Is FLNB p.Ala666= (c.1998C>T) pathogenic?

FLNB p.Ala666= (c.1998C>T) is classified Likely benign in FLNB (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). Rare (popmax 0.175%, nfe); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Ala666= (c.1998C>T)?

FLNB p.Ala666= (c.1998C>T) is associated with FLNB-Related Spectrum Disorders (ClinVar).

How common is FLNB p.Ala666= (c.1998C>T) in the general population?

FLNB p.Ala666= (c.1998C>T) is rare (popmax 0.175%, nfe) (gnomAD).

FLNB p.Ala666=

c.1998C>T · rs143161769 · VCV709969

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.175%, nfe)

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 -20	GERP -5.4
Overall
CADD	0.1	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.175% European (non-Finnish) · 2,060/1,179,980 alleles

Filtering AF 0.168% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.166%

Overall 0.134% 2,165/1,614,022 alleles · rare exomes 2,035/1,461,838 · genomes 130/152,184 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.175%	573
Remaining individualsnot grpmax-eligible	0.072%	1,389
Finnishnot grpmax-eligible	0.0344%	2,909
African / African-American	0.0333%	3,000
East Asian	0.0111%	8,978
Admixed American	0.00833%	12,003
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
South Asian	0.0022%	45,531

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.Ala666=
Coding: c.1998C>T
MANE Select: NM_001457
dbSNP: rs143161769
Type: single nucleotide variant
Location: chr3:58108514 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB

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

Disease context

FLNB-Related Spectrum Disorders

Similar variants

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
FLNB p.Tyr63His 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-ala666 (accessed [today's date]).

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