensembl biotype	protein_coding
OMIM	182271
Entrez	6707

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 3 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000295367, ENST00000331860, ENST00000443178, ENST00000495845

RefSeq mRNA: 2 — MANE Select: NM_001097589 NM_001097589, NM_005416

CCDS: CCDS1033

Canonical transcript exons

ENST00000295367 — 2 exons

Exon	Start	End
ENSE00001901937	153003002	153003856
ENSE00001949962	153001749	153001793

Expression profiles

Bgee: expression breadth ubiquitous, 174 present calls, max score 100.00.

FANTOM5 (CAGE): breadth broad, TPM avg 54.9432 / max 21929.2554, expressed in 183 samples.

FANTOM5 promoters (24 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5337	54.1656	178
5341	0.3012	18
5342	0.1094	12
5351	0.0346	10
5358	0.0343	10
5360	0.0267	6
5345	0.0255	10
5355	0.0251	8
5352	0.0236	8
5359	0.0223	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	100.00	gold quality
oral cavity	UBERON:0000167	99.99	gold quality
pharyngeal mucosa	UBERON:0000355	99.99	gold quality
buccal mucosa cell	CL:0002336	99.98	gold quality
body of tongue	UBERON:0011876	99.97	gold quality
amniotic fluid	UBERON:0000173	99.95	gold quality
tongue squamous epithelium	UBERON:0006919	99.94	gold quality
gingiva	UBERON:0001828	99.90	gold quality
gingival epithelium	UBERON:0001949	99.86	gold quality
tongue	UBERON:0001723	99.81	gold quality
esophagus mucosa	UBERON:0002469	99.79	gold quality
periodontal ligament	UBERON:0008266	99.71	gold quality
cervix epithelium	UBERON:0004801	99.69	gold quality
squamous epithelium	UBERON:0006914	99.56	gold quality
superior surface of tongue	UBERON:0007371	99.56	gold quality
cervix squamous epithelium	UBERON:0006922	99.53	gold quality
esophagus squamous epithelium	UBERON:0006920	99.41	gold quality
epithelium of esophagus	UBERON:0001976	99.11	gold quality
nasal cavity epithelium	UBERON:0005384	97.10	gold quality
sperm	CL:0000019	95.24	gold quality
vagina	UBERON:0000996	95.12	gold quality
male germ cell	CL:0000015	93.50	gold quality
esophagus	UBERON:0001043	91.49	gold quality
uterine cervix	UBERON:0000002	90.96	gold quality
right coronary artery	UBERON:0001625	89.21	gold quality
ectocervix	UBERON:0012249	89.18	gold quality
gall bladder	UBERON:0002110	88.41	gold quality
palpebral conjunctiva	UBERON:0001812	87.22	gold quality
tonsil	UBERON:0002372	86.59	gold quality
right uterine tube	UBERON:0001302	86.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	88599.56
E-ANND-2	yes	24567.63
E-MTAB-8221	yes	19963.05
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF3, FOS, JUN

miRNA regulators (miRDB)

13 targeting SPRR3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-651-5P	99.64	68.49	1104
HSA-MIR-338-3P	98.14	67.38	1137
HSA-MIR-1245B-3P	98.01	68.91	1387
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-6812-5P	97.56	65.39	1059
HSA-MIR-4456	97.50	64.88	1678
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-6834-5P	96.25	64.88	823
HSA-MIR-759	96.16	66.77	873
HSA-MIR-1298-5P	95.96	64.81	573

Literature-anchored findings (GeneRIF, showing 17)

• SPR3 transcripts were significantly increased in human papillomavirus 11-infected tissues and minimally increased in human papillomavirus 59-infected tissues (PMID:14748073)
• A marker of human esophageal neoplastic progression (PMID:15221970)
• Esophagin/SPRR3 may play a role in the maintenance of normal esophageal epithelial homeostasis, and aberrant expression of Esophagin/SPRR3 may contribute to the tumorigenesis of esophageal squamous cell carcinoma (PMID:17935133)
• Association of psoriasis to PGLYRP and SPRR genes at PSORS4 locus on 1q shows heterogeneity between Finnish, Swedish and Irish families. (PMID:18643845)
• These data suggest that SPRR3 may play a role in vascular smooth muscle cells adaptation to local biomechanical stress within the plaque microenvironment. (PMID:18832573)
• Sciellin, SPRR3, and periplakin transcripts were all upregulated (4.67-, 4.95-, 2.77-fold, respectively) by prolonged exposure to cyclic strain (24-72 h), but not at earlier time points. (PMID:19211270)
• Results suggest that increased expression of SPRR3 is involved in colorectal tumorigenesis. (PMID:20379613)
• two isoforms of SPRR3 were characterized from saliva of preterm human newborn and autoptic fetal oral mucosa, parotid and submandibular gland samples. (PMID:20599699)
• The SPRR3 variant associated with eczema carried an extra 24-bp repeat in the central domain, which may alter the physical properties of the cornified cell envelope (PMID:21490620)
• The quantitative analysis of SPRR3 mRNA is a robust and reliable method to monitor the malignant transformation of the healthy esophageal mucosa into esophageal squamous cell carcinoma. (PMID:21777580)
• This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways (PMID:22076481)
• Results implicate that SPRR3 might serve as a radiation-sensitive predictor of ESCC. (PMID:23820115)
• SPRR3v2 mRNA level in non-lesional AD skin correlated with severity of AD, and SPRR3 protein level in non-lesional AD skin correlated inversely with pruritus. (PMID:27304082)
• Fine particulate matter (PM2.5) inhibits ciliogenesis by increasing SPRR3 expression via c-Jun activation in RPE cells and skin keratinocytes. (PMID:30850686)
• Small Proline-Rich Protein 3 Regulates IL-33/ILC2 Axis to Promote Allergic Airway Inflammation. (PMID:35126350)
• SPRR3 Contributes to Aggressiveness of Pancreatic Cancer Cells via NF-kappaB Signaling Pathway. (PMID:36685674)
• Predictive role and molecular biological function of proline-rich small repeat protein SPRR3 in the diagnosis of lung adenocarcinoma. (PMID:39134193)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Sprr3	ENSMUSG00000045539
rattus_norvegicus	Sprr3	ENSRNOG00000024046

Paralogs (20): LCE2B (ENSG00000159455), SPRR2G (ENSG00000159516), LCE3D (ENSG00000163202), SPRR1B (ENSG00000169469), SPRR1A (ENSG00000169474), LCE1D (ENSG00000172155), SPRR4 (ENSG00000184148), LCE3A (ENSG00000185962), LCE3E (ENSG00000185966), LCE5A (ENSG00000186207), LCE1E (ENSG00000186226), LCE2A (ENSG00000187173), LCE2C (ENSG00000187180), LCE2D (ENSG00000187223), LCE3B (ENSG00000187238), KPLCE (ENSG00000198854), PRR9 (ENSG00000203783), LELP1 (ENSG00000203784), LCE1F (ENSG00000240386), LCE3C (ENSG00000244057)

Protein

Protein identifiers

Small proline-rich protein 3 — Q9UBC9 (reviewed: Q9UBC9)

Alternative names: 22 kDa pancornulin, Cornifin beta, Esophagin

All UniProt accessions (2): B1AN48, Q9UBC9

UniProt curated annotations — full annotation on UniProt →

Function. Cross-linked envelope protein of keratinocytes.

Subcellular location. Cytoplasm.

Induction. During squamous differentiation of epidermal keratinocytes.

Similarity. Belongs to the cornifin (SPRR) family.

RefSeq proteins (2): NP_001091058, NP_005407 (=MANE)

Domains & families (InterPro)

Pfam: PF02389

UniProt features (27 total): repeat 14, region of interest 3, sequence variant 3, compositionally biased region 2, sequence conflict 2, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBC9-F1	52.87	0.00

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): 2

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-1266738	Developmental Biology
R-HSA-6805567	Keratinization

MSigDB gene sets: 85 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, SARRIO_EPITHELIAL_MESENCHYMAL_TRANSITION_DN, GOBP_WOUND_HEALING, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOZGIT_ESR1_TARGETS_UP, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_KERATINIZATION, GOBP_SKIN_DEVELOPMENT, chr1q21, GOCC_CORNIFIED_ENVELOPE, WANG_BARRETTS_ESOPHAGUS_DN, COULOUARN_TEMPORAL_TGFB1_SIGNATURE_UP, DODD_NASOPHARYNGEAL_CARCINOMA_DN, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, LIU_CDX2_TARGETS_DN

GO Biological Process (4): epidermis development (GO:0008544), keratinocyte differentiation (GO:0030216), keratinization (GO:0031424), wound healing (GO:0042060)

GO Molecular Function (2): structural molecule activity (GO:0005198), protein binding (GO:0005515)

GO Cellular Component (6): cornified envelope (GO:0001533), Golgi apparatus (GO:0005794), cytosol (GO:0005829), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
cellular anatomical structure	3
tissue development	1
epidermal cell differentiation	1
skin development	1
keratinocyte differentiation	1
multicellular organismal process	1
response to wounding	1
tissue regeneration	1
molecular_function	1
binding	1
plasma membrane	1
endomembrane system	1
intracellular membrane-bounded organelle	1
extracellular vesicle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

836 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
SPRR3	IVL	P07476	866
SPRR3	LORICRIN	P23490	853
SPRR3	S100A10	P08206	759
SPRR3	S100A6	P06703	746
SPRR3	C4BPA	P04003	721
SPRR3	SPRR2A	P35326	699
SPRR3	TCHH	Q07283	679
SPRR3	SPRR4	Q96PI1	668
SPRR3	S100A1	P23297	628
SPRR3	SPRR2D	P22532	624
SPRR3	LCE3D	Q9BYE3	582
SPRR3	SPRR2E	P22531	571
SPRR3	TGM3	Q08188	554
SPRR3	SPRR2G	Q9BYE4	523
SPRR3	KRT33A	O76009	521

IntAct

37 interactions, top by confidence:

A	B	Type	Score
SNW1	AQR	psi-mi:“MI:0914”(association)	0.650
NSL1	NDC80	psi-mi:“MI:0914”(association)	0.640
SPRR3	JOSD2	psi-mi:“MI:0915”(physical association)	0.590
RAC2	RAC1	psi-mi:“MI:0914”(association)	0.560
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
	AP3B1	psi-mi:“MI:0914”(association)	0.350
AKT1	CSTB	psi-mi:“MI:0914”(association)	0.350
SRRT	A2ML1	psi-mi:“MI:0914”(association)	0.350
HSF2	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRXL2A	A2ML1	psi-mi:“MI:0914”(association)	0.350
STK11	A2ML1	psi-mi:“MI:0914”(association)	0.350
EBF2	LILRA5	psi-mi:“MI:0914”(association)	0.350
JAK2	BACH1	psi-mi:“MI:0914”(association)	0.350
UTP11	KLHL41	psi-mi:“MI:0914”(association)	0.350
RCAN2	HSBP1	psi-mi:“MI:0914”(association)	0.350
GOLGA7B	FGFR1	psi-mi:“MI:0914”(association)	0.350
LY86	TMEM131L	psi-mi:“MI:0914”(association)	0.350
ZNF550	A2ML1	psi-mi:“MI:0914”(association)	0.350
CORO1C	A2ML1	psi-mi:“MI:0914”(association)	0.350
FNDC5	A2ML1	psi-mi:“MI:0914”(association)	0.350
TIMM10	IGLL5	psi-mi:“MI:0914”(association)	0.350
GAS2L1	ZZEF1	psi-mi:“MI:0914”(association)	0.350
FNBP4	AMY1A	psi-mi:“MI:0914”(association)	0.350
TIMD4	ST3GAL3	psi-mi:“MI:0914”(association)	0.350
BMP4	A2ML1	psi-mi:“MI:0914”(association)	0.350
CHRNB2	SNX2	psi-mi:“MI:0914”(association)	0.350
CX3CL1	ANKRD13A	psi-mi:“MI:0914”(association)	0.350

BioGRID (36): SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Proximity Label-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), JOSD2 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS), SPRR3 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTR4, A6QNZ4, O14633, O70554, O70555, O70556, O70557, O70558, O70559, O70560, O70562, P15265, P22528, P22531, P22532, P35321, P35322, P35323, P35324, P35325, P35326, P49901, Q28658, Q32L04, Q4KL71, Q4R956, Q5T5B0, Q5T750, Q5T752, Q5T754, Q5T870, Q5T871, Q5TA76, Q5TA77, Q5TA78, Q5TA79, Q5TA81, Q5TA82, Q5TCM9, Q62266

Diamond homologs: O09116, Q28658, Q9UBC9, P35324, Q62266, Q62267, Q63532

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	28
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

273 predictions. Top by Δscore:

Variant	Effect	Δscore
1:153001790:GCAG:G	donor_gain	1.0000
1:153001791:CAGG:C	donor_loss	1.0000
1:153001792:AGGTG:A	donor_loss	1.0000
1:153001793:GGT:G	donor_loss	1.0000
1:153001794:GT:G	donor_loss	1.0000
1:153002683:GTGT:G	donor_gain	1.0000
1:153001794:G:GG	donor_gain	0.9900
1:153001795:T:A	donor_loss	0.9900
1:153002839:A:G	donor_gain	0.9900
1:153002685:GT:G	donor_gain	0.9800
1:153002687:G:GG	donor_gain	0.9800
1:153001789:AGCAG:A	donor_gain	0.9700
1:153001790:GCAGG:G	donor_gain	0.9700
1:153002835:GAAGA:G	donor_gain	0.9700
1:153002882:G:T	donor_gain	0.9700
1:153002996:CTCTA:C	acceptor_loss	0.9700
1:153002997:TCTA:T	acceptor_loss	0.9700
1:153002998:CTA:C	acceptor_loss	0.9700
1:153002999:TAGGT:T	acceptor_loss	0.9700
1:153001791:CAG:C	donor_gain	0.9600
1:153002682:A:AG	donor_gain	0.9400
1:153003000:A:AG	acceptor_gain	0.9400
1:153003001:G:GG	acceptor_gain	0.9400
1:153001792:AG:A	donor_gain	0.9300
1:153001793:GG:G	donor_gain	0.9300
1:153002999:TAGG:T	acceptor_gain	0.9300
1:153002989:GTTTT:G	acceptor_loss	0.9200
1:153002902:GCTC:G	donor_gain	0.9000
1:153003000:AGGTC:A	acceptor_gain	0.8900
1:153002919:A:T	donor_gain	0.8700

AlphaMissense

1084 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:153003024:A:C	S2R	0.686
1:153003026:T:A	S2R	0.686
1:153003026:T:G	S2R	0.686
1:153003117:T:C	F33L	0.601
1:153003119:T:A	F33L	0.601
1:153003119:T:G	F33L	0.601
1:153003384:T:C	F122L	0.595
1:153003386:C:A	F122L	0.595
1:153003386:C:G	F122L	0.595

dbSNP variants (sampled 300 via entrez): RS1000808636 (1:153002354 C>A), RS1001403725 (1:153002405 G>A), RS1002835801 (1:153003656 C>A,T), RS1002912325 (1:153002437 G>A), RS1004394387 (1:153003936 G>C), RS1005506872 (1:153001341 G>A), RS1006255842 (1:153001417 C>T), RS1006567281 (1:152999956 G>A), RS1006716952 (1:153002982 A>G), RS1006868761 (1:153001134 A>T), RS1009056649 (1:153001863 C>T), RS1009559028 (1:153004029 G>A,T), RS1010990447 (1:153004249 C>A,T), RS1011390728 (1:153000598 T>C), RS1011935323 (1:153000115 A>G)

Disease associations

OMIM: gene MIM:182271 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST002740_17	Inflammatory skin disease	2.000000e-15
GCST007564_25	Asthma or allergic disease (pleiotropy)	5.000000e-09
GCST008916_87	Asthma	2.000000e-13

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295970 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
hydroquinone	increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression, increases methylation	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Particulate Matter	increases abundance, increases expression, decreases reaction	2
deoxynivalenol	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
4-aminophenylarsenoxide	decreases reaction, affects binding	1
CGP 52608	affects binding, increases reaction	1
monomethylarsonous acid	increases expression	1
(+)-JQ1 compound	decreases expression	1
Arsenic Trioxide	affects binding, decreases reaction	1
Allergens	increases expression, decreases reaction, increases abundance	1
Antimony Potassium Tartrate	decreases expression	1
Arsenic	affects methylation	1
Vehicle Emissions	decreases reaction, increases abundance, increases expression	1
Fluorouracil	affects expression	1
Furaldehyde	affects cotreatment, decreases expression, affects localization	1
Nickel	increases expression	1
Sodium Chloride	affects cotreatment, affects localization, decreases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tretinoin	decreases expression, increases expression	1
8-Bromo Cyclic Adenosine Monophosphate	increases expression	1
Isotretinoin	decreases expression	1
Aflatoxin B1	increases expression	1
Lactic Acid	decreases expression	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
CHEMBL4118964	Binding	Binding affinity to SPRR3 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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