Is FLNB p.Arg649Ter (c.1945C>T) pathogenic?

FLNB p.Arg649Ter (c.1945C>T) is classified Pathogenic in FLNB (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-14). Very rare (popmax 0.00034%, nfe); Associated with FLNB-related disorder.

What condition is associated with FLNB p.Arg649Ter (c.1945C>T)?

FLNB p.Arg649Ter (c.1945C>T) is associated with FLNB-related disorder, spondylocarpotarsal synostosis syndrome (ClinVar).

How common is FLNB p.Arg649Ter (c.1945C>T) in the general population?

FLNB p.Arg649Ter (c.1945C>T) is very rare (popmax 0.00034%, nfe) (gnomAD).

FLNB p.Arg649Ter

c.1945C>T · rs80356517 · VCV21280

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Conditions

FLNB-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	predicted	premature termination codon in exon 13 of 46
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP 2.7, phastCons 0.49
Overall
CADD	39.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00034% European (non-Finnish) · 4/1,175,422 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000412% 6/1,456,730 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00312%	32,010
European (non-Finnish)grpmax	0.00034%	293,856

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg649Ter
Coding: c.1945C>T
MANE Select: NM_001457
dbSNP: rs80356517
Type: single nucleotide variant
Location: chr3:58108461 (GRCh38)
Gene constraint: LOEUF 0.504 · pLI <0.01 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 76.96 · 23 PDB

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

Disease context

Also linked: spondylocarpotarsal synostosis syndrome

Similar variants

FLNB p.Arg649Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNB p.Arg1948Ter Pathogenic ★★ same condition
FLNB p.Glu227Lys Pathogenic ★★ same condition
FLNB p.Gly168Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FLNB p.Gly1691Ser Pathogenic ★★ ⚠ same condition
FLNB p.Phe2023Ser Likely pathogenic ★★ same condition
FLNB p.Tyr1395Ter Pathogenic/Likely pathogenic ★★ same condition
FLNB c.3724+4G>C 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-arg649ter (accessed [today's date]).

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