Is FLNB p.Arg999Pro (c.2996G>C) pathogenic?

FLNB p.Arg999Pro (c.2996G>C) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.2338); Ultra-rare (popmax 0.0119%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLNB p.Arg999Pro (c.2996G>C)?

FLNB p.Arg999Pro (c.2996G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FLNB p.Arg999Pro (c.2996G>C) in the general population?

FLNB p.Arg999Pro (c.2996G>C) is ultra-rare (popmax 0.0119%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Arg999Pro (c.2996G>C)?

AlphaMissense predicts likely benign (score 0.2338) — an in-silico prediction, not a clinical call.

FLNB p.Arg999Pro

c.2996G>C · rs755928543 · VCV1508014

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2338 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0119%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2338	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -6.38	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.5	GERP 1.7, phastCons 0.72
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	22.0	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 0.0119% European (non-Finnish) · 140/1,180,038 alleles

Filtering AF 0.0102% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00964%

Overall 0.00874% 141/1,614,026 alleles · ultra-rare exomes 129/1,461,888 · genomes 12/152,138 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0119%	8,429
Remaining individualsnot grpmax-eligible	0.0016%	62,488

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.Arg999Pro
Coding: c.2996G>C
MANE Select: NM_001457
dbSNP: rs755928543
Type: single nucleotide variant
Location: chr3:58121373 (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

Similar variants

FLNB p.Arg999Trp Uncertain significance ★★ ⚠ same residue
FLNB p.Arg999Gln Uncertain significance ★★ ⚠ same residue
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

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-arg999pro (accessed [today's date]).

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