Is FLG p.Trp3333Ter (c.9999G>A) pathogenic?

FLG p.Trp3333Ter (c.9999G>A) is classified Pathogenic/Likely pathogenic in FLG (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-03-09). Very rare (popmax 0.0044%, sas); Associated with dermatitis, atopic, 2.

What condition is associated with FLG p.Trp3333Ter (c.9999G>A)?

FLG p.Trp3333Ter (c.9999G>A) is associated with dermatitis, atopic, 2 (ClinVar).

How common is FLG p.Trp3333Ter (c.9999G>A) in the general population?

FLG p.Trp3333Ter (c.9999G>A) is very rare (popmax 0.0044%, sas) (gnomAD).

FLG p.Trp3333Ter

c.9999G>A · VCV3767602

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0044%, sas)

Conditions

dermatitis, atopic, 2

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	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 -20	GERP -3.3
Overall
CADD	34.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0044% South Asian · 4/90,988 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000892%

Overall 0.00124% 20/1,613,630 alleles · very rare exomes 20/1,461,690 · genomes 0/151,940 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0044%	22,747
African / African-American	0.00267%	37,484
European (non-Finnish)	0.00119%	84,274

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.Trp3333Ter
Coding: c.9999G>A
MANE Select: NM_002016
Type: single nucleotide variant
Location: chr1:152304887 (GRCh38)

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

Disease context

dermatitis, atopic, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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-trp3333ter (accessed [today's date]).

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