Is FLNB p.Pro223= (c.669G>A) pathogenic?

FLNB p.Pro223= (c.669G>A) is classified Benign/Likely benign in FLNB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). Low-frequency (popmax 1.47%, afr); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Pro223= (c.669G>A)?

FLNB p.Pro223= (c.669G>A) is associated with FLNB-Related Spectrum Disorders (ClinVar).

How common is FLNB p.Pro223= (c.669G>A) in the general population?

FLNB p.Pro223= (c.669G>A) is low-frequency (popmax 1.47%, afr) (gnomAD).

FLNB p.Pro223=

c.669G>A · rs140815373 · VCV258118

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.47%, afr)

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -14	GERP -5.4
Overall
CADD	0.057	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.47% African / African-American · 1,104/74,988 alleles

Filtering AF 1.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.37%

Overall 0.133% 2,150/1,614,010 alleles · low-frequency exomes 1,404/1,461,820 · genomes 746/152,190 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.47%	68
Ashkenazi Jewishnot grpmax-eligible	0.706%	142
Admixed American	0.28%	357
Remaining individualsnot grpmax-eligible	0.224%	446
Middle Eastern	0.132%	758
European (non-Finnish)	0.0437%	2,287
South Asian	0.00439%	22,771
East Asian	0.00223%	44,882

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: FLNB
Protein: p.Pro223=
Coding: c.669G>A
MANE Select: NM_001457
dbSNP: rs140815373
Type: single nucleotide variant
Location: chr3:58081658 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 223: the calponin-homology (ch) 2 domain; the 'actin-binding' region

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

Disease context

FLNB-Related Spectrum Disorders

Similar variants

FLNB p.Pro223Leu Uncertain significance ★ ⚠ same residue
FLNB p.Glu1661Lys Uncertain significance ★★ ⚠ same condition
FLNB p.Glu78Gly Uncertain significance ★★ ⚠ same condition
FLNB p.His1117Arg Uncertain significance ★★ ⚠ same condition
FLNB p.Leu1440Pro Uncertain significance ★★ ⚠ same condition
FLNB p.Pro396Ser Uncertain significance ★★ ⚠ same condition
FLNB p.Ser1096Phe Uncertain significance ★★ ⚠ same condition
FLNB p.Ser188Cys 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/flnb-p-pro223 (accessed [today's date]).

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