Is FLG p.Arg3487Ter (c.10459A>T) pathogenic?

FLG p.Arg3487Ter (c.10459A>T) is classified Likely pathogenic in FLG (ClinVar, No assertion criteria, 1 submitter). Very rare (popmax 0.00224%, eas); Associated with ichthyosis vulgaris.

What condition is associated with FLG p.Arg3487Ter (c.10459A>T)?

FLG p.Arg3487Ter (c.10459A>T) is associated with ichthyosis vulgaris (ClinVar).

How common is FLG p.Arg3487Ter (c.10459A>T) in the general population?

FLG p.Arg3487Ter (c.10459A>T) is very rare (popmax 0.00224%, eas) (gnomAD).

FLG p.Arg3487Ter

c.10459A>T · rs1396693199 · VCV996656

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Conditions

ichthyosis vulgaris

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	36.0	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 0.00224% East Asian · 1/44,598 alleles

Overall 6.2e-05% 1/1,612,134 alleles · very rare exomes 1/1,460,704 · genomes 0/151,430 · joint denominator

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.Arg3487Ter
Coding: c.10459A>T
MANE Select: NM_002016
dbSNP: rs1396693199
Type: single nucleotide variant
Location: chr1:152304427 (GRCh38)
Gene constraint: LOEUF 1.932 · pLI <0.01 (gnomAD)
Residue 3487: the 'disordered' region

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

Disease context

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

Similar variants

FLG p.Arg1798Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Gln1790Ter Pathogenic ★★ same condition
FLG p.Gln355Ter Pathogenic ★★ same condition
FLG p.Ser2080Ter Pathogenic ★★ same condition
FLG p.Ser2554Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Ser3296Ter Pathogenic ★★ same condition
FLG p.Arg1133Gln Uncertain significance ★★ ⚠ same condition
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same condition

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-arg3487ter (accessed [today's date]).

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