Is FLNB p.Leu1440Pro (c.4319T>C) pathogenic?

FLNB p.Leu1440Pro (c.4319T>C) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-11-11). AlphaMissense: likely benign (0.042); Very rare (popmax 8.48e-05%, nfe); Associated with FLNB-Related Spectrum Disorders.

What condition is associated with FLNB p.Leu1440Pro (c.4319T>C)?

FLNB p.Leu1440Pro (c.4319T>C) is associated with FLNB-Related Spectrum Disorders (ClinVar).

How common is FLNB p.Leu1440Pro (c.4319T>C) in the general population?

FLNB p.Leu1440Pro (c.4319T>C) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Leu1440Pro (c.4319T>C)?

AlphaMissense predicts likely benign (score 0.042) — an in-silico prediction, not a clinical call.

FLNB p.Leu1440Pro

c.4319T>C · rs754634696 · VCV346343

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.042 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

FLNB-Related Spectrum Disorders

Computational evidence

Protein change
AlphaMissense	0.042	likely benign
REVEL	0.18	moderately benign-leaning
SaProt	LLR -2.97	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 -2.5	GERP -5.4
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	10.78	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 8.48e-05% European (non-Finnish) · 1/1,179,876 alleles

Overall 6.84e-05% 1/1,461,314 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.Leu1440Pro
Coding: c.4319T>C
MANE Select: NM_001457
dbSNP: rs754634696
Type: single nucleotide variant
Location: chr3:58130837 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1440: the 'interaction with fblp1' region

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

Disease context

FLNB-Related Spectrum Disorders

Similar variants

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FLNB p.Ser1096Phe Uncertain significance ★★ ⚠ same condition
FLNB p.Ser188Cys Uncertain significance ★★ ⚠ same condition
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FLNB c.292+12G>C 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-leu1440pro (accessed [today's date]).

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