Is FLNB p.Lys399Arg (c.1196A>G) pathogenic?

FLNB p.Lys399Arg (c.1196A>G) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-02-01). AlphaMissense: likely benign (0.0674); Ultra-rare (popmax 0.0903%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLNB p.Lys399Arg (c.1196A>G)?

FLNB p.Lys399Arg (c.1196A>G) is associated with Inborn genetic diseases, connective tissue disorder (ClinVar).

How common is FLNB p.Lys399Arg (c.1196A>G) in the general population?

FLNB p.Lys399Arg (c.1196A>G) is ultra-rare (popmax 0.0903%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Lys399Arg (c.1196A>G)?

AlphaMissense predicts likely benign (score 0.0674) — an in-silico prediction, not a clinical call.

FLNB p.Lys399Arg

c.1196A>G · rs145673747 · VCV449801

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0674 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0903%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0674	likely benign
REVEL	0.258	benign-leaning
SaProt	LLR -6.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	21.7	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 0.0903% European (non-Finnish) · 1,065/1,180,042 alleles

Filtering AF 0.0857% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0839%

Overall 0.0722% 1,165/1,614,200 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0903%	1,108
Remaining individualsnot grpmax-eligible	0.0656%	1,524
Admixed American	0.0483%	2,069
Finnishnot grpmax-eligible	0.0234%	4,269
Middle Eastern	0.0165%	6,062
African / African-American	0.0107%	9,382
South Asian	0.00549%	18,216
East Asian	0.00223%	44,884

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.Lys399Arg
Coding: c.1196A>G
MANE Select: NM_001457
dbSNP: rs145673747
Type: single nucleotide variant
Location: chr3:58098759 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: connective tissue disorder

Similar variants

FLNB p.Phe161Cys Likely pathogenic ★★ same condition
FLNB c.4862-3C>T Uncertain significance ★★ same condition
FLNB p.Ala1191Thr Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1191Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1391Thr Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1427Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1608Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1704Ser 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-lys399arg (accessed [today's date]).

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