Is FLNB p.Ser1255Pro (c.3763T>C) pathogenic?

FLNB p.Ser1255Pro (c.3763T>C) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-01-04). AlphaMissense: likely pathogenic (0.7562); Very rare (popmax 8.47e-05%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FLNB p.Ser1255Pro (c.3763T>C)?

FLNB p.Ser1255Pro (c.3763T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FLNB p.Ser1255Pro (c.3763T>C) in the general population?

FLNB p.Ser1255Pro (c.3763T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FLNB p.Ser1255Pro (c.3763T>C)?

AlphaMissense predicts likely pathogenic (score 0.7562) — an in-silico prediction, not a clinical call.

FLNB p.Ser1255Pro

c.3763T>C · rs2471127637 · VCV2847279

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7562 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7562	likely pathogenic
REVEL	0.63	indeterminate
SaProt	LLR -8.01	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.93	GERP -1, phastCons 0.74
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	21.6	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 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.84e-05% 1/1,461,892 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.Ser1255Pro
Coding: c.3763T>C
MANE Select: NM_001457
dbSNP: rs2471127637
Type: single nucleotide variant
Location: chr3:58124370 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1255: the 'interaction with fblp1' 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

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FLNB p.Ala1391Thr Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1427Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1608Val Uncertain significance ★★ ⚠ same condition
FLNB p.Ala1704Ser Uncertain significance ★★ same condition
FLNB p.Ala2193Thr 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-ser1255pro (accessed [today's date]).

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