Is FLG p.Arg992fs (c.2976_2977del) pathogenic?

FLG p.Arg992fs (c.29762977del) is classified Pathogenic in FLG (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-08-18). Rare (popmax 0.157%, sas); Associated with autosomal dominant ichthyosis vulgaris.

What condition is associated with FLG p.Arg992fs (c.2976_2977del)?

FLG p.Arg992fs (c.2976_2977del) is associated with autosomal dominant ichthyosis vulgaris, ichthyosis vulgaris (ClinVar).

How common is FLG p.Arg992fs (c.2976_2977del) in the general population?

FLG p.Arg992fs (c.2976_2977del) is rare (popmax 0.157%, sas) (gnomAD).

FLG p.Arg992fs

c.2976_2977del · rs776968118 · VCV1685822

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

rare (popmax 0.157%, sas)

Conditions

autosomal dominant ichthyosis vulgaris

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -6.7	GERP -2.9
Overall
CADD	16.76	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	chr1:152303355 segmental duplication, simple repeat · ambiguous alignment · reads may not map uniquely · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.157% South Asian · 143/91,074 alleles

Filtering AF 0.136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.128%

Overall 0.0102% 165/1,614,134 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.157%	637
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00446%	22,430
European (non-Finnish)	0.00102%	98,335

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FLG
Protein: p.Arg992fs
Coding: c.2976_2977del
dbSNP: rs776968118
Type: Microsatellite
Location: chr1:152311909 (GRCh38)

Full FLG gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant ichthyosis vulgaris — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: ichthyosis vulgaris

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/flg-p-arg992fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown