Is FLNB p.Val2146= (c.6438G>A) pathogenic?

FLNB p.Val2146= (c.6438G>A) is classified Benign in FLNB (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-01). Common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele; Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Val2146= (c.6438G>A)?

FLNB p.Val2146= (c.6438G>A) is associated with FLNB-Related Spectrum Disorders, connective tissue disorder (ClinVar).

FLNB p.Val2146=

Q: How common is FLNB p.Val2146= (c.6438G>A) in the general population?

FLNB p.Val2146= (c.6438G>A) is common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6438G>A · rs60599272 · VCV346356

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Common

common (popmax 10.1%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.025	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -0.45, phastCons 1
Overall
CADD	7.213	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.1% African / African-American · 7,588/75,058 alleles

Filtering AF 9.92% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.84%

Overall 0.538% 8,685/1,614,242 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	10.1%	10
Middle Eastern	0.726%	138
Remaining individualsnot grpmax-eligible	0.678%	147
Admixed American	0.641%	156
Ashkenazi Jewishnot grpmax-eligible	0.0304%	3,290
South Asian	0.0187%	5,358
European (non-Finnish)	0.0185%	5,413

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.Val2146=
Coding: c.6438G>A
MANE Select: NM_001457
dbSNP: rs60599272
Type: single nucleotide variant
Location: chr3:58153445 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 2146: a β-strand; the 'interaction with the cytoplasmic tail of gp1ba' region; the 'interaction with flna 1' region; 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

Also linked: connective tissue disorder

Similar variants

FLNB p.Phe161Cys Likely pathogenic ★★ same condition
FLNB p.Glu1661Lys Uncertain significance ★★ ⚠ same condition
FLNB p.Glu78Gly Uncertain significance ★★ ⚠ same condition
FLNB p.Gly496Cys 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

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-val2146 (accessed [today's date]).

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