Is FLNB p.Arg2172His (c.6515G>A) pathogenic?

FLNB p.Arg2172His (c.6515G>A) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-06-27). AlphaMissense: likely benign (0.0732); Ultra-rare (popmax 0.0746%, afr); Associated with connective tissue disorder.

What condition is associated with FLNB p.Arg2172His (c.6515G>A)?

FLNB p.Arg2172His (c.6515G>A) is associated with connective tissue disorder (ClinVar).

How common is FLNB p.Arg2172His (c.6515G>A) in the general population?

FLNB p.Arg2172His (c.6515G>A) is ultra-rare (popmax 0.0746%, afr) (gnomAD).

What do computational predictors say about FLNB p.Arg2172His (c.6515G>A)?

AlphaMissense predicts likely benign (score 0.0732) — an in-silico prediction, not a clinical call.

FLNB p.Arg2172His

c.6515G>A · rs139846706 · VCV618136

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0732 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0746%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.0732	likely benign
REVEL	0.158	moderately benign-leaning
SaProt	LLR -7.84	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 5.9	GERP 0.63, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 32 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	25.0	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 0.0746% African / African-American · 56/75,074 alleles

Filtering AF 0.0589% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0533%

Overall 0.00997% 161/1,614,164 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0746%	1,341
European (non-Finnish)	0.00822%	12,165
Remaining individualsnot grpmax-eligible	0.008%	12,502
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,028
South Asian	0.0011%	91,092

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.Arg2172His
Coding: c.6515G>A
MANE Select: NM_001457
dbSNP: rs139846706
Type: single nucleotide variant
Location: chr3:58153522 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 2172: a β-strand; 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

connective tissue disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLNB p.Arg2172Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNB p.Phe161Cys Likely pathogenic ★★ same condition
FLNB p.Gly496Cys Uncertain significance ★★ ⚠ same condition
FLNB p.Thr1003Met Uncertain significance ★★ ⚠ same condition
FLNB p.Thr1579Ile Uncertain significance ★★ ⚠ same condition
FLNB c.1611-4G>A Benign ★★ same condition
FLNB c.292+8C>A Benign/Likely benign ★★ same condition
FLNB c.4222+8A>G Benign/Likely benign ★★ 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-arg2172his (accessed [today's date]).

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