Is FLNB p.Ser2227Cys (c.6680C>G) pathogenic?

FLNB p.Ser2227Cys (c.6680C>G) is classified Benign/Likely benign in FLNB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-02). AlphaMissense: likely benign (0.1379); Rare (popmax 0.987%, eas); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Ser2227Cys (c.6680C>G)?

FLNB p.Ser2227Cys (c.6680C>G) is associated with FLNB-Related Spectrum Disorders (ClinVar).

How common is FLNB p.Ser2227Cys (c.6680C>G) in the general population?

FLNB p.Ser2227Cys (c.6680C>G) is rare (popmax 0.987%, eas) (gnomAD).

What do computational predictors say about FLNB p.Ser2227Cys (c.6680C>G)?

AlphaMissense predicts likely benign (score 0.1379) — an in-silico prediction, not a clinical call.

FLNB p.Ser2227Cys

c.6680C>G · rs138327769 · VCV258117

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1379 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.987%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.1379	likely benign
REVEL	0.794	moderately pathogenic-leaning
SaProt	LLR -9.87	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 32 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.987% East Asian · 443/44,870 alleles

Filtering AF 0.911% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.881%

Overall 0.0349% 564/1,613,964 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.987%	101
Remaining individualsnot grpmax-eligible	0.072%	1,389
South Asian	0.0538%	1,859
African / African-American	0.0307%	3,262
Admixed American	0.00333%	30,010
European (non-Finnish)	0.00017%	589,943

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.Ser2227Cys
Coding: c.6680C>G
MANE Select: NM_001457
dbSNP: rs138327769
Type: single nucleotide variant
Location: chr3:58154836 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 2227: a β-strand; the 'interaction with inppl1' 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.Ser2227Ala 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-ser2227cys (accessed [today's date]).

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