FLG

filaggrin, the group of S100 fused type protein family|EF-hand domain containing

Basic information

Region (hg38): 1:152302164-152325239

Links

ENSG00000143631 ∙ NCBI:2312 ∙ OMIM:135940 ∙ HGNC:3748 ∙ Uniprot:P20930 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant ichthyosis vulgaris (Limited), mode of inheritance: AR
• autosomal dominant ichthyosis vulgaris (Strong), mode of inheritance: AD
• autosomal dominant ichthyosis vulgaris (Strong), mode of inheritance: AD
• autosomal dominant ichthyosis vulgaris (Definitive), mode of inheritance: Semidominant

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Icthyosis vulgaris	AD/AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Dermatologic	12473059; 12838398; 17030239; 16550169; 16444271; 16815158; 17291859; 21692775; 21712002; 21790526; 22299762; 22951058; 22962861; 22989708

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the FLG gene.

• not provided (483 variants)
• Inborn genetic diseases (473 variants)
• Ichthyosis vulgaris (135 variants)
• not specified (29 variants)
• Dermatitis, atopic, 2 (14 variants)
• Ichthyosis vulgaris;Dermatitis, atopic, 2 (8 variants)
• FLG-related disorders (8 variants)
• Dermatitis, atopic, 2;Ichthyosis vulgaris (6 variants)
• FLG-related condition (5 variants)
• Dermatitis, atopic, 2, susceptibility to (4 variants)
• Autosomal dominant ichthyosis vulgaris (3 variants)
• Eczema (2 variants)
• Ichthyosis vulgaris;Atopic eczema (1 variants)
• FLG-Related Disorder (1 variants)
• See cases (1 variants)
• Palmoplantar blistering;Palmoplantar hyperhidrosis;Ichthyosis;Atrophic scars (1 variants)
• 8 conditions (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the FLG gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous				102	29	131
missense			414	148	97	659
nonsense	72	22	4			98
start loss						0
frameshift	43	17		2		62
inframe indel			3			3
splice donor/acceptor (+/-2bp)		1				1
splice region						0
non coding					5	5
Total	115	40	421	252	131

Highest pathogenic variant AF is 0.000493

Variants in FLG

This is a list of pathogenic ClinVar variants found in the FLG region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
1-152302521-G-A			Benign (Jul 05, 2018)
1-152302716-T-C		Inborn genetic diseases	Uncertain significance (Oct 13, 2023)
1-152302741-G-A			Likely benign (Mar 01, 2023)
1-152302758-C-T		Inborn genetic diseases	Uncertain significance (Jun 23, 2023)
1-152302796-C-T		FLG-related disorder	Benign/Likely benign (Aug 14, 2019)
1-152302797-G-C		Inborn genetic diseases	Uncertain significance (Oct 05, 2023)
1-152302797-G-T			Likely benign (Jul 05, 2018)
1-152302818-T-A		Inborn genetic diseases	Uncertain significance (Mar 20, 2023)
1-152302822-T-A		Ichthyosis vulgaris	Conflicting classifications of pathogenicity (May 12, 2022)
1-152302829-C-T		FLG-related disorder	Likely benign (Mar 01, 2023)
1-152302882-T-C		Inborn genetic diseases	Uncertain significance (Jan 19, 2024)
1-152302890-A-G		Inborn genetic diseases	Uncertain significance (Dec 15, 2023)
1-152302897-C-G		Inborn genetic diseases	Uncertain significance (Jan 02, 2024)
1-152302934-A-T			Pathogenic (Apr 28, 2023)
1-152302945-T-C		Inborn genetic diseases	Conflicting classifications of pathogenicity (Mar 01, 2024)
1-152302977-G-A			Benign (Jul 14, 2018)
1-152303006-A-G			Likely benign (Sep 01, 2023)
1-152303034-T-TG			Pathogenic (Sep 22, 2022)
1-152303047-G-T		Inborn genetic diseases	Uncertain significance (Oct 05, 2021)
1-152303059-C-T		Inborn genetic diseases	Uncertain significance (Apr 19, 2023)
1-152303083-A-G			Benign (Jul 09, 2018)
1-152303103-T-G		Inborn genetic diseases	Uncertain significance (Feb 16, 2023)
1-152303163-T-C		Inborn genetic diseases	Uncertain significance (Jan 05, 2022)
1-152303166-C-T		Inborn genetic diseases	Likely benign (Mar 24, 2023)
1-152303172-G-A		Inborn genetic diseases	Uncertain significance (Nov 10, 2022)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
FLG	protein_coding	protein_coding	ENST00000368799	2	23029

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.000288	0.203	125623	0	11	125634	0.0000438

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-18.5	4436	2.07e+3	2.15	0.000126	25424
Missense in Polyphen		819	381.32	2.1478		4505
Synonymous	-21.0	1569	809	1.94	0.0000497	8052
Loss of Function	-1.69	4	1.65	2.42	6.88e-8	23

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000905	0.0000905
Ashkenazi Jewish	0.00	0.00
East Asian	0.00	0.00
Finnish	0.00	0.00
European (Non-Finnish)	0.0000705	0.0000704
Middle Eastern	0.00	0.00
South Asian	0.0000329	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Aggregates keratin intermediate filaments and promotes disulfide-bond formation among the intermediate filaments during terminal differentiation of mammalian epidermis.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:16444271}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:16550169, ECO:0000269|PubMed:16815158, ECO:0000269|PubMed:17030239, ECO:0000269|PubMed:17291859}. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry.
• Pathway: Keratinization;Developmental Biology;Formation of the cornified envelope (Consensus)

Intolerance Scores

• loftool: 0.995
• rvis_EVS: 24.3
• rvis_percentile_EVS: 99.99

Haploinsufficiency Scores

• pHI: 0.0897
• ghis: 0.389

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: N
• gene_indispensability_score: 0.284

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Gene ontology

• Biological process: multicellular organism development;peptide cross-linking;keratinocyte differentiation;establishment of skin barrier;cornification
• Cellular component: cornified envelope;nucleus;cytosol;intermediate filament;keratohyalin granule;intracellular membrane-bounded organelle;collagen-containing extracellular matrix
• Molecular function: structural molecule activity;calcium ion binding;protein binding;structural constituent of epidermis;transition metal ion binding