FLG

Summary

FLG (filaggrin, HGNC:3748) is a protein-coding gene on chromosome 1q21.3, encoding Filaggrin (P20930). Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.

The protein encoded by this gene is an intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. It is initially synthesized as a polyprotein precursor, profilaggrin (consisting of multiple filaggrin units of 324 aa each), which is localized in keratohyalin granules, and is subsequently proteolytically processed into individual functional filaggrin molecules. Mutations in this gene are associated with ichthyosis vulgaris.

Source: NCBI Gene 2312 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant ichthyosis vulgaris (Definitive, GenCC) — +2 more curated relationships
• Clinical variants (ClinVar): 227 total — 35 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_002016

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3748
Approved symbol	FLG
Name	filaggrin
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	FLG1, FLG-1
Ensembl gene	ENSG00000143631
Ensembl biotype	protein_coding
OMIM	135940
Entrez	2312

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000368799

RefSeq mRNA: 1 — MANE Select: NM_002016 NM_002016

CCDS: CCDS30860

Canonical transcript exons

ENST00000368799 — 3 exons

Exon	Start	End
ENSE00000960656	152315319	152315477
ENSE00001447981	152302165	152314747
ENSE00001687643	152325189	152325239

Expression profiles

Bgee: expression breadth ubiquitous, 162 present calls, max score 99.83.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 3.2741 / max 1599.4783, expressed in 120 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14539	3.1886	116
14538	0.0450	9
14537	0.0405	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
upper leg skin	UBERON:0004262	99.83	gold quality
upper arm skin	UBERON:0004263	99.74	gold quality
skin of hip	UBERON:0001554	99.73	gold quality
penis	UBERON:0000989	99.68	gold quality
mammalian vulva	UBERON:0000997	99.66	gold quality
nipple	UBERON:0002030	98.96	gold quality
tongue squamous epithelium	UBERON:0006919	97.91	gold quality
skin of leg	UBERON:0001511	97.14	gold quality
zone of skin	UBERON:0000014	96.73	gold quality
skin of abdomen	UBERON:0001416	95.99	gold quality
epithelium of esophagus	UBERON:0001976	88.56	gold quality
oral cavity	UBERON:0000167	88.30	gold quality
esophagus squamous epithelium	UBERON:0006920	88.21	gold quality
amniotic fluid	UBERON:0000173	86.50	gold quality
pharyngeal mucosa	UBERON:0000355	84.16	gold quality
lower esophagus mucosa	UBERON:0035834	83.99	gold quality
squamous epithelium	UBERON:0006914	80.84	gold quality
buccal mucosa cell	CL:0002336	79.52	gold quality
gingiva	UBERON:0001828	76.94	gold quality
gingival epithelium	UBERON:0001949	70.99	silver quality
esophagus mucosa	UBERON:0002469	70.98	gold quality
cortical plate	UBERON:0005343	69.61	gold quality
sperm	CL:0000019	66.90	gold quality
male germ cell	CL:0000015	65.64	gold quality
cervix epithelium	UBERON:0004801	61.43	silver quality
esophagus	UBERON:0001043	61.25	gold quality
vagina	UBERON:0000996	60.88	gold quality
sural nerve	UBERON:0015488	59.32	silver quality
ventricular zone	UBERON:0003053	58.74	gold quality
islet of Langerhans	UBERON:0000006	58.06	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	4.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, AR, HOPX, LRRFIP1, MED1, NCOA3, PAX6, POU3F2, PPARG, RORA, SP1, TP53, VDR

miRNA regulators (miRDB)

28 targeting FLG, 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-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-345-3P	99.89	70.23	1421
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-4766-5P	99.75	69.23	2662
HSA-MIR-8084	99.73	69.57	1760
HSA-MIR-670-5P	99.67	69.94	1565
HSA-MIR-26A-2-3P	99.64	66.82	786
HSA-MIR-26A-1-3P	99.64	66.81	788
HSA-MIR-766-3P	99.47	65.24	1811
HSA-MIR-4762-3P	99.43	69.72	2363
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-32-3P	99.36	68.20	2517
HSA-MIR-3154	98.94	66.55	1455
HSA-MIR-1301-3P	98.64	68.27	1071
HSA-MIR-5047	98.64	68.62	1035
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-3977	98.00	68.17	1500
HSA-MIR-6779-3P	97.51	65.82	789
HSA-MIR-625-3P	97.32	66.55	554
HSA-MIR-3121-5P	97.30	66.62	1146
HSA-MIR-3976	96.67	67.79	1187

Literature-anchored findings (GeneRIF, showing 40)

• PAD1 and 3 are able to modify filaggrin (PMID:15675958)
• inverse association between the 12 repeat allele and self-perceived frequent dry skin (P=0.0293) (PMID:16261374)
• two independent loss-of-function genetic variants (R510X and 2282del4) in the gene encoding filaggrin (FLG) are very strong predisposing factors for atopic dermatitis (PMID:16550169)
• role of loss of function mutation as reisk factors for atopic dermatitis and asthma (PMID:16570058)
• new mutation, 3702delG, in addition to further instances of the reported mutations R501X and 2282del4 (PMID:16810297)
• filaggrin mutations determine major susceptibility to early-onset atopic dermatitis that persists into adulthood (PMID:16990802)
• filaggrin gene mutations predispose for early onset of atopic dermatitis (PMID:17008875)
• Filaggrin mutations have a role in early-onset and extrinsic atopic dermatitis (PMID:17096018)
• Compromised profilaggrin production leads to epidermal and allergic disorders and our findings emphasize the need for a detailed investigation of the role deacetylase inhibitors in the maintenance of epidermal homeostasis. (PMID:17195011)
• despite a markedly altered filaggrin expression in psoriatic skin, loss-of-function variants of the FLG gene are neither associated with psoriasis vulgaris nor with psoriatic arthritis (PMID:17255953)
• Results provide further confirmation of the importance of mutations in filaggrin and the skin barrier in atopic dermatitis pathogenesis. (PMID:17301831)
• No association for any of the FLG mutations with chronic plague-type psoriasis (PMID:17380114)
• Two common filaggrin (FLG) null mutations cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. (PMID:17417636)
• there is a spectrum of both prevalent and rare mutations that collectively have a significant impact on susceptibility to atopic disease (PMID:17502856)
• FLG mutations are associated not only with eczema-associated asthma susceptibility but also with asthma severity independent of eczema status. (PMID:17531295)
• When alopecia areata (AA) occurs in conjunction with filaggrin-associated atopic disorder, the clinical presentation of AA may be more severe. (PMID:17581619)
• Filaggrin mutations are genetic modifying factors exacerbating X-linked ichthyosis (PMID:17657246)
• Propionibacterium acnes extracts increased filaggrin and integrins in epidermal explants and cultured keratinocytes. (PMID:17684752)
• loss-of-function mutations in the FLG gene may contribute to the development of humoural autoimmunity, targeting citrullinated determinants in early rheumatoid arthritis (PMID:17704064)
• Meta-analysis of sizes of filaggrin (FLG) effects in family studies underline the importance of a genetically determined epidermal barrier disruption via FLG in atopic eczema. (PMID:17980411)
• Atopic dermatitis was associated with filaggrin variants R510X and 2282del4 in adults and children. (PMID:17989887)
• Filaggrin was not detected, suggesting that the differentiation in keratoacanthoma is not epidermoid. (PMID:18005116)
• R501X and c.3321delA in family with ichthyosis vulgasis complicated by atopic dermatitis (PMID:18007582)
• Evaluation of allele frequencies suggested R501X and 2282del4 filaggrin mutations do not confer susceptibility to psoriasis and atopic dermatitis in Italian patients. (PMID:18032906)
• filaggrin mutations may have a role in allergic contact sensitization to nickel (PMID:18049447)
• REVIEW: mutations provide new data concerning the genetics of atopic asthma as well as intriguing insight into disease mechanisms of systemic allergies involving antigen exposure in skin with defective barrier function (PMID:18068483)
• Filaggrin mutations consistently associated with atopic dermatitis and other allergic phenotypes do not appear to influence either susceptibility to asthma or asthma severity phenotypes. (PMID:18073125)
• filaggrin mutations may have a role in early-onset and persistent atopic eczema (PMID:18094728)
• filaggrin is not expressed in upper airway or esophageal epithelium and is unlikely to play a role in barrier function at those mucosal surfaces (PMID:18172455)
• This study evaluated families in Sweden and found an association of the filaggrin gene variants R501X and 2282del4 in the development and severity of atopic eczema. (PMID:18176743)
• FLG P478S polymorphism may confer susceptibility to the development of psoriasis among Taiwanese Chinese (PMID:18193244)
• filaggrin mutations cause ichthyosis vulgaris and are significantly associated with atopic dermatitis in Japan (PMID:18200065)
• Unique and recurrent mutations in the filaggrin gene in Singaporean Chinese patients with ichthyosis vulgaris. (PMID:18239616)
• Loss-of-function mutations in the filaggrin gene lead to reduced level of natural moisturizing factor in the stratum corneum. (PMID:18305568)
• there is an association between the presence of FLG null mutations and the risk of asthma exacerbations in asthmatic children and young adults. (PMID:18307574)
• Filaggrin null mutations are significantly associated with mild-to-moderate atopic eczema in childhood, with a recessive pattern of inheritance. (PMID:18313126)
• FLG mutations are strong genetic determinants of eczema, early wheeze, asthma in the context of eczema, and atopic sensitization. (PMID:18325573)
• Review highlights association studies on FLG loss-of-function mutations, atopic and non atopic phenotypes, and the role of filaggrin in epidermal barrier function. (PMID:18384254)
• p21, a cyclin-dependent kinase inhibitor downstream of S100/A11, is required for calcium-mediated induction of HBD-3 and filaggrin. (PMID:18385759)
• filaggrin mutations are key organ specific factors predominantly affecting the development of eczema and confer significant risks of allergic sensitization and allergic rhinitis as well as asthma in the context of eczema. (PMID:18396323)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Flg	ENSMUSG00000102439

Paralogs (3): FLG2 (ENSG00000143520), HRNR (ENSG00000197915), RPTN (ENSG00000215853)

Protein

Protein identifiers

Filaggrin — P20930 (reviewed: P20930)

All UniProt accessions (1): P20930

UniProt curated annotations — full annotation on UniProt →

Function. Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.

Subcellular location. Cytoplasmic granule.

Tissue specificity. Expressed in skin, thymus, stomach, tonsils, testis, placenta, kidney, pancreas, mammary gland, bladder, thyroid, salivary gland and trachea, but not detected in heart, brain, liver, lung, bone marrow, small intestine, spleen, prostate, colon, or adrenal gland. In the skin, mainly expressed in stratum granulosum of the epidermis.

Post-translational modifications. Filaggrin is initially synthesized as a large, insoluble, highly phosphorylated precursor containing many tandem copies of 324 AA, which are not separated by large linker sequences. During terminal differentiation it is dephosphorylated and proteolytically cleaved. The N-terminal of the mature protein is heterogeneous, and is blocked by the formation of pyroglutamate. Undergoes deimination of some arginine residues (citrullination).

Disease relevance. Ichthyosis vulgaris (VI) [MIM:146700] The most common form of ichthyosis inherited as an autosomal dominant trait. It is characterized by palmar hyperlinearity, keratosis pilaris and a fine scale that is most prominent over the lower abdomen, arms, and legs. Ichthyosis vulgaris is characterized histologically by absent or reduced keratohyalin granules in the epidermis and mild hyperkeratosis. The disease can be associated with frequent asthma, eczema or hay fever. The disease is caused by variants affecting the gene represented in this entry. Dermatitis atopic 2 (ATOD2) [MIM:605803] Atopic dermatitis is a complex, inflammatory disease with multiple alleles at several loci thought to be involved in the pathogenesis. It commonly begins in infancy or early childhood and is characterized by a chronic relapsing form of skin inflammation, a disturbance of epidermal barrier function that culminates in dry skin, and IgE-mediated sensitization to food and environmental allergens. It is manifested by lichenification, excoriation, and crusting, mainly on the flexural surfaces of the elbow and knee. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Induction. In cultured foreskin fibroblasts, up-regulated in response to Ca(2+) stimulation.

Similarity. Belongs to the S100-fused protein family.

RefSeq proteins (1): NP_002007* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001751	S100/CaBP7/8-like_CS	Conserved_site
IPR002048	EF_hand_dom	Domain
IPR003303	Filaggrin	Family
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR013787	S100_Ca-bd_sub	Domain
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR034325	S-100_dom	Domain
IPR052503	S100-fused_Epidermal_Struct	Family

Pfam: PF01023, PF03516

UniProt features (221 total): compositionally biased region 125, sequence variant 52, repeat 23, binding site 5, sequence conflict 4, helix 4, domain 2, turn 2, region of interest 2, chain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4PCW	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

No AlphaFold model available for P20930 — AlphaFold DB does not currently provide models for proteins above ~3000 aa.

Functional residue map

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

Ligand- & substrate-binding residues (5): 62; 64; 66; 68; 73

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-6809371	Formation of the cornified envelope
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin

MSigDB gene sets: 114 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_DN, GOBP_EPITHELIUM_DEVELOPMENT, JAEGER_METASTASIS_DN, HEIDENBLAD_AMPLICON_8Q24_DN, GOBP_EPIDERMAL_CELL_DIFFERENTIATION, GOBP_EPIDERMIS_DEVELOPMENT, GOBP_KERATINIZATION, GOBP_SKIN_DEVELOPMENT, ACEVEDO_METHYLATED_IN_LIVER_CANCER_DN, chr1q21, GOCC_RIBONUCLEOPROTEIN_GRANULE, GOCC_CORNIFIED_ENVELOPE, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, GOBP_CORNIFICATION, PHONG_TNF_RESPONSE_NOT_VIA_P38

GO Biological Process (4): keratinocyte differentiation (GO:0030216), establishment of skin barrier (GO:0061436), cornification (GO:0070268), peptide cross-linking (GO:0018149)

GO Molecular Function (6): calcium ion binding (GO:0005509), structural constituent of skin epidermis (GO:0030280), transition metal ion binding (GO:0046914), structural molecule activity (GO:0005198), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (6): cornified envelope (GO:0001533), nucleus (GO:0005634), cytosol (GO:0005829), extracellular matrix (GO:0031012), keratohyalin granule (GO:0036457), cytoplasmic ribonucleoprotein granule (GO:0036464)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Keratinization	1
Developmental Cell Lineages of the Integumentary System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
metal ion binding	2
cellular anatomical structure	2
epidermal cell differentiation	1
skin development	1
skin epidermis development	1
programmed cell death	1
keratinization	1
cornified envelope assembly	1
protein modification process	1
structural molecule activity	1
molecular_function	1
binding	1
cation binding	1
plasma membrane	1
intracellular membrane-bounded organelle	1
external encapsulating structure	1
ribonucleoprotein granule	1

Protein interactions and networks

STRING

1939 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
FLG	LORICRIN	P23490	996
FLG	IVL	P07476	994
FLG	KRT1	P04264	942
FLG	KRT10	P13645	917
FLG	SPINK5	Q9NQ38	916
FLG	CASP14	P31944	862
FLG	PADI3	Q9ULW8	839
FLG	DSG1	Q02413	814
FLG	TGM1	P22735	808
FLG	KLK7	P49862	766
FLG	ST14	Q9Y5Y6	739
FLG	TSLP	Q969D9	720
FLG	SPRR1A	P35321	715
FLG	KRT5	P13647	707
FLG	ING1	Q9UK53	704

IntAct

100 interactions, top by confidence:

A	B	Type	Score
NPHP1	NPHP4	psi-mi:“MI:0914”(association)	0.930
MCL1	PRKAB2	psi-mi:“MI:0914”(association)	0.640
CCNC	MED19	psi-mi:“MI:0914”(association)	0.640
ALDH3A1	RCCD1	psi-mi:“MI:0914”(association)	0.640
CFAP298	PEX7	psi-mi:“MI:0914”(association)	0.620
KLK5	FLG	psi-mi:“MI:0194”(cleavage reaction)	0.570
FLG	KLK5	psi-mi:“MI:0403”(colocalization)	0.570
FLG	KLK5	psi-mi:“MI:2364”(proximity)	0.570
ZSCAN12	A2ML1	psi-mi:“MI:0914”(association)	0.530
FTH1	A2ML1	psi-mi:“MI:0914”(association)	0.530
KIR3DS1	PPL	psi-mi:“MI:0914”(association)	0.530
UCP2	CST4	psi-mi:“MI:0914”(association)	0.530
STK16	FLG	psi-mi:“MI:0914”(association)	0.530
TBC1D22B	A2ML1	psi-mi:“MI:0914”(association)	0.530
GMCL1	A2ML1	psi-mi:“MI:0914”(association)	0.530
FRMD1	A2ML1	psi-mi:“MI:0914”(association)	0.530
ACAD9	PPL	psi-mi:“MI:0914”(association)	0.530
DTL	DNAJA2	psi-mi:“MI:0914”(association)	0.530
DPPA4	ALOX12B	psi-mi:“MI:0914”(association)	0.530
INPP5A	RCCD1	psi-mi:“MI:0914”(association)	0.530
MLLT6	RGPD8	psi-mi:“MI:0914”(association)	0.530
E6	CASK	psi-mi:“MI:0914”(association)	0.520
FLG	FLNC	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (126): FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS), FLG (Affinity Capture-MS)

ESM2 similar proteins: A0A0J9YWL9, A0A0J9YY54, A0A0U1RQI7, A0A494C071, A6NNC1, A6QL64, B3KS81, D3YZV8, E2RYF7, E9Q6E9, F1LWT0, F8W0I5, O60732, P0C8Z4, P0DKJ7, P0DKJ8, P0DKL2, P0DPF3, P18751, P20930, P43537, P53353, P59797, P62521, Q01456, Q08AG5, Q12816, Q3BBV2, Q5H9R4, Q5HY64, Q5JPF3, Q6P902, Q6ZQX7, Q86T75, Q86VE3, Q86VQ3, Q8BGJ3, Q8N307, Q8N7U7, Q8N7X1

Diamond homologs: A6QP92, P20930, P37709, P97347, Q07283, Q2VIS4, Q5D862, Q5QJ38, Q6XPR3, Q9D3P1, Q9UBG3, A7K6Y9, O77691, O77791, P02632, P02633, P02634, P02638, P02639, P04271, P04631, P05942, P05964, P06702, P06703, P07091, P10462, P14069, P23297, P24480, P25815, P26447, P27003, P28318, P28783, P29034, P29377, P30801, P33763, P33764

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HOPX	“up-regulates quantity by expression”	FLG	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	17
Uncertain significance	100
Likely benign	12
Benign	37

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1032025	NM_002016.2(FLG):c.5368C>T (p.Gln1790Ter)	Pathogenic
1212174	NM_002016.2(FLG):c.9061G>T (p.Gly3021Ter)	Pathogenic
1228379	NM_002016.2(FLG):c.5198C>G (p.Ser1733Ter)	Pathogenic
1299865	NM_002016.2(FLG):c.1378G>T (p.Glu460Ter)	Pathogenic
1325967	NM_002016.2(FLG):c.1685C>A (p.Ser562Ter)	Pathogenic
1342082	NM_002016.2(FLG):c.482_485del (p.Arg161fs)	Pathogenic
1691654	NM_002016.2(FLG):c.9683_9684del (p.Asp3227_Ser3228insTer)	Pathogenic
208582	NM_002016.2(FLG):c.2143C>T (p.Gln715Ter)	Pathogenic
225060	NM_002016.2(FLG):c.6239C>A (p.Ser2080Ter)	Pathogenic
225360	NM_002016.2(FLG):c.9887C>A (p.Ser3296Ter)	Pathogenic
225362	NM_002016.2(FLG):c.3905C>A (p.Ser1302Ter)	Pathogenic
280412	NM_002016.2(FLG):c.1063C>T (p.Gln355Ter)	Pathogenic
280555	NM_002016.2(FLG):c.4786C>T (p.Gln1596Ter)	Pathogenic
372768	NM_002016.2(FLG):c.4004_4005del (p.Glu1335fs)	Pathogenic
373097	NM_002016.2(FLG):c.11528C>G (p.Ser3843Ter)	Pathogenic
3769042	NM_002016.2(FLG):c.3632C>A (p.Ser1211Ter)	Pathogenic
3777386	NM_002016.2(FLG):c.8287C>T (p.Gln2763Ter)	Pathogenic
3900622	NM_002016.2(FLG):c.1776del (p.Ser593fs)	Pathogenic
419209	NM_002016.2(FLG):c.3551C>A (p.Ser1184Ter)	Pathogenic
422769	NM_002016.2(FLG):c.10191del (p.Glu3397fs)	Pathogenic
422934	NM_002016.2(FLG):c.9722del (p.Gly3241fs)	Pathogenic
423169	NM_002016.2(FLG):c.2906del (p.Asn969fs)	Pathogenic
432612	NM_002016.2(FLG):c.7081C>T (p.Arg2361Ter)	Pathogenic
450599	NM_002016.2(FLG):c.9595C>T (p.Gln3199Ter)	Pathogenic
450871	NM_002016.2(FLG):c.7358C>A (p.Ser2453Ter)	Pathogenic
451498	NM_002016.2(FLG):c.3510del (p.Ser1171fs)	Pathogenic
489034	NM_002016.2(FLG):c.3010C>T (p.Gln1004Ter)	Pathogenic
503619	NM_002016.2(FLG):c.5186C>G (p.Ser1729Ter)	Pathogenic
503791	NM_002016.2(FLG):c.9280del (p.Ala3094fs)	Pathogenic
50928	NM_002016.2(FLG):c.3254_3257del (p.Ser1085fs)	Pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

26306 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:152314664:A:C	F74L	0.998
1:152314664:A:T	F74L	0.998
1:152314666:A:G	F74L	0.998
1:152315350:A:G	L36P	0.998
1:152315359:A:G	L33P	0.998
1:152314665:A:G	F74S	0.996
1:152315374:A:G	L28S	0.996
1:152315412:G:C	F15L	0.996
1:152315412:G:T	F15L	0.996
1:152315414:A:G	F15L	0.996
1:152314673:G:C	F71L	0.995
1:152314673:G:T	F71L	0.995
1:152314675:A:G	F71L	0.995
1:152314642:C:G	A82P	0.994
1:152314659:A:G	L76P	0.993
1:152314662:A:G	L75P	0.993
1:152314674:A:G	F71S	0.993
1:152315347:A:G	L37P	0.993
1:152315413:A:G	F15S	0.993
1:152314636:C:G	A84P	0.991
1:152314704:A:G	L61S	0.991
1:152314641:G:T	A82D	0.990
1:152315416:A:G	L14P	0.990
1:152314644:A:G	L81S	0.989
1:152314716:A:G	F57S	0.989
1:152315335:A:G	F41S	0.988
1:152315323:A:G	L45P	0.987
1:152314668:T:A	E73V	0.985
1:152314665:A:C	F74C	0.984
1:152315374:A:C	L28W	0.984

dbSNP variants (sampled 300 via entrez): RS1000021227 (1:152323858 C>A,T), RS1000099844 (1:152323073 G>T), RS1000191539 (1:152302492 T>C), RS1000289060 (1:152307222 TC>T), RS1000465903 (1:152325090 C>A), RS1000747908 (1:152302250 A>G), RS1001093105 (1:152318363 C>T), RS1001103170 (1:152324749 G>T), RS1001346014 (1:152323976 A>C,T), RS1001372177 (1:152324338 C>T), RS1001887819 (1:152318998 G>C), RS1001922133 (1:152302588 A>T), RS1002017153 (1:152302723 G>A), RS1002090880 (1:152302968 A>G), RS1002162809 (1:152315629 T>G)

Disease associations

OMIM: gene MIM:135940 | disease phenotypes: MIM:605803, MIM:144110

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant ichthyosis vulgaris	Definitive	Semidominant
ichthyosis vulgaris	Strong	Semidominant
recessive X-linked ichthyosis	Supportive	X-linked

Mondo (7): ichthyosis vulgaris (MONDO:0024304), dermatitis, atopic, 2 (MONDO:0011596), congenital portosystemic shunt (MONDO:0018811), hyperhidrosis palmaris ET plantaris (MONDO:0007754), ichthyosis (MONDO:0019269), autosomal dominant ichthyosis vulgaris (MONDO:0007810), recessive X-linked ichthyosis (MONDO:0010622)

Orphanet (2): Congenital portosystemic shunt (Orphanet:480531), Ichthyosis (Orphanet:79354)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0008064	Ichthyosis

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D007057	Ichthyosis	C16.131.831.512; C16.614.492; C17.800.428.333; C17.800.804.512
D016112	Ichthyosis Vulgaris	C16.131.831.512.410; C16.320.850.405; C17.800.428.333.410; C17.800.804.512.410; C17.800.827.405
C565293	Dermatitis, Atopic, 2 (supp.)
C563185	Hyperhidrosis Palmaris Et Plantaris (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases reaction, decreases expression, increases abundance, increases expression	5
Tobacco Smoke Pollution	affects expression, decreases expression, increases expression	4
sodium arsenate	increases abundance, decreases expression	3
Estradiol	decreases expression, affects response to substance, increases secretion, decreases reaction, affects cotreatment (+1 more)	3
Tetrachlorodibenzodioxin	increases reaction, decreases expression, affects binding, decreases activity, decreases reaction (+1 more)	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
bisphenol A	affects expression, affects response to substance, decreases secretion, increases secretion, affects reaction	2
Antimony Potassium Tartrate	increases abundance, increases reaction, decreases reaction, decreases expression	2
Benzo(a)pyrene	increases methylation, increases mutagenesis	2
Cadmium	decreases expression, increases abundance, increases expression	2
Tretinoin	decreases expression, increases expression	2
Particulate Matter	increases expression, decreases expression, decreases reaction, increases abundance, increases reaction	2
4-oxoretinoic acid	decreases expression	1
oxybenzone	affects response to substance, decreases secretion, increases secretion	1
propylparaben	affects abundance, affects response to substance	1
diethyl phthalate	affects abundance, affects response to substance	1
2,4,5-trichlorophenol	affects response to substance, decreases secretion	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
alpha-naphthoflavone	affects binding, decreases activity, decreases reaction, increases expression	1
diisononyl phthalate	affects abundance, affects response to substance	1
quercitrin	increases expression	1
arsenite	decreases expression, increases abundance, decreases reaction	1
methylparaben	affects response to substance, affects abundance	1
mono-(2-ethylhexyl)phthalate	affects abundance, affects response to substance	1
brusatol	decreases expression, decreases reaction, increases abundance, increases reaction	1
4-hydroxybenzophenone	affects response to substance, decreases secretion, increases secretion	1
diisobutyl phthalate	affects abundance, affects response to substance	1
butylbenzyl phthalate	affects abundance, affects response to substance	1
monobutyl phthalate	affects abundance, affects response to substance	1
ferrous chloride	decreases expression	1

Cellosaurus cell lines

3 cell lines: 3 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_UK21	KCLi002-A	Induced pluripotent stem cell	Female
CVCL_UK22	KCLi003-A	Induced pluripotent stem cell	Female
CVCL_VN39	KCLi001-A	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04996485	PHASE4	UNKNOWN	Scientific Substantiation and Assessment of the Effectiveness of Pathogenetic Methods of Therapy for Congenital Ichthyosis in Children
NCT00004690	PHASE3	COMPLETED	Phase III Study of Monolaurin Cream Therapy for Patients With Congenital Ichthyosis
NCT05295732	PHASE3	COMPLETED	The ASCEND Study: Evaluating TMB-001 in the Treatment of RXLI or ARCI Ichthyosis
NCT03173547	PHASE2	COMPLETED	A Six Week Topical Cream Study for Subjects With Ichthyosis Vulgaris
NCT02864082	PHASE2	COMPLETED	A Safety and Tolerability Study of Topical PAT-001 in Congenital Ichthyosis
NCT03041038	PHASE2	COMPLETED	The Efficacy and Safety of Secukinumab in Patients With Ichthyoses
NCT04154293	PHASE2	COMPLETED	A Vehicle Controlled Study to Evaluate Safety and Efficacy of Topical TMB-001 for Treatment of Congenital Ichthyosis
NCT04697056	PHASE2	TERMINATED	A Study to Evaluate the Efficacy and Safety of Imsidolimab (ANB019) in the Treatment of Participants With Ichthyosis
NCT06136403	PHASE2	RECRUITING	A 44-week Monocentric Open Study Assessing the Efficacy and Safety of Deucravacitinib in Adults With Inflammatory Genodermatoses
NCT06362447	PHASE2	NOT_YET_RECRUITING	Efficacy of Injectable Gentamicin in Hereditary Ichthyosis
NCT00074685	Not specified	COMPLETED	National Registry for Ichthyosis and Related Disorders
NCT01016106	Not specified	COMPLETED	Genetic Screening for Filaggrin Mutation in Atopic Dermatitis and Ichthyosis Vulgaris in the African American Population
NCT02978209	Not specified	UNKNOWN	Comparison of Different Concentrations of Carbamide as Moisturizers in Ichthyosis Vulgaris
NCT04750161	Not specified	UNKNOWN	The Role Of Neutrophil Proteases As Global Regulators Of Il-1 Family Cytokine Activity In Skin Disorders
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension
NCT02854540	Not specified	COMPLETED	Management of Palmar Hyperhidrosis With Hydrogel-based Iontophoresis
NCT04549792	EARLY_PHASE1	COMPLETED	An Open-Label and Long-Term Extension Study to Evaluate the Efficacy and Safety of Ustekinumab in the Treatment of Patients With Ichthyoses
NCT07050810	EARLY_PHASE1	ENROLLING_BY_INVITATION	Thera-Clean® Microbubbles System in Patients With Skin Diseases
NCT02655861	Not specified	TERMINATED	A Multi-center, Prospective Evaluation of Infants and Children With Congenital Ichthyosis
NCT03051347	Not specified	COMPLETED	Asthma and Atopic Dermatitis Validation of PROMIS Pediatric Instruments
NCT03417856	Not specified	ENROLLING_BY_INVITATION	Defining the Skin and Blood Biomarkers of Ichthyosis
NCT03464994	Not specified	COMPLETED	Ophthalmological Abnormalities in Hereditary Ichthyosis (ICHTYO-KERATO)
NCT03641261	Not specified	COMPLETED	Therapeutic Education Using an Internet Application in Hereditary Ichthyosis
NCT03796052	Not specified	COMPLETED	Study Determining Safety and Efficacy of Avena Sativa (Oat) Skincare Products for Treating Skin Dryness and Itching in Cancer Patients
NCT05610306	Not specified	COMPLETED	Quality of Life in Middle-aged and Older Patients With Congenital Ichthyosis
NCT05954416	Not specified	RECRUITING	FARD (RaDiCo Cohort) (RaDiCo-FARD)
NCT06123091	Not specified	UNKNOWN	Exploring Patient Reported Outcomes in Inherited Ichthyosis
NCT06330324	Not specified	ENROLLING_BY_INVITATION	Reproductive Options in Inherited Skin Diseases
NCT06330350	Not specified	RECRUITING	Qualitative Study in Patients With Genodermatoses and Healthcare Professionals on Reproductive Counselling
NCT07066150	Not specified	COMPLETED	A Clinical Evaluation of Marula-Derived Ceramide Cream on Skin Barrier Function Enhancement