Is FLG p.Arg455Ser (c.1363C>A) pathogenic?

FLG p.Arg455Ser (c.1363C>A) is classified Uncertain significance in FLG (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-01). AlphaMissense: likely benign (0.2598); Ultra-rare (popmax 0.0156%, eas).

How common is FLG p.Arg455Ser (c.1363C>A) in the general population?

FLG p.Arg455Ser (c.1363C>A) is ultra-rare (popmax 0.0156%, eas) (gnomAD).

What do computational predictors say about FLG p.Arg455Ser (c.1363C>A)?

AlphaMissense predicts likely benign (score 0.2598) — an in-silico prediction, not a clinical call.

FLG p.Arg455Ser

c.1363C>A · VCV3771579

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2598 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0156%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

⚠ 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
AlphaMissense	0.2598	likely benign
REVEL	0.06	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP -3	GERP -0.86
Regional constraint	o/e 1.77	unconstrained · MANE · 8,404 bp · p 0 · regional, not allelic
Overall
CADD	16.08	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 0.0156% East Asian · 7/44,830 alleles

Filtering AF 0.00727% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00515%

Overall 0.000868% 14/1,613,826 alleles · ultra-rare exomes 13/1,461,874 · genomes 1/151,952 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0156%	6,404
African / African-American	0.00134%	74,840
South Asian	0.0011%	91,054
European (non-Finnish)	0.000424%	236,004

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.Arg455Ser
Coding: c.1363C>A
MANE Select: NM_002016
Type: single nucleotide variant
Location: chr1:152313523 (GRCh38)

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

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-arg455ser (accessed [today's date]).

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