Is FLNB p.Pro1257= (c.3771G>A) pathogenic?

FLNB p.Pro1257= (c.3771G>A) is classified Benign/Likely benign in FLNB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-04-01). Low-frequency (popmax 1.45%, nfe); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Pro1257= (c.3771G>A)?

FLNB p.Pro1257= (c.3771G>A) is associated with FLNB-Related Spectrum Disorders, connective tissue disorder (ClinVar).

How common is FLNB p.Pro1257= (c.3771G>A) in the general population?

FLNB p.Pro1257= (c.3771G>A) is low-frequency (popmax 1.45%, nfe) (gnomAD).

FLNB p.Pro1257=

c.3771G>A · rs146851485 · VCV346338

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.45%, nfe)

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.57 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.94	GERP -4.9, phastCons 0.001
Overall
CADD	7.435	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.45% European (non-Finnish) · 17,054/1,180,030 alleles

Filtering AF 1.43% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.42%

Overall 1.14% 18,334/1,614,184 alleles · low-frequency exomes 17,181/1,461,886 · genomes 1,153/152,298 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.45%	69
Remaining individualsnot grpmax-eligible	0.872%	115
Finnishnot grpmax-eligible	0.339%	295
Admixed American	0.333%	300
African / African-American	0.22%	455
Ashkenazi Jewishnot grpmax-eligible	0.206%	485
South Asian	0.0966%	1,035
Middle Eastern	0.0495%	2,021
East Asian	0.00223%	44,886

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.Pro1257=
Coding: c.3771G>A
MANE Select: NM_001457
dbSNP: rs146851485
Type: single nucleotide variant
Location: chr3:58124378 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1257: a β-strand; the 'interaction with fblp1' 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.Pro1257Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
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

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-pro1257 (accessed [today's date]).

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