Is FLG p.Ser333Phe (c.998C>T) pathogenic?

FLG p.Ser333Phe (c.998C>T) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely benign (0.2428); Ultra-rare (popmax 0.0233%, amr); Associated with Inborn genetic diseases.

What condition is associated with FLG p.Ser333Phe (c.998C>T)?

FLG p.Ser333Phe (c.998C>T) is associated with Inborn genetic diseases (ClinVar).

How common is FLG p.Ser333Phe (c.998C>T) in the general population?

FLG p.Ser333Phe (c.998C>T) is ultra-rare (popmax 0.0233%, amr) (gnomAD).

What do computational predictors say about FLG p.Ser333Phe (c.998C>T)?

AlphaMissense predicts likely benign (score 0.2428) — an in-silico prediction, not a clinical call.

FLG p.Ser333Phe

c.998C>T · VCV4257991

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2428 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0233%, amr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2428	likely benign
REVEL	0.068	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP 0.45
Overall
CADD	15.15	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0233% Admixed American · 14/59,988 alleles

Filtering AF 0.0141% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0112%

Overall 0.00229% 37/1,613,858 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0233%	4,285
European (non-Finnish)	0.00186%	53,636
Remaining individualsnot grpmax-eligible	0.0016%	62,480

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.Ser333Phe
Coding: c.998C>T
MANE Select: NM_002016
Type: single nucleotide variant
Location: chr1:152313888 (GRCh38)
Gene constraint: LOEUF 1.932 · pLI <0.01 (gnomAD)
Residue 333: the 'disordered' region

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLG p.Arg1798Ter Pathogenic/Likely pathogenic ★★ same condition
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same condition
FLG p.Gly2545Val Uncertain significance ★★ ⚠ same condition
FLG p.Gly2637Val Uncertain significance ★★ ⚠ same condition
FLG p.His2487Asn Uncertain significance ★★ ⚠ same condition
FLG p.Thr3143Ile Uncertain significance ★★ ⚠ same condition
FLG p.Ala1797Thr Uncertain significance ★ ⚠ same condition
FLG p.Ala2189Ser 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-ser333phe (accessed [today's date]).

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