Is FLNB p.Ala1059Val (c.3176C>T) pathogenic?

FLNB p.Ala1059Val (c.3176C>T) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-10-18). AlphaMissense: ambiguous (0.4211); Rare (popmax 0.102%, sas); Associated with connective tissue disorder.

What condition is associated with FLNB p.Ala1059Val (c.3176C>T)?

FLNB p.Ala1059Val (c.3176C>T) is associated with connective tissue disorder (ClinVar).

How common is FLNB p.Ala1059Val (c.3176C>T) in the general population?

FLNB p.Ala1059Val (c.3176C>T) is rare (popmax 0.102%, sas) (gnomAD).

What do computational predictors say about FLNB p.Ala1059Val (c.3176C>T)?

AlphaMissense predicts ambiguous (score 0.4211) — an in-silico prediction, not a clinical call.

FLNB p.Ala1059Val

c.3176C>T · rs570950728 · VCV1620856

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4211 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.102%, sas)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

connective tissue disorder

Computational evidence

Protein change
AlphaMissense	0.4211	ambiguous
REVEL	0.768	pathogenic-leaning
SaProt	LLR -10.44	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	24.0	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 0.102% South Asian · 93/91,090 alleles

Filtering AF 0.0853% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.079%

Overall 0.00725% 117/1,614,158 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.102%	979
Remaining individualsnot grpmax-eligible	0.0048%	20,837
European (non-Finnish)	0.00178%	56,191

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.Ala1059Val
Coding: c.3176C>T
MANE Select: NM_001457
dbSNP: rs570950728
Type: single nucleotide variant
Location: chr3:58123142 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1059: a β-strand

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.Ala1059= Likely benign ★ 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-ala1059val (accessed [today's date]).

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