Is FLNB p.Arg1689His (c.5066G>A) pathogenic?

FLNB p.Arg1689His (c.5066G>A) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-06). AlphaMissense: ambiguous (0.4457); Very rare (popmax 0.00333%, amr).

How common is FLNB p.Arg1689His (c.5066G>A) in the general population?

FLNB p.Arg1689His (c.5066G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about FLNB p.Arg1689His (c.5066G>A)?

AlphaMissense predicts ambiguous (score 0.4457) — an in-silico prediction, not a clinical call.

FLNB p.Arg1689His

c.5066G>A · rs139001404 · VCV1686707

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4457 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.4457	ambiguous
REVEL	0.633	indeterminate
SaProt	LLR -8.06	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 32 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	32.0	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 0.00333% Admixed American · 2/60,012 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00136% 22/1,614,020 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	30,006
African / African-American	0.00267%	37,467
European (non-Finnish)	0.00144%	69,410
South Asian	0.0011%	91,078

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.Arg1689His
Coding: c.5066G>A
MANE Select: NM_001457
dbSNP: rs139001404
Type: single nucleotide variant
Location: chr3:58138486 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1689: a β-strand

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

Similar variants

FLNB p.Arg1689Cys Uncertain significance ★ ⚠ same residue
FLNB c.4390+2T>C Pathogenic/Likely pathogenic ★★ same type
FLNB c.5110-1G>A Likely pathogenic ★★ same type
FLNB p.Arg1463Ter Pathogenic/Likely pathogenic ★★ same type
FLNB p.Arg1948Ter Pathogenic ★★ same type
FLNB p.Arg649Ter Pathogenic ★★ same type
FLNB p.Asp167Gly Likely pathogenic ★★ ⚠ same type
FLNB p.Glu227Lys Pathogenic ★★ same type

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-arg1689his (accessed [today's date]).

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