Is FLNB p.Thr140= (c.420G>A) pathogenic?

FLNB p.Thr140= (c.420G>A) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-01). Rare (popmax 0.263%, eas); Associated with connective tissue disorder.

What condition is associated with FLNB p.Thr140= (c.420G>A)?

FLNB p.Thr140= (c.420G>A) is associated with connective tissue disorder (ClinVar).

How common is FLNB p.Thr140= (c.420G>A) in the general population?

FLNB p.Thr140= (c.420G>A) is rare (popmax 0.263%, eas) (gnomAD).

FLNB p.Thr140=

c.420G>A · rs192491895 · VCV736702

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.263%, eas)

Conditions

connective tissue disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -12	GERP -5.5
Overall
CADD	0.542	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.263% East Asian · 118/44,854 alleles

Filtering AF 0.224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.21%

Overall 0.0431% 696/1,614,088 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.553%	181
East Asiangrpmax	0.263%	380
Remaining individualsnot grpmax-eligible	0.0304%	3,290
South Asian	0.0242%	4,140
Middle Eastern	0.0165%	6,062
European (non-Finnish)	0.0145%	6,901
Admixed American	0.0117%	8,573
African / African-American	0.00533%	18,757

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr140=
Coding: c.420G>A
MANE Select: NM_001457
dbSNP: rs192491895
Type: single nucleotide variant
Location: chr3:58077173 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 140: the calponin-homology (ch) 2 domain; the 'actin-binding' 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.Thr140Met Uncertain significance ★★ ⚠ 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-thr140 (accessed [today's date]).

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