Is FLG p.Ser2080Ter (c.6239C>A) pathogenic?

FLG p.Ser2080Ter (c.6239C>A) is classified Pathogenic in FLG (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-21). Ultra-rare (popmax 0.0243%, nfe); Associated with ichthyosis vulgaris.

What condition is associated with FLG p.Ser2080Ter (c.6239C>A)?

FLG p.Ser2080Ter (c.6239C>A) is associated with ichthyosis vulgaris (ClinVar).

How common is FLG p.Ser2080Ter (c.6239C>A) in the general population?

FLG p.Ser2080Ter (c.6239C>A) is ultra-rare (popmax 0.0243%, nfe) (gnomAD).

FLG p.Ser2080Ter

c.6239C>A · rs147145234 · VCV225060

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0243%, nfe)

Conditions

ichthyosis vulgaris

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 in a haploinsufficient gene (ClinGen); NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.14	GERP -1.9
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 0.0243% European (non-Finnish) · 287/1,180,022 alleles

Filtering AF 0.022% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0211%

Overall 0.0184% 297/1,614,048 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0243%	4,112
African / African-American	0.00801%	12,489
Remaining individualsnot grpmax-eligible	0.0064%	15,622

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.Ser2080Ter
Coding: c.6239C>A
MANE Select: NM_023110 · reported on NM_002016
dbSNP: rs147145234
Type: single nucleotide variant
Location: chr1:152308647 (GRCh38)
Structure: AlphaFold pLDDT 74.30 · 86 PDB

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.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
FLG p.Gly2545Val 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-ser2080ter (accessed [today's date]).

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