FLG2

Chr 1AR

filaggrin 2

ENSG00000143520 UniProt: Q5D862 OMIM: 616284

Essential for normal cell-cell adhesion in the cornified cell layers (PubMed:29758285). Important for proper integrity and mechanical strength of the stratum corneum of the epidermis (PubMed:29505760)

OMIM Research

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Peeling skin syndrome 6MIM #618084

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Peeling skin syndrome 6; no ClinGen or GenCC tier

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.92

LOEUF

Multiple*

Mechanism· predicted

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.92LOEUF

pLI 0.018

Z-score -0.43

OE 1.38 (0.44–1.92)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-1.19Z-score

OE missense 1.10 (1.05–1.15)

1260 obs / 1146.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?1.38 (0.44–1.92)

0≤0.351.4

Missense OE?1.10 (1.05–1.15)

0≤0.61.4

Synonymous OE?1.18

0≤1.21.6

LoF obs/exp: 2 / 1.4Missense obs/exp: 1260 / 1146.2Syn Z: -3.04

Background carrier burden — how many people carry a rare variant somewhere in FLG2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 18

2,912 rare PASS variants

Rare truncating (LoF)

1 in 230

336 rare PASS variants

Rare synonymous (reference)

1 in 26

1,119 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FLG2. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 23	1 in 280
South Asian	~43k	1 in 18	1 in 190
Remaining (unassigned)	~30k	1 in 17	1 in 190
European (Finnish)	~27k	1 in 52	1 in 290
Admixed American	~22k	1 in 15	1 in 270
African / African American	~21k	1 in 14	1 in 270
East Asian	~20k	1 in 21	1 in 190
Ashkenazi Jewish	~13k	1 in 73	1 in 1,300
Middle Eastern	~2,884	1 in 21	1 in 260

Each group is summed over the variants that are rare in that group. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓