Is FLNB p.Thr1323Ser (c.3967A>T) pathogenic?

FLNB p.Thr1323Ser (c.3967A>T) is classified Uncertain significance in FLNB (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1158); Ultra-rare (popmax 0.045%, amr).

How common is FLNB p.Thr1323Ser (c.3967A>T) in the general population?

FLNB p.Thr1323Ser (c.3967A>T) is ultra-rare (popmax 0.045%, amr) (gnomAD).

What do computational predictors say about FLNB p.Thr1323Ser (c.3967A>T)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

FLNB p.Thr1323Ser

c.3967A>T · rs202156074 · VCV593948

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.303	indeterminate
SaProt	LLR -2.99	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 35 kb · p 0.0019 · regional, not allelic
Overall
CADD	23.6	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 0.045% Admixed American · 27/60,014 alleles

Filtering AF 0.0317% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0273%

Overall 0.00458% 74/1,614,156 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.045%	2,223
European (non-Finnish)	0.00373%	26,818
Remaining individualsnot grpmax-eligible	0.0032%	31,252
African / African-American	0.00133%	75,056

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.Thr1323Ser
Coding: c.3967A>T
MANE Select: NM_001457
dbSNP: rs202156074
Type: single nucleotide variant
Location: chr3:58125649 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB
Residue 1323: the 'interaction with fblp1' region

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

Similar variants

FLNB c.4390+2T>C Pathogenic/Likely pathogenic ★★ same type
FLNB c.5110-1G>A Likely pathogenic ★★ same type
FLNB p.Arg1463Ter Pathogenic/Likely pathogenic ★★ same type
FLNB p.Arg1948Ter Pathogenic ★★ same type
FLNB p.Arg649Ter Pathogenic ★★ same type
FLNB p.Asp167Gly Likely pathogenic ★★ ⚠ same type
FLNB p.Glu227Lys Pathogenic ★★ same type
FLNB p.Gly168Ser Pathogenic/Likely pathogenic ★★ ⚠ same type

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-thr1323ser (accessed [today's date]).

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