Is FLNB p.Val2575Ile (c.7723G>A) pathogenic?

FLNB p.Val2575Ile (c.7723G>A) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-03-21). AlphaMissense: likely benign (0.151); Very rare (popmax 0.00878%, sas); Associated with atelosteogenesis type I.

What condition is associated with FLNB p.Val2575Ile (c.7723G>A)?

FLNB p.Val2575Ile (c.7723G>A) is associated with atelosteogenesis type I, atelosteogenesis type III, Larsen syndrome (ClinVar).

How common is FLNB p.Val2575Ile (c.7723G>A) in the general population?

FLNB p.Val2575Ile (c.7723G>A) is very rare (popmax 0.00878%, sas) (gnomAD).

What do computational predictors say about FLNB p.Val2575Ile (c.7723G>A)?

AlphaMissense predicts likely benign (score 0.151) — an in-silico prediction, not a clinical call.

FLNB p.Val2575Ile

c.7723G>A · rs369949841 · VCV986736

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.151 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00878%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atelosteogenesis type I

Computational evidence

Protein change
AlphaMissense	0.151	likely benign
REVEL	0.273	benign-leaning
SaProt	LLR -2.09	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 8.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 32 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	25.1	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 0.00878% South Asian · 8/91,078 alleles

Filtering AF 0.00437% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00312%

Overall 0.00328% 53/1,614,040 alleles · very rare exomes 49/1,461,884 · genomes 4/152,156 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00878%	11,385
European (non-Finnish)	0.00356%	28,096
Remaining individualsnot grpmax-eligible	0.0016%	62,484
Finnishnot grpmax-eligible	0.00156%	64,022
African / African-American	0.00133%	74,916

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.Val2575Ile
Coding: c.7723G>A
MANE Select: NM_001457
dbSNP: rs369949841
Type: single nucleotide variant
Location: chr3:58170676 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 2575: the 'interaction with inppl1' region; the 'self-association site, tail' region; the 'interaction with flna 2' region

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

Disease context

atelosteogenesis type I — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atelosteogenesis type III Larsen syndrome

Similar variants

FLNB p.Glu227Lys Pathogenic ★★ same condition
FLNB p.Gly168Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FLNB p.Gly1691Asp Pathogenic/Likely pathogenic ★★ ⚠ same condition
FLNB p.Gly1691Ser Pathogenic ★★ ⚠ same condition
FLNB p.Gly361Asp Pathogenic ★★ same condition
FLNB p.Phe161Cys Likely pathogenic ★★ same condition
FLNB c.3724+4G>C Uncertain significance ★★ same condition
FLNB p.Ala259Val 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-val2575ile (accessed [today's date]).

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