TGM5

Summary

TGM5 (transglutaminase 5, HGNC:11781) is a protein-coding gene on chromosome 15q15.2, encoding Protein-glutamine gamma-glutamyltransferase 5 (O43548). Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.

This gene encodes a member of the transglutaminase family. The encoded protein catalyzes formation of protein cross-links between glutamine and lysine residues, often resulting in stabilization of protein assemblies. This reaction is calcium dependent. Mutations in this gene have been associated with acral peeling skin syndrome.

Source: NCBI Gene 9333 — RefSeq curated summary.

At a glance

• Gene–disease (curated): acral peeling skin syndrome (Definitive, GenCC)
• GWAS associations: 2
• Clinical variants (ClinVar): 209 total — 6 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 15
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_201631

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11781
Approved symbol	TGM5
Name	transglutaminase 5
Location	15q15.2
Locus type	gene with protein product
Status	Approved
Aliases	TGX, TGMX
Ensembl gene	ENSG00000104055
Ensembl biotype	protein_coding
OMIM	603805
Entrez	9333

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 retained_intron, 2 protein_coding

ENST00000220420, ENST00000349114, ENST00000396996, ENST00000563838, ENST00000635871

RefSeq mRNA: 2 — MANE Select: NM_201631 NM_004245, NM_201631

CCDS: CCDS32211, CCDS32212

Canonical transcript exons

ENST00000220420 — 13 exons

Exon	Start	End
ENSE00000931160	43260400	43260579
ENSE00001147423	43260052	43260297
ENSE00001147456	43239163	43239266
ENSE00001147468	43240852	43240990
ENSE00001147475	43252759	43252936
ENSE00001147485	43253506	43253634
ENSE00001147494	43256568	43256686
ENSE00003589197	43238817	43239056
ENSE00003589539	43233554	43233687
ENSE00003636950	43235469	43235837
ENSE00003693531	43234769	43234929
ENSE00003894953	43232590	43233344
ENSE00003895116	43266840	43266928

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 92.99.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1747 / max 25.6312, expressed in 52 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149601	0.0564	25
149600	0.0327	8
149597	0.0298	16
149598	0.0297	12
149599	0.0159	7
149596	0.0102	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
skin of leg	UBERON:0001511	92.99	gold quality
skin of abdomen	UBERON:0001416	92.85	gold quality
zone of skin	UBERON:0000014	91.02	gold quality
diaphragm	UBERON:0001103	90.58	gold quality
gingival epithelium	UBERON:0001949	87.92	gold quality
olfactory bulb	UBERON:0002264	87.88	gold quality
gingiva	UBERON:0001828	86.83	gold quality
tongue squamous epithelium	UBERON:0006919	86.48	gold quality
type B pancreatic cell	CL:0000169	85.76	gold quality
hair follicle	UBERON:0002073	85.00	silver quality
lower esophagus mucosa	UBERON:0035834	84.69	gold quality
squamous epithelium	UBERON:0006914	84.34	gold quality
cervix squamous epithelium	UBERON:0006922	83.05	silver quality
epithelium of esophagus	UBERON:0001976	82.56	gold quality
esophagus squamous epithelium	UBERON:0006920	82.28	gold quality
esophagus mucosa	UBERON:0002469	82.25	gold quality
cervix epithelium	UBERON:0004801	81.63	gold quality
mammalian vulva	UBERON:0000997	81.39	gold quality
upper arm skin	UBERON:0004263	81.07	gold quality
penis	UBERON:0000989	79.85	gold quality
mucosa of paranasal sinus	UBERON:0005030	79.21	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.38	gold quality
upper leg skin	UBERON:0004262	78.35	gold quality
endometrium epithelium	UBERON:0004811	77.95	gold quality
left ventricle myocardium	UBERON:0006566	77.17	gold quality
vastus lateralis	UBERON:0001379	77.09	gold quality
superficial temporal artery	UBERON:0001614	76.62	gold quality
epithelium of nasopharynx	UBERON:0001951	76.24	silver quality
cardiac muscle of right atrium	UBERON:0003379	76.16	gold quality
oral cavity	UBERON:0000167	75.89	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	15.34

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

40 targeting TGM5, 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-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-3529-3P	99.90	73.55	3045
HSA-MIR-12119	99.87	68.35	1653
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-513A-3P	99.39	70.63	3620
HSA-MIR-513C-3P	99.39	70.63	3620
HSA-MIR-7151-5P	99.37	67.82	613
HSA-MIR-3191-5P	99.24	66.52	1722
HSA-MIR-664A-3P	99.22	71.08	2696
HSA-MIR-3606-3P	99.11	69.84	3254
HSA-MIR-1909-5P	98.94	64.01	484
HSA-MIR-224-3P	98.91	68.42	1815
HSA-MIR-522-3P	98.91	68.56	1817
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-518C-5P	98.53	69.20	1640
HSA-MIR-2117	98.48	67.97	1307
HSA-MIR-4782-5P	98.35	69.33	1474
HSA-MIR-5706	98.35	69.33	1463
HSA-MIR-4303	98.01	68.13	2304

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• transglutaminase 5 contributes, as a secondary effect, to the hyperkeratotic phenotype in ichthyosis (both vulgaris and lamellar) and in psoriasis. (PMID:12230511)
• Results demonstrate that transglutaminase 5 is able to induce cell death when intracellularly overexpressed. (PMID:15290346)
• Data show that transglutaminase (TGase) 5 is acetylated at the N-terminal end, is active upon treatment with phorbol acetate, and co-localises with vimentin intermediate filaments. (PMID:15290349)
• Transglutaminase 5 is expressed during hair follicle homeostasis. (PMID:16117804)
• A homozygous missense mutation in TGM5 abolishes epidermal TGM5 activity and causes acral peeling skin syndrome. (PMID:16380904)
• TG5 full-length enzyme has very low enzymatic activity, while the 53-kDa proteolytically processed form is highly active. (PMID:18509357)
• A missense mutation in TGM5 causes acral peeling skin syndrome in a Tunisian family. (PMID:19440220)
• Acral peeling skin syndrome with TGM5 gene mutations may resemble epidermolysis bullosa simplex in young individuals. (PMID:20164844)
• analysis of a recurrent mutation in the TGM5 gene in European patients with acral peeling skin syndrome (PMID:22036214)
• TGM5 mutations impact epidermal differentiation in acral peeling skin syndrome. (PMID:22622422)
• Genetic variation in the epidermal transglutaminase genes is not associated with atopic dermatitis. (PMID:23189155)
• study concludes polymorphisms of TGM5, PPAP2B and PSMA4 are not major contributors tonon-small cell lung cancer susceptibility in never-smoking hinese population, this primarily can be attributed to the significantly distinct genetic background of Asian populations from western populations (PMID:24518713)
• Data trebles the number of TMG5 mutations and provides further evidence that pCly113Cys is a founder mutation in the European population. (PMID:24628291)
• Acral PSS (APSS) (OMIM 609796), typically non-inflammatory, is confined to distal extremities with localized exfoliation of the epidermis. It is caused by mutations in the TGM5 gene, encoding transglutaminase 5[3] or in the CTSA gene, encoding cystatin A and it is inherited in autosomal recessive pattern (PMID:25510201)
• We report both European and non-European families with acral peeling skin syndrome carrying mutations in the TGM5 gene. In 5 patients, we found 3 novel mutations: c.1001+2_1001+3del, c.1171G>A and c.1498C>T. (PMID:25644735)
• Phenotypic suppression of acral peeling skin syndrome in a patient with autosomal recessive congenital ichthyosis. (PMID:32618001)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	tgm8	ENSDARG00000097651
danio_rerio	tgm5l	ENSDARG00000098837
mus_musculus	Tgm5	ENSMUSG00000053675
rattus_norvegicus	Tgm5	ENSRNOG00000058755

Paralogs (8): TGM1 (ENSG00000092295), F13A1 (ENSG00000124491), TGM3 (ENSG00000125780), TGM7 (ENSG00000159495), TGM4 (ENSG00000163810), EPB42 (ENSG00000166947), TGM6 (ENSG00000166948), TGM2 (ENSG00000198959)

Protein

Protein identifiers

Protein-glutamine gamma-glutamyltransferase 5 — O43548 (reviewed: O43548)

Alternative names: Transglutaminase X, Transglutaminase-5

All UniProt accessions (1): O43548

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Contributes to the formation of the cornified cell envelope of keratinocytes.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in foreskin keratinocytes.

Disease relevance. Peeling skin syndrome 2 (PSS2) [MIM:609796] A non-inflammatory and localized form of peeling skin syndrome, a genodermatosis characterized by the continuous shedding of the outer layers of the epidermis. In PSS2 patients, skin peeling is painless and strictly limited to the dorsa of the hands and feet. It is accompanied by painless erythema and spontaneous non-scarring healing. Ultrastructural and histological analysis shows a level of blistering high in the epidermis at the stratum granulosum-stratum corneum junction. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 Ca(2+) ion per subunit.

Induction. By 12-O-tetradecanoylphorbol-13-acetate (TPA) and calcium in NHEK cells.

Similarity. Belongs to the transglutaminase superfamily. Transglutaminase family.

Isoforms (2)

UniProt ID	Names	Canonical?
O43548-1	Long	yes
O43548-2	Short

RefSeq proteins (2): NP_004236, NP_963925* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001102	Transglutaminase_N	Domain
IPR002931	Transglutaminase-like	Domain
IPR008958	Transglutaminase_C	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR013808	Transglutaminase_AS	Active_site
IPR014756	Ig_E-set	Homologous_superfamily
IPR023608	Transglutaminase_animal	Family
IPR036238	Transglutaminase_C_sf	Homologous_superfamily
IPR036985	Transglutaminase-like_sf	Homologous_superfamily
IPR038765	Papain-like_cys_pep_sf	Homologous_superfamily
IPR050779	Transglutaminase	Family

Pfam: PF00868, PF00927, PF01841

Enzyme classification (BRENDA):

• EC 2.3.2.13 — protein-glutamine gamma-glutamyltransferase (BRENDA: 68 organisms, 476 substrates, 772 inhibitors, 122 Km, 49 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
PUTRESCINE	0.035–9.63	13
L-LYSINE	2.9–15.8	6
N-CBZ-GLN-GLY	12.83–59.5	5
HYDROXYLAMINE	1.37–61.9	4
NALPHA-BENZYLOXYCARBONYL-L-GLN-GLY	11.2–30	4
CASEIN	0.006–0.012	3
CBZ-GLN-GLY	0.0169–5.9	3
CBZ-GLN-GLY-OH	3.53–8.55	3
METHYLAMINE	0.024–0.061	3
MONODANSYLCADAVERINE	0.01–0.034	3
N-CARBOXYBENZOYL-L-GLUTAMINYL-GLYCINE	0.0547–69.4	3
PENTYLAMINE	0.0029–0.0203	3
Z-GLN-GLY	1.8–11.6	3
ACETYL-ALPHAS1-CASEIN	0.0029–0.0032	2
GTP	0.0044–0.01	2

Catalyzed reactions (Rhea), 1 shown:

• L-glutaminyl-[protein] + L-lysyl-[protein] = [protein]-L-lysyl-N(6)-5-L-glutamyl-[protein] + NH4(+) (RHEA:54816)

UniProt features (19 total): sequence variant 6, binding site 4, active site 3, initiator methionine 1, chain 1, modified residue 1, splice variant 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43548-F1	91.68	0.83

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 (3): 278; 337; 360

Ligand- & substrate-binding residues (4): 453; 400; 402; 448

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: 104 (showing top): GOBP_PEPTIDE_CROSS_LINKING, YY1_Q6, MODULE_99, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_10D_UP, GOBP_EPIDERMIS_DEVELOPMENT, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_16D_UP, VALK_AML_CLUSTER_16, YAGI_AML_WITH_T_9_11_TRANSLOCATION, GCCATNTTG_YY1_Q6, YAGI_AML_WITH_11Q23_REARRANGED, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_8D_UP, GOMF_ACYLTRANSFERASE_ACTIVITY, GOMF_AMINOACYLTRANSFERASE_ACTIVITY, MYB_Q6, AR_Q6

GO Biological Process (3): epidermis development (GO:0008544), protein modification process (GO:0036211), peptide cross-linking (GO:0018149)

GO Molecular Function (5): protein-glutamine gamma-glutamyltransferase activity (GO:0003810), metal ion binding (GO:0046872), protein binding (GO:0005515), transferase activity (GO:0016740), acyltransferase activity (GO:0016746)

GO Cellular Component (2): cytoplasm (GO:0005737), plasma membrane (GO:0005886)

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
tissue development	1
protein metabolic process	1
macromolecule modification	1
protein modification process	1
aminoacyltransferase activity	1
catalytic activity, acting on a protein	1
cation binding	1
binding	1
catalytic activity	1
transferase activity	1
intracellular anatomical structure	1
cellular anatomical structure	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

758 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TGM5	CDSN	Q15517	741
TGM5	DSG4	Q86SJ6	667
TGM5	EXPH5	Q8NEV8	624
TGM5	PKP1	Q13835	551
TGM5	CHST8	Q9H2A9	519
TGM5	FERMT1	Q9BQL6	513
TGM5	LORICRIN	P23490	492
TGM5	KLK8	O60259	489
TGM5	CSTA	P01040	475
TGM5	IVL	P07476	471
TGM5	ACP4	Q9BZG2	462
TGM5	ALOXE3	Q9BYJ1	452
TGM5	KRT10	P13645	450
TGM5	GRB7	Q14451	443
TGM5	RXFP4	Q8TDU9	422

IntAct

44 interactions, top by confidence:

A	B	Type	Score
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
TGM5	GRB7	psi-mi:“MI:0915”(physical association)	0.560
TGM5	KANK2	psi-mi:“MI:0915”(physical association)	0.560
TGM5	RBM41	psi-mi:“MI:0915”(physical association)	0.560
TGM5	LARP4	psi-mi:“MI:0915”(physical association)	0.560
TGM5	LGALS7	psi-mi:“MI:0915”(physical association)	0.560
CASP6	TGM5	psi-mi:“MI:0915”(physical association)	0.560
HIP1	TGM5	psi-mi:“MI:0915”(physical association)	0.560
LAMP2	TGM5	psi-mi:“MI:0915”(physical association)	0.560
PRPF40A	TGM5	psi-mi:“MI:0915”(physical association)	0.560
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
CCDC51	TGM5	psi-mi:“MI:0914”(association)	0.530
TGM5	UBB	psi-mi:“MI:0914”(association)	0.530
TGM5	EIF4E2	psi-mi:“MI:0914”(association)	0.350
NEK8	TGM5	psi-mi:“MI:0914”(association)	0.350
STX17	A2ML1	psi-mi:“MI:0914”(association)	0.350
GOT1	A2ML1	psi-mi:“MI:0914”(association)	0.350
PRSS16	KLK10	psi-mi:“MI:0914”(association)	0.350
ZC3HC1	SULT2B1	psi-mi:“MI:0914”(association)	0.350
ATP6AP2	KLK10	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): TGM5 (Affinity Capture-MS), SPICE1 (Affinity Capture-MS), RFTN1 (Affinity Capture-MS), TGM5 (Affinity Capture-MS), UBB (Affinity Capture-MS), TGM5 (Affinity Capture-MS), ZNHIT6 (Affinity Capture-MS), DOCK7 (Affinity Capture-MS), PDZD11 (Affinity Capture-MS), EIF4E2 (Affinity Capture-MS), TWISTNB (Affinity Capture-MS), VWA9 (Affinity Capture-MS), TGM5 (Affinity Capture-MS), TGM5 (Affinity Capture-MS), TGM5 (Two-hybrid)

ESM2 similar proteins: A2VDP6, A4D0V7, B1WB06, F1N2K1, O43548, P06802, P15396, P22413, P50127, P79949, P97259, Q05004, Q08834, Q08BN9, Q09328, Q14C87, Q14DG7, Q2TU62, Q3L7M0, Q3U095, Q52KP5, Q5R748, Q5RCA5, Q5XI89, Q5ZLK4, Q6AX23, Q6DNG6, Q6UWF7, Q6ZXA0, Q76HP2, Q76HP3, Q86UX2, Q8BG22, Q8C7K6, Q8K1B9, Q8N323, Q8NCG5, Q8NHY0, Q8R4G6, Q8VI38

Diamond homologs: A6QP57, D4A5U3, O08619, O43548, O46510, O95932, P00488, P08587, P16452, P21980, P21981, P22735, P22758, P23606, P49221, P51176, P52181, P52183, Q01841, Q05187, Q08188, Q08189, Q8BH61, Q8BZH1, Q96PF1, Q99041, Q9D7I9, Q9GLK0, Q9JLF6, Q9WVJ6, P49222, P12260

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	11
Uncertain significance	135
Likely benign	13
Benign	28

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
1200686	NM_201631.4(TGM5):c.1016G>A (p.Trp339Ter)	Pathogenic
157570	NM_201631.4(TGM5):c.640del (p.Leu214fs)	Pathogenic
157571	NM_201631.4(TGM5):c.1811_1815delinsTCCTTCA (p.Ser604fs)	Pathogenic
420028	NM_201631.4(TGM5):c.1001+2_1001+3del	Pathogenic
449109	NM_201631.4(TGM5):c.104G>A (p.Arg35Gln)	Pathogenic
450467	NM_201631.4(TGM5):c.1304del (p.Asp435fs)	Pathogenic
1068290	NM_201631.4(TGM5):c.556-1G>C	Likely pathogenic
1325190	NM_201631.4(TGM5):c.393C>A (p.Tyr131Ter)	Likely pathogenic
1325191	NM_201631.4(TGM5):c.829C>T (p.Gln277Ter)	Likely pathogenic
1685463	NM_201631.4(TGM5):c.10+2T>C	Likely pathogenic
2664323	NM_201631.4(TGM5):c.115T>A (p.Phe39Ile)	Likely pathogenic
3065974	NM_201631.4(TGM5):c.2161T>C (p.Ter721Gln)	Likely pathogenic
3577130	NM_201631.4(TGM5):c.1037G>A (p.Arg346Gln)	Likely pathogenic
3577131	NM_201631.4(TGM5):c.643C>T (p.Arg215Trp)	Likely pathogenic
3780711	NM_201631.4(TGM5):c.1664del (p.Leu555fs)	Likely pathogenic
4845841	NM_201631.4(TGM5):c.700_709dup (p.Val237delinsGlyTer)	Likely pathogenic
803071	NM_201631.4(TGM5):c.684+1G>A	Likely pathogenic

SpliceAI

2306 predictions. Top by Δscore:

Variant	Effect	Δscore
15:43233345:C:CC	acceptor_gain	1.0000
15:43233548:ACTT:A	donor_loss	1.0000
15:43233549:CTTA:C	donor_loss	1.0000
15:43233550:TTACA:T	donor_loss	1.0000
15:43233551:TA:T	donor_loss	1.0000
15:43233552:A:AC	donor_gain	1.0000
15:43233552:ACA:A	donor_loss	1.0000
15:43233553:C:CA	donor_gain	1.0000
15:43233553:CA:C	donor_gain	1.0000
15:43233553:CAA:C	donor_gain	1.0000
15:43233553:CAAG:C	donor_gain	1.0000
15:43233553:CAAGA:C	donor_gain	1.0000
15:43234767:A:AC	donor_gain	1.0000
15:43234768:C:CC	donor_gain	1.0000
15:43235465:GTAC:G	donor_loss	1.0000
15:43235466:TA:T	donor_loss	1.0000
15:43235467:ACC:A	donor_loss	1.0000
15:43235468:C:CT	donor_loss	1.0000
15:43235468:CCTT:C	donor_gain	1.0000
15:43238812:CTTA:C	donor_gain	1.0000
15:43238813:TTAC:T	donor_loss	1.0000
15:43238814:TA:T	donor_loss	1.0000
15:43238815:A:AC	donor_gain	1.0000
15:43238815:A:AG	donor_loss	1.0000
15:43238815:AC:A	donor_gain	1.0000
15:43238815:ACCTT:A	donor_gain	1.0000
15:43238816:C:CC	donor_gain	1.0000
15:43238816:C:CT	donor_loss	1.0000
15:43238816:CC:C	donor_gain	1.0000
15:43238816:CCT:C	donor_gain	1.0000

AlphaMissense

4784 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:43252847:G:C	S258R	0.999
15:43252847:G:T	S258R	0.999
15:43252849:T:G	S258R	0.999
15:43256582:A:G	W181R	0.998
15:43256582:A:T	W181R	0.998
15:43252786:A:G	W279R	0.996
15:43252786:A:T	W279R	0.996
15:43252787:G:C	C278W	0.996
15:43256580:C:A	W181C	0.996
15:43256580:C:G	W181C	0.996
15:43252789:A:G	C278R	0.995
15:43252795:C:A	G276W	0.995
15:43252828:A:G	W265R	0.995
15:43252828:A:T	W265R	0.995
15:43252836:A:G	L262P	0.995
15:43252858:A:G	W255R	0.995
15:43252858:A:T	W255R	0.995
15:43239253:A:G	W339R	0.994
15:43239253:A:T	W339R	0.994
15:43239259:G:C	H337D	0.994
15:43240947:G:C	F302L	0.994
15:43240947:G:T	F302L	0.994
15:43240949:A:G	F302L	0.994
15:43240954:G:A	T300I	0.994
15:43240963:C:G	R297P	0.994
15:43252763:G:C	C286W	0.994
15:43252784:C:A	W279C	0.994
15:43252784:C:G	W279C	0.994
15:43256626:C:T	G166D	0.994
15:43238878:G:C	S428R	0.993

dbSNP variants (sampled 300 via entrez): RS1000040484 (15:43252131 C>T), RS1000049315 (15:43247019 G>A,T), RS1000106292 (15:43253636 T>C), RS1000162492 (15:43255110 G>C), RS1000178124 (15:43263275 T>A), RS1000403886 (15:43246778 G>A), RS1000439453 (15:43261606 C>T), RS1000465044 (15:43266740 T>A), RS1000488002 (15:43254870 T>C), RS1000493116 (15:43256570 G>A,T), RS1000603926 (15:43258293 T>C), RS1000623920 (15:43258456 C>T), RS1000644691 (15:43250527 G>A), RS1000685347 (15:43259922 G>A,T), RS1000714445 (15:43248849 G>C)

Disease associations

OMIM: gene MIM:603805 | disease phenotypes: MIM:609796, MIM:270300

GenCC curated gene-disease

Disease	Classification	Inheritance
acral peeling skin syndrome	Definitive	Autosomal recessive

Mondo (2): acral peeling skin syndrome (MONDO:0012345), peeling skin syndrome 1 (MONDO:0024548)

Orphanet (3): Acral peeling skin syndrome (Orphanet:263534), Generalized peeling skin syndrome (Orphanet:263543), Peeling skin syndrome type B (Orphanet:263553)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000953	Hyperpigmentation of the skin
HP:0000964	Eczematoid dermatitis
HP:0001597	Abnormal nail morphology
HP:0007605	Excessive wrinkling of palmar skin
HP:0008064	Ichthyosis
HP:0008066	Abnormal blistering of the skin
HP:0008499	High hypermetropia
HP:0010783	Erythema
HP:0012393	Allergy
HP:0012733	Macule
HP:0034838	Cleavage at junction of stratum corneum and stratum granulosum
HP:0040189	Scaling skin
HP:0200034	Papule
HP:0200041	Skin erosion

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST000459_4	Lung cancer	1.000000e-06
GCST009524_192	Household income (MTAG)	2.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009695	household income

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
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

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression, increases methylation	4
sodium arsenite	decreases expression	3
Tetrachlorodibenzodioxin	increases expression	2
Tretinoin	increases expression	2
Aflatoxin B1	increases expression	2
aristolochic acid I	increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenate	decreases expression, increases abundance	1
tris(2-butoxyethyl) phosphate	affects expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
tamibarotene	increases expression	1
CGP 52608	affects binding, increases reaction	1
clothianidin	decreases expression	1
abrine	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	increases expression	1
Temozolomide	increases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Acetylglucosamine	increases expression	1
Arsenic	decreases expression, increases abundance	1
Cisplatin	increases expression	1
Succimer	affects cotreatment, decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Tobacco Smoke Pollution	increases expression	1
Urethane	decreases expression	1
Asbestos, Crocidolite	increases expression	1
Okadaic Acid	increases expression	1
Lactic Acid	decreases expression	1
Magnetite Nanoparticles	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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