GeneBe

FLG

protein-coding

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

Gene summary

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.[provided by RefSeq, Dec 2009]

MANE transcript

NM_002016.2

Inheritance

XL, AD, AR, SD

ClinVar variants

P:296U:1362B:755

Top phenotype

Icthyosis vulgaris

gnomAD constraint

pLI —, LoF o/e 2.42

Max pathogenic AF

—

Genomic locus

chr1:152,302,165-152,325,239

External References & Databases

Ensembl (ENSG00000143631)NCBI Gene (2312)OMIM (135940)HGNC:3748GenCCUniProt (P20930)AlphaFoldClinVar (FLG)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~23.1 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

recessive X-linked ichthyosisSUPPORTIVE

Inheritance Pattern: XL

Disease ID:MONDO:0010622

Submitter: Orphanet

autosomal dominant ichthyosis vulgarisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007810

Submitter: Genomics England PanelApp

autosomal dominant ichthyosis vulgarisLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0007810

Submitter: G2P

autosomal dominant ichthyosis vulgarisDEFINITIVE

Inheritance Pattern: SD

Disease ID:MONDO:0007810

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

ichthyosis vulgarisSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0024304

Submitter: PanelApp Australia

autosomal dominant ichthyosis vulgarisSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007810

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Icthyosis vulgarisAD/AR

Manifestation: Dermatologic

Intervention: General

Rationale: 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

Refs: 12473059; 12838398; 17030239; 16550169; 16444271; 16815158; 17291859; 21692775; 21712002; 21790526; 22299762; 22951058; 22962861; 22989708Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FLG variants in ClinVar

34 Conditions Cataloged
Inborn genetic diseasesTotal: 1473
not providedTotal: 680
not specifiedTotal: 333
Ichthyosis vulgarisTotal: 208
FLG-related disorderTotal: 119
Dermatitis, atopic, 2Total: 107
Autosomal dominant ichthyosis vulgarisTotal: 11
Ichthyosis and erythrokeratodermaTotal: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_002016.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
2
clinvar
333
clinvar
8
clinvar
 343
missense
1323
clinvar
365
clinvar
47
clinvar
 1735
nonsense
83
clinvar
98
clinvar
20
clinvar
 201
start loss
0
frameshift
54
clinvar
59
clinvar
17
clinvar
2
clinvar
 132
splice donor/acceptor (+/-2bp)
2
clinvar
 2
Total1371591362700552413

Highest pathogenic variant AF is 0.018972682

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_002016.2RefSeqNP_002007.12MANE Select
ENST00000368799.2EnsemblENSP00000357789.12MANE Select

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Keratinization
  • Developmental Biology
  • Formation of the cornified envelope

Biological Process

  • multicellular organism development
  • peptide cross-linking
  • keratinocyte differentiation
  • establishment of skin barrier
  • cornification

Molecular Function

  • structural molecule activity
  • calcium ion binding
  • protein binding
  • structural constituent of epidermis
  • transition metal ion binding

Cellular Component

  • cornified envelope
  • nucleus
  • cytosol
  • intermediate filament
  • keratohyalin granule

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000368799
Coding exons
2
Length
23029
Individuals with no LoFs
125623
Homozygous LoFs
0
Heterozygous LoFs
11
Defined
125634
p
0.0000438
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-18.544362.07e+32.150.00012625424
Missense (PolyPhen)819381.322.14784505
Synonymous-21.015698091.940.00004978052
Loss of Function-1.6941.652.426.88e-823

Population LoF Frequency

PopulationCAFp-valueStatus
African0.0000620.000062rare
Latino/Admixed American0.0000290.000029rare
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)0.0000710.000070rare
South Asian0.0000330.000033rare
Other00.0absent

dbNSFP Gene Annotations

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.;

Intolerance Scores

LoFtool
0.995
RVIS EVS
24.3
RVIS percentile EVS
99.99

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.284

Gene Damage Prediction

AllRecessiveDominant
MendelianHighHighHigh
Primary ImmunodeficiencyHighHighHigh
CancerHighHighHigh
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