CSTA

Summary

CSTA (cystatin A, HGNC:2481) is a protein-coding gene on chromosome 3q21.1, encoding Cystatin-A (P01040). This is an intracellular thiol proteinase inhibitor.

The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins, and kininogens. This gene encodes a stefin that functions as a cysteine protease inhibitor, forming tight complexes with papain and the cathepsins B, H, and L. The protein is one of the precursor proteins of cornified cell envelope in keratinocytes and plays a role in epidermal development and maintenance. Stefins have been proposed as prognostic and diagnostic tools for cancer.

Source: NCBI Gene 1475 — RefSeq curated summary.

At a glance

• Gene–disease (curated): peeling skin syndrome 4 (Strong, GenCC) — +2 more curated relationships
• GWAS associations: 4
• Clinical variants (ClinVar): 33 total — 5 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 19
• MANE Select transcript: NM_005213

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2481
Approved symbol	CSTA
Name	cystatin A
Location	3q21.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000121552
Ensembl biotype	protein_coding
OMIM	184600
Entrez	1475

Gene structure

Transcript identifiers

Ensembl transcripts: 2 — 2 protein_coding

ENST00000264474, ENST00000479204

RefSeq mRNA: 1 — MANE Select: NM_005213 NM_005213

CCDS: CCDS3011

Canonical transcript exons

ENST00000264474 — 3 exons

Exon	Start	End
ENSE00001078746	122337547	122337648
ENSE00001154683	122341439	122341969
ENSE00001154693	122325248	122325358

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 99.99.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.5757 / max 4112.8988, expressed in 990 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
38229	62.5757	990

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	99.99	gold quality
oral cavity	UBERON:0000167	99.98	gold quality
gingiva	UBERON:0001828	99.97	gold quality
gingival epithelium	UBERON:0001949	99.97	gold quality
cervix squamous epithelium	UBERON:0006922	99.97	gold quality
body of tongue	UBERON:0011876	99.97	gold quality
tongue squamous epithelium	UBERON:0006919	99.96	gold quality
penis	UBERON:0000989	99.95	gold quality
mammalian vulva	UBERON:0000997	99.94	gold quality
tongue	UBERON:0001723	99.93	gold quality
lower esophagus mucosa	UBERON:0035834	99.93	gold quality
epithelium of nasopharynx	UBERON:0001951	99.86	gold quality
superior surface of tongue	UBERON:0007371	99.86	gold quality
nasopharynx	UBERON:0001728	99.83	gold quality
cervix epithelium	UBERON:0004801	99.83	gold quality
squamous epithelium	UBERON:0006914	99.81	gold quality
upper leg skin	UBERON:0004262	99.75	gold quality
esophagus squamous epithelium	UBERON:0006920	99.69	gold quality
esophagus mucosa	UBERON:0002469	99.66	gold quality
upper arm skin	UBERON:0004263	99.64	gold quality
skin of hip	UBERON:0001554	99.51	gold quality
amniotic fluid	UBERON:0000173	99.50	gold quality
monocyte	CL:0000576	99.36	gold quality
nipple	UBERON:0002030	99.33	gold quality
mononuclear cell	CL:0000842	99.32	gold quality
leukocyte	CL:0000738	99.29	gold quality
trabecular bone tissue	UBERON:0002483	99.16	gold quality
skin of abdomen	UBERON:0001416	98.98	gold quality
epithelium of esophagus	UBERON:0001976	98.98	gold quality
periodontal ligament	UBERON:0008266	98.93	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 27.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	31035.64
E-MTAB-10855	yes	3847.01
E-MTAB-8142	yes	3744.02
E-MTAB-10432	yes	1506.11
E-GEOD-139324	yes	1397.53
E-MTAB-10042	yes	1358.03
E-CURD-55	yes	1216.63
E-HCAD-32	yes	1208.17
E-MTAB-8322	yes	1016.44
E-MTAB-10553	yes	765.92
E-HCAD-6	yes	752.17
E-MTAB-6653	yes	602.62
E-HCAD-4	yes	357.07
E-CURD-122	yes	78.95
E-CURD-114	yes	70.36

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, JUN, JUND, TFAP2A, TFAP2C, TFAP2D, ZHX2

miRNA regulators (miRDB)

44 targeting CSTA, 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-1252-5P	100.00	69.80	2774
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3617-3P	99.98	67.86	918
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-589-3P	99.91	69.62	2088
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-1252-3P	99.55	67.71	2862
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-374A-3P	98.87	67.82	1531
HSA-MIR-487A-5P	98.85	69.37	993
HSA-MIR-487B-5P	98.85	69.48	987

Literature-anchored findings (GeneRIF, showing 38)

• expression of cystatin A is regulated via mitogen-activated protein kinase pathways positively by Ras/MEKK1/MKK7/JNK and negatively by Ras/Raf/MEK1/ERK. (PMID:11451947)
• crystal structure in complex with cathepsin H (PMID:12581647)
• The 1,25(OH)(2)D3-responsive element in cystatin A gene is identical to TRE, T2 (-272 to -278). Suppression of Raf-1/MEK1/ERK1,2 signaling pathway increases cystatin A expression of normal human keratinocytes. (PMID:12682854)
• backbone dynamics of the monomeric and domain-swapped dimeric forms of stefin A by (15)N relaxation using a model-free approach (PMID:14747998)
• By using ThT fluorescence, X-ray diffraction, and atomic force microscopy (AFM), it has been shown that human stefins A and B (subfamily A of cystatins) form amyloid fibrils (PMID:15048832)
• No association with psoriasis susceptibility (PMID:15175029)
• Chimeras of stefinA and B have been prepared and guanidine denaturation curves and folding rates have been examined. (PMID:16342276)
• only stefins A and B, i.e. type I cystatins, are up-regulated in lung tumours and thus able to counteract harmful tumour-associated proteolytic activity (PMID:16969475)
• Cystatin A suppresses UVB-induced apoptosis of keratinocytes by the inhibition of caspase 3 activation. (PMID:17412564)
• +344C allele associated with unstable mRNA could result in failing to protect the skin barrier in atopic dermatitis patients from both exogenous and endogenous proteases. (PMID:17441792)
• We conclude that Stefin A expression reduces distant metastasis in breast cancer and propose that this may be due to the inhibition of cysteine cathepsins, such as cathepsin B. (PMID:17985332)
• CSTA TCC haplotype is only associated with psoriasis in those individuals carrying the risk allele at the HLA-Cw6 locus (PMID:18364739)
• Cystatin A binds reduced forms of mite group 1 allergens Der f 1 and Der p 1, in which the cysteine residue at the catalytic center of the protease activity is reduced by treatment with L-cysteine but does not bind oxidized forms. (PMID:19933866)
• A higher pretreated serum level of cystatin A was found to be associated with a higher nodal stage and poorer prognosis of nasopharyngeal carcinoma patients. (PMID:20461718)
• Up-regulation of stefin A, an endogenous inhibitor of cathepsin S, was found in inverted papilloma tissues as compared with its expression level in normal sinus mucosa tissues. (PMID:21038029)
• Findings establish that genetic variability, smoking, and COPD all influence CSTA expression, as does SCC, supporting the concept that CSTA may make pivotal contributions to NSCLC pathogenesis in early and late stages of disease development. (PMID:21325429)
• CSTA significantly increases the risk of developing psoriasis in HLA-Cw6 individuals (PMID:21412248)
• study identified loss-of-function mutations in the gene for protease inhibitor cystatin A as the underlying genetic cause of exfoliative ichthyosis (PMID:21944047)
• findings provide a new molecular understanding of the mechanisms of MYOC-causative glaucoma and reveal CSTA, a serum biomarker for cancer, as a potential biomarker and drug for the treatment of MYOC-induced glaucoma (PMID:22615763)
• Imiquimod suppresses propagation of herpes simplex virus 1 by upregulation of cystatin A via the adenosine receptor A1 pathway (PMID:22787201)
• We identified a homozygous nonsense mutation (p.Lys22X) in the CSTA gene in acral peeling skin syndrome. (PMID:23534700)
• Data indicate that desmoplakin (DSP) and cystatin A (CSTA) interaction and insulin-like growth factor 1 (IGF-1), IGF-binding protein 7 (IGFBP7) and syndecan 1 (SDC1) interaction were observed in protein-protein interaction (PPI) network. (PMID:23546957)
• High levels of bioactive recombinant stefins A and B can be produced by fermentation in P. pastoris. (PMID:23656633)
• a novel pathway of CSTA regulation involving Dsg2 (PMID:25785582)
• Both MIP-3alpha and cystatin A overexpressions in NPC tumor tissues were strong independent factors of poor prognosis in NPC patients. (PMID:26634210)
• CSTA/TYROBP gene interaction might play pivotal roles in the occurrence and development of Postmenopausal Osteoporosis . (PMID:26676054)
• High expression of stefin A may be an important factor contributing to the development and metastasis of Hepatocellular Carcinoma. (PMID:26753874)
• The results suggest that C12orf39, CSTA, and CALCB are novel ATF4 target genes, and that C12orf39 promoter activity is activated by ATF4 through amino acid response element. (PMID:26967115)
• UV phototoxicity-induced pre-elafin inside keratinocytes prior to cornified envelope formation could be involved in UV-induced keratinocyte apoptosis via cystatin-A downregulation resulting in pro-caspase-3 activation. (PMID:28119996)
• Expression of CSTA was detected in some tumor tissues and many tumor-infiltrating immune cells. Cathepsin B expression was also observed in most tumor tissues and tumor-infiltrating immune cells (PMID:28898495)
• Identify myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer. (PMID:29086922)
• role of cystatin A in breast cancer and its functional link with ERalpha (PMID:29246862)
• High levels of CSTA expression in Esophageal Squamous Cell Carcinoma were correlated with tumor progression and advanced cancer stage, including lymph node metastasis. (PMID:29642180)
• Low CSTA expression is associated with brain metastasis in lung cancer. (PMID:30854931)
• Interplay of ERalpha binding and DNA methylation in the intron-2 determines the expression and estrogen regulation of cystatin A in breast cancer cells. (PMID:31926189)
• Decreased CSTA expression promotes lymphatic metastasis and predicts poor survival in oral squamous cell carcinoma. (PMID:33831734)
• In Silico, In Vitro, and Clinical Investigations of Cathepsin B and Stefin A mRNA Expression and a Correlation Analysis in Kidney Cancer. (PMID:35563761)
• Correlated with better prognosis, CSTA inhibits metastasis of nasopharyngeal carcinoma cells via suppressing AKT signaling through promoting METTL3 degradation. (PMID:36963524)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	cst14b.1	ENSDARG00000117133
mus_musculus	Stfa2	ENSMUSG00000022902
mus_musculus	Csta1	ENSMUSG00000034362
mus_musculus	Stfa3	ENSMUSG00000054905
mus_musculus	Stfa2l1	ENSMUSG00000059657
mus_musculus	Cstdc5	ENSMUSG00000071561
mus_musculus	Stfa1	ENSMUSG00000071562
mus_musculus	Cstdc6	ENSMUSG00000079594
mus_musculus	Cstdc4	ENSMUSG00000079597
mus_musculus	Csta3	ENSMUSG00000094733
mus_musculus	Csta2	ENSMUSG00000095620
rattus_norvegicus	Stfa3l1	ENSRNOG00000030984
rattus_norvegicus	Stfa2l1	ENSRNOG00000033929
rattus_norvegicus		ENSRNOG00000066258
rattus_norvegicus		ENSRNOG00000076450
rattus_norvegicus	Stfa2l2	ENSRNOG00000076506
rattus_norvegicus		ENSRNOG00000081315
rattus_norvegicus	Stfa2l3	ENSRNOG00000082869
rattus_norvegicus	Csta	ENSRNOG00000086046
rattus_norvegicus	Stfa3	ENSRNOG00000088435
rattus_norvegicus	Stfa2	ENSRNOG00000089123

Paralogs (1): CSTB (ENSG00000160213)

Protein

Protein identifiers

Cystatin-A — P01040 (reviewed: P01040)

Alternative names: Cystatin-AS, Stefin-A

All UniProt accessions (2): C9J0E4, P01040

UniProt curated annotations — full annotation on UniProt →

Function. This is an intracellular thiol proteinase inhibitor. Has an important role in desmosome-mediated cell-cell adhesion in the lower levels of the epidermis.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in the skin throughout the epidermis.

Disease relevance. Peeling skin syndrome 4 (PSS4) [MIM:607936] A genodermatosis characterized by congenital exfoliative ichthyosis, sharing some features with ichthyosis bullosa of Siemens and annular epidermolytic ichthyosis. PSS4 presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of non-erythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma. Electron microscopy analysis of skin biopsies, reveals mostly normal-appearing upper layers of the epidermis, but prominent intercellular edema of the basal and suprabasal cell layers with aggregates of tonofilaments in the basal keratinocytes. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the cystatin family.

RefSeq proteins (1): NP_005204* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000010	Cystatin_dom	Domain
IPR001713	Prot_inh_stefin	Family
IPR018073	Prot_inh_cystat_CS	Conserved_site
IPR046350	Cystatin_sf	Homologous_superfamily

Pfam: PF00031

UniProt features (17 total): strand 5, helix 5, chain 2, initiator methionine 1, short sequence motif 1, site 1, modified residue 1, sequence variant 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
3KSE	X-RAY DIFFRACTION	1.71
3KFQ	X-RAY DIFFRACTION	1.99
1NB5	X-RAY DIFFRACTION	2.4
3K9M	X-RAY DIFFRACTION	2.61
1NB3	X-RAY DIFFRACTION	2.8
8GT0	X-RAY DIFFRACTION	3.28
8GT7	X-RAY DIFFRACTION	3.28
1CYU	SOLUTION NMR
1CYV	SOLUTION NMR
1DVC	SOLUTION NMR
1DVD	SOLUTION NMR
1GD3	SOLUTION NMR
1GD4	SOLUTION NMR
1N9J	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P01040-F1	93.57	0.85

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 4 (reactive site)

Post-translational modifications (1): 1

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope

MSigDB gene sets: 270 (showing top): GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_PROTEOLYSIS, JAEGER_METASTASIS_DN, CHUNG_BLISTER_CYTOTOXICITY_DN, MODULE_45, MODULE_418, GOBP_PEPTIDE_CROSS_LINKING, GOZGIT_ESR1_TARGETS_DN, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, DARWICHE_SKIN_TUMOR_PROMOTER_DN, DARWICHE_PAPILLOMA_RISK_LOW_UP, DARWICHE_PAPILLOMA_RISK_HIGH_UP, DARWICHE_SQUAMOUS_CELL_CARCINOMA_UP, MODULE_16, ZHAN_MULTIPLE_MYELOMA_CD1_UP

GO Biological Process (5): peptide cross-linking (GO:0018149), keratinocyte differentiation (GO:0030216), negative regulation of proteolysis (GO:0045861), cell-cell adhesion (GO:0098609), cell adhesion (GO:0007155)

GO Molecular Function (5): protease binding (GO:0002020), cysteine-type endopeptidase inhibitor activity (GO:0004869), endopeptidase inhibitor activity (GO:0004866), protein binding (GO:0005515), peptidase inhibitor activity (GO:0030414)

GO Cellular Component (6): cornified envelope (GO:0001533), obsolete extracellular space (GO:0005615), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), peptidase inhibitor complex (GO:1904090)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Keratinization	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
protein modification process	1
epidermal cell differentiation	1
skin development	1
proteolysis	1
regulation of proteolysis	1
negative regulation of protein metabolic process	1
cell adhesion	1
cellular process	1
enzyme binding	1
cysteine-type endopeptidase activity	1
endopeptidase inhibitor activity	1
endopeptidase activity	1
peptidase inhibitor activity	1
endopeptidase regulator activity	1
binding	1
enzyme inhibitor activity	1
peptidase activity	1
peptidase regulator activity	1
plasma membrane	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
protein-containing complex	1

Protein interactions and networks

STRING

1842 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CSTA	SLC12A8	A0AV02	958
CSTA	CTSS	P25774	906
CSTA	CTSH	P09668	884
CSTA	COL6A5	A8TX70	884
CSTA	CTSB	P07858	851
CSTA	TGM1	P22735	779
CSTA	CTSL	P07711	768
CSTA	SEC24A	O95486	713
CSTA	CST4	P01036	677
CSTA	CST2	P09228	658
CSTA	SERPINB3	P29508	651
CSTA	CST1	P01037	629
CSTA	CST3	P01034	621
CSTA	SERPINB4	P48594	606
CSTA	CST5	P28325	567

IntAct

104 interactions, top by confidence:

A	B	Type	Score
EGFR	CTNND1	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
ASF1A	HAT1	psi-mi:“MI:0914”(association)	0.640
ASF1B	HAT1	psi-mi:“MI:0914”(association)	0.640
RCCD1	SPAG9	psi-mi:“MI:0914”(association)	0.640
CTSB	CSTA	psi-mi:“MI:0407”(direct interaction)	0.590
DMWD	CSTA	psi-mi:“MI:0915”(physical association)	0.560
GRN	CSTA	psi-mi:“MI:0915”(physical association)	0.560
CSTA	HSPB1	psi-mi:“MI:0915”(physical association)	0.560
CSTA	WFS1	psi-mi:“MI:0915”(physical association)	0.560
CSTA	RNF11	psi-mi:“MI:0915”(physical association)	0.560
CSTA	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
NASP	HAT1	psi-mi:“MI:0914”(association)	0.530

BioGRID (156): CSTA (Two-hybrid), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS), CSTA (Affinity Capture-MS)

ESM2 similar proteins: A0A224AHH8, A0A6B9KZ52, A0A6I8TMQ9, B1P1J3, B2Z449, B2Z450, B7PKZ2, J7FQE8, P01039, P01040, P01041, P04080, P0DXA0, P25417, P30086, P31044, P35173, P35174, P35175, P35478, P35479, P35481, P48737, P56567, P60575, P60576, P70296, P80416, Q06445, Q10994, Q28986, Q28987, Q28988, Q29290, Q3YIX4, Q5R1U3, Q5R4R0, Q62426, Q65YR7, Q65YR8

Diamond homologs: B2Z449, J7FQE8, P01040, P01041, P04080, P25417, P35173, P35174, P35175, P35478, P35479, P56567, P60575, P60576, P80416, Q10994, Q28986, Q28987, Q28988, Q29290, Q5R1U3, Q62426, Q65YR7, Q76LA0, Q862Z5, Q8I030, Q8WNR9, P01039, P80736, Q65YR8

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	3
Uncertain significance	14
Likely benign	2
Benign	8

Top pathogenic / likely-pathogenic (8)

Variant ID	HGVS	Classification
1183989	Single allele	Pathogenic
208472	NM_005213.4(CSTA):c.64A>T (p.Lys22Ter)	Pathogenic
29892	NM_005213.4(CSTA):c.67-2A>T	Pathogenic
29893	NM_005213.4(CSTA):c.256C>T (p.Gln86Ter)	Pathogenic
3357701	NM_005213.4(CSTA):c.192T>A (p.Tyr64Ter)	Pathogenic
208473	NM_005213.4(CSTA):c.172C>T (p.Arg58Ter)	Likely pathogenic
3779552	NM_005213.4(CSTA):c.105C>A (p.Tyr35Ter)	Likely pathogenic
450304	NM_005213.4(CSTA):c.102_103del (p.Tyr35fs)	Likely pathogenic

SpliceAI

221 predictions. Top by Δscore:

Variant	Effect	Δscore
3:122325355:TAAGG:T	donor_loss	1.0000
3:122325356:AAGGT:A	donor_loss	1.0000
3:122325357:AGG:A	donor_loss	1.0000
3:122325358:GGTG:G	donor_loss	1.0000
3:122325359:GTGA:G	donor_loss	1.0000
3:122337545:A:AG	acceptor_gain	1.0000
3:122337545:AG:A	acceptor_gain	1.0000
3:122337546:G:GA	acceptor_gain	1.0000
3:122337546:GG:G	acceptor_gain	1.0000
3:122337546:GGT:G	acceptor_gain	1.0000
3:122337546:GGTT:G	acceptor_gain	1.0000
3:122337546:GGTTA:G	acceptor_gain	1.0000
3:122337603:GC:G	donor_gain	1.0000
3:122337646:AAGG:A	donor_loss	1.0000
3:122337647:AGG:A	donor_loss	1.0000
3:122337649:G:T	donor_loss	1.0000
3:122325359:G:GG	donor_gain	0.9900
3:122337541:CTTTA:C	acceptor_gain	0.9900
3:122337542:TTTA:T	acceptor_gain	0.9900
3:122337543:TTA:T	acceptor_gain	0.9900
3:122337544:TA:T	acceptor_gain	0.9900
3:122337545:A:C	acceptor_gain	0.9900
3:122337546:G:C	acceptor_gain	0.9900
3:122337595:G:GT	donor_gain	0.9900
3:122341427:A:AG	acceptor_gain	0.9900
3:122341429:T:G	acceptor_gain	0.9900
3:122341433:TTTCA:T	acceptor_loss	0.9900
3:122341436:CAGGT:C	acceptor_loss	0.9900
3:122341437:AGGT:A	acceptor_loss	0.9900
3:122325355:TAAG:T	donor_gain	0.9800

AlphaMissense

637 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:122341478:T:C	F70L	0.954
3:122341480:C:A	F70L	0.954
3:122341480:C:G	F70L	0.954
3:122341562:T:C	F98L	0.954
3:122341564:T:A	F98L	0.954
3:122341564:T:G	F98L	0.954
3:122337618:A:C	Q46H	0.944
3:122337618:A:T	Q46H	0.944
3:122337629:G:A	G50E	0.940
3:122337625:G:C	A49P	0.938
3:122337560:T:C	L27P	0.935
3:122337644:T:A	I55N	0.934
3:122337648:G:C	K56N	0.934
3:122337648:G:T	K56N	0.934
3:122337629:G:T	G50V	0.931
3:122341476:T:A	V69E	0.922
3:122341470:T:C	L67S	0.919
3:122337599:C:A	A40D	0.913
3:122337617:A:C	Q46P	0.910
3:122337548:T:A	V23D	0.909
3:122341440:T:A	V57E	0.906
3:122337644:T:C	I55T	0.896
3:122337628:G:A	G50R	0.894
3:122337628:G:C	G50R	0.894
3:122337644:T:G	I55S	0.894
3:122341563:T:C	F98S	0.893
3:122337607:T:G	Y43D	0.886
3:122325303:G:A	G4E	0.883
3:122325351:T:A	V20D	0.881
3:122337622:G:C	V48L	0.880

dbSNP variants (sampled 300 via entrez): RS1000509694 (3:122341480 C>A), RS1000745850 (3:122328136 C>A,T), RS1000835357 (3:122340959 T>A), RS1000970691 (3:122334826 G>C), RS1001093090 (3:122327865 C>T), RS1001466111 (3:122338374 A>C,G), RS1001573351 (3:122327811 T>C), RS1001801228 (3:122340013 C>T), RS1001894494 (3:122339742 C>T), RS1001924573 (3:122327243 A>G,T), RS1002284887 (3:122326693 G>C), RS1002296147 (3:122333840 T>C,G), RS1002455324 (3:122340798 G>A), RS1002522236 (3:122336786 A>G,T), RS1002864079 (3:122332852 A>G)

Disease associations

OMIM: gene MIM:184600 | disease phenotypes: MIM:614038, MIM:607936, MIM:601198, MIM:145980

GenCC curated gene-disease

Disease	Classification	Inheritance
peeling skin syndrome 4	Strong	Autosomal recessive
acral peeling skin syndrome	Supportive	Autosomal recessive
exfoliative ichthyosis	Supportive	Autosomal recessive

Mondo (7): deafness-lymphedema-leukemia syndrome (MONDO:0013540), GATA2 deficiency with susceptibility to MDS/AML (MONDO:0042982), peeling skin syndrome 4 (MONDO:0011937), autosomal dominant hypocalcemia 1 (MONDO:0011013), familial hypocalciuric hypercalcemia (MONDO:0018458), acral peeling skin syndrome (MONDO:0012345), exfoliative ichthyosis (MONDO:0017339)

Orphanet (3): Deafness-lymphedema-leukemia syndrome (Orphanet:3226), Exfoliative ichthyosis (Orphanet:289586), Familial hypocalciuric hypercalcemia (Orphanet:405)

HPO phenotypes

19 total (19 of 19 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000953	Hyperpigmentation of the skin
HP:0000962	Hyperkeratosis
HP:0000964	Eczematoid dermatitis
HP:0000982	Palmoplantar keratoderma
HP:0007605	Excessive wrinkling of palmar skin
HP:0008064	Ichthyosis
HP:0008066	Abnormal blistering of the skin
HP:0008404	Nail dystrophy
HP:0008499	High hypermetropia
HP:0010783	Erythema
HP:0012393	Allergy
HP:0012733	Macule
HP:0025092	Epidermal acanthosis
HP:0040162	Orthokeratosis
HP:0040189	Scaling skin
HP:0100725	Lichenification
HP:0200034	Papule
HP:0200041	Skin erosion

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000769_5	Calcium levels	2.000000e-22
GCST002911_2	Calcium levels	1.000000e-07
GCST005982_13	Calcium levels	1.000000e-38
GCST010243_121	Apolipoprotein B levels	2.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0004615	apolipoprotein B measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C564309	Exfoliative Ichthyosis, Autosomal Recessive, Ichthyosis Bullosa of Siemens-like (supp.)
C536316	Peeling skin syndrome, acral type (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	6
Estradiol	affects cotreatment, increases expression, decreases expression	6
Cyclosporine	increases expression	5
Arsenic Trioxide	affects expression, increases expression	4
bisphenol A	increases expression, decreases expression, decreases methylation	3
sodium arsenite	decreases expression, increases expression	3
Cisplatin	affects expression, affects cotreatment, increases expression	3
Tetrachlorodibenzodioxin	decreases expression, affects cotreatment, increases expression	3
Aflatoxin B1	affects expression, increases expression	3
perfluorooctanoic acid	affects cotreatment, increases expression	2
Air Pollutants	affects expression, increases abundance, decreases expression	2
Aspirin	increases expression	2
Methotrexate	affects response to substance, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	increases expression	2
Cadmium Chloride	affects expression, decreases expression	2
Copper Sulfate	increases expression, affects expression	2
Esketamine	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
glycidyl methacrylate	increases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	increases expression	1
sodium bichromate	affects expression	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT00743782	PHASE2	COMPLETED	Comparing Pump With Subcutaneous Injection Delivery of PTH 1-34 in the Management of Chronic Hypoparathyroidism
NCT04581629	PHASE2	COMPLETED	Safety, Tolerability, and Efficacy of Encaleret in Participants With Autosomal Dominant Hypocalcemia (ADH) Type 1
NCT03050268	Not specified	RECRUITING	Familial Investigations of Childhood Cancer Predisposition
NCT01905826	Not specified	RECRUITING	Natural History Study of GATA2 Deficiency and Related Disorders
NCT07080385	PHASE2/PHASE3	RECRUITING	Pharmacokinetics, Efficacy, and Safety of Encaleret in Pediatric Participants With Autosomal Dominant Hypocalcemia Type 1 (ADH1)
NCT04872894	Not specified	COMPLETED	Familial Hypocalciuric Hypercalcemia: Clinical Aspects and Evolution