Is FLNB p.Ser2496Trp (c.7487C>G) pathogenic?

FLNB p.Ser2496Trp (c.7487C>G) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-15). AlphaMissense: ambiguous (0.4744); Very rare (popmax 0.0011%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLNB p.Ser2496Trp (c.7487C>G)?

FLNB p.Ser2496Trp (c.7487C>G) is associated with Inborn genetic diseases (ClinVar).

How common is FLNB p.Ser2496Trp (c.7487C>G) in the general population?

FLNB p.Ser2496Trp (c.7487C>G) is very rare (popmax 0.0011%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Ser2496Trp (c.7487C>G)?

AlphaMissense predicts ambiguous (score 0.4744) — an in-silico prediction, not a clinical call.

FLNB p.Ser2496Trp

c.7487C>G · rs149182236 · VCV3003459

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4744 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4744	ambiguous
REVEL	0.565	indeterminate
SaProt	LLR -10.15	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 2.8, phastCons 1
Regional constraint	o/e 0.82	unconstrained · MANE · 32 kb · p 1.7e-10 · regional, not allelic
Overall
CADD	28.6	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 0.0011% European (non-Finnish) · 13/1,179,970 alleles

Filtering AF 0.000615% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000474%

Overall 0.000889% 13/1,461,832 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.Ser2496Trp
Coding: c.7487C>G
MANE Select: NM_001457
dbSNP: rs149182236
Type: single nucleotide variant
Location: chr3:58169659 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 2496: the 'interaction with inppl1' region; the 'self-association site, tail' region; the 'hinge 2' region

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

Similar variants

FLNB p.Ser2496Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNB p.Ser2496= Benign ★ same residue
FLNB c.4862-3C>T Uncertain significance ★★ same condition
FLNB p.Ala1191Thr Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1191Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1391Thr Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1427Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1608Val 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-ser2496trp (accessed [today's date]).

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