Is FLNB p.Phe1251= (c.3753T>C) pathogenic?

FLNB p.Phe1251= (c.3753T>C) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-18). Ultra-rare (popmax 0.033%, mid); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Phe1251= (c.3753T>C)?

FLNB p.Phe1251= (c.3753T>C) is associated with FLNB-Related Spectrum Disorders (ClinVar).

How common is FLNB p.Phe1251= (c.3753T>C) in the general population?

FLNB p.Phe1251= (c.3753T>C) is ultra-rare (popmax 0.033%, mid) (gnomAD).

FLNB p.Phe1251=

c.3753T>C · rs751650356 · VCV509067

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

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 · T>A here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.6	GERP -0.35, phastCons 1
Overall
CADD	3.989	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,062 alleles

Filtering AF 0.00977% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00912%

Overall 0.00917% 148/1,614,208 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,031
European (non-Finnish)	0.0114%	8,806
South Asian	0.00769%	13,011
Admixed American	0.005%	20,010
Remaining individualsnot grpmax-eligible	0.0032%	31,253

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.Phe1251=
Coding: c.3753T>C
MANE Select: NM_001457
dbSNP: rs751650356
Type: single nucleotide variant
Location: chr3:58124360 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1251: 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

Similar variants

FLNB p.Glu1661Lys Uncertain significance ★★ ⚠ same condition
FLNB p.Glu78Gly 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
FLNB p.Ser1096Phe Uncertain significance ★★ ⚠ same condition
FLNB p.Ser188Cys Uncertain significance ★★ ⚠ same condition
FLNB p.Tyr63His 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-phe1251 (accessed [today's date]).

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