Is FLNB p.Val428Ile (c.1282G>A) pathogenic?

FLNB p.Val428Ile (c.1282G>A) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-25). AlphaMissense: likely benign (0.0665); Very rare (popmax 0.000424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLNB p.Val428Ile (c.1282G>A)?

FLNB p.Val428Ile (c.1282G>A) is associated with Inborn genetic diseases (ClinVar).

How common is FLNB p.Val428Ile (c.1282G>A) in the general population?

FLNB p.Val428Ile (c.1282G>A) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Val428Ile (c.1282G>A)?

AlphaMissense predicts likely benign (score 0.0665) — an in-silico prediction, not a clinical call.

FLNB p.Val428Ile

c.1282G>A · rs1189658661 · VCV1462842

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0665 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0665	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -4.72	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 0.84	GERP -2.8, phastCons 0.5
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	17.67	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000424% European (non-Finnish) · 5/1,180,042 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,614,056 alleles · very rare

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.Val428Ile
Coding: c.1282G>A
MANE Select: NM_001457
dbSNP: rs1189658661
Type: single nucleotide variant
Location: chr3:58098845 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB

Full FLNB gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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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-val428ile (accessed [today's date]).

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