Is FLNB p.Val289Met (c.865G>A) pathogenic?

FLNB p.Val289Met (c.865G>A) is classified Conflicting classifications of pathogenicity in FLNB (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-09-08). AlphaMissense: ambiguous (0.351); Ultra-rare (popmax 0.0267%, eas); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Val289Met (c.865G>A)?

FLNB p.Val289Met (c.865G>A) is associated with FLNB-Related Spectrum Disorders, spondylocarpotarsal synostosis syndrome (ClinVar).

How common is FLNB p.Val289Met (c.865G>A) in the general population?

FLNB p.Val289Met (c.865G>A) is ultra-rare (popmax 0.0267%, eas) (gnomAD).

What do computational predictors say about FLNB p.Val289Met (c.865G>A)?

AlphaMissense predicts ambiguous (score 0.351) — an in-silico prediction, not a clinical call.

FLNB p.Val289Met

c.865G>A · rs764368324 · VCV346307

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.351 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0267%, eas)

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.351	ambiguous
REVEL	0.321	indeterminate
SaProt	LLR -9.77	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP -1.8, phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 89 kb · p 2.4e-13 · regional, not allelic
Overall
CADD	23.3	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 0.0267% East Asian · 12/44,898 alleles

Filtering AF 0.0154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0121%

Overall 0.0026% 42/1,614,034 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0267%	3,742
South Asian	0.00769%	13,011
European (non-Finnish)	0.00178%	56,192
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00133%	74,938

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.Val289Met
Coding: c.865G>A
MANE Select: NM_001457
dbSNP: rs764368324
Type: single nucleotide variant
Location: chr3:58094913 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 289: a β-strand

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

Disease context

FLNB-Related Spectrum Disorders

Also linked: spondylocarpotarsal synostosis syndrome

Similar variants

FLNB p.Val289Leu Uncertain significance ★ ⚠ same residue
FLNB p.Arg1948Ter Pathogenic ★★ same condition
FLNB p.Arg649Ter Pathogenic ★★ same condition
FLNB p.Gly168Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FLNB p.Gly1691Ser Pathogenic ★★ ⚠ same condition
FLNB c.3724+4G>C Uncertain significance ★★ same condition
FLNB p.Arg1545Gln Uncertain significance ★★ ⚠ same condition
FLNB p.Arg2289His 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-val289met (accessed [today's date]).

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