Is FLNC p.Ala2289Ser (c.6865G>T) pathogenic?

FLNC p.Ala2289Ser (c.6865G>T) is classified Likely benign in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-24). AlphaMissense: likely benign (0.0613); Very rare (popmax 0.00224%, eas); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Ala2289Ser (c.6865G>T)?

FLNC p.Ala2289Ser (c.6865G>T) is associated with Cardiovascular phenotype (ClinVar).

How common is FLNC p.Ala2289Ser (c.6865G>T) in the general population?

FLNC p.Ala2289Ser (c.6865G>T) is very rare (popmax 0.00224%, eas) (gnomAD).

What do computational predictors say about FLNC p.Ala2289Ser (c.6865G>T)?

AlphaMissense predicts likely benign (score 0.0613) — an in-silico prediction, not a clinical call.

FLNC p.Ala2289Ser

c.6865G>T · VCV3279210

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00224%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0613	likely benign
REVEL	0.261	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.55
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	6.36	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00224% East Asian · 1/44,602 alleles

Overall 6.22e-05% 1/1,607,808 alleles · very rare exomes 1/1,455,432 · genomes 0/152,376 · joint denominator

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: FLNC
Protein: p.Ala2289Ser
Coding: c.6865G>T
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128854550 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2289: the 'required for interaction with pgm5' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLNC p.Ala2289Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNC c.1210+1G>A Likely pathogenic ★★ same condition
FLNC c.2550+2T>C Pathogenic/Likely pathogenic ★★ same condition
FLNC c.2930-1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNC c.5199+1G>T Pathogenic/Likely pathogenic ★★ same condition
FLNC c.5398+1G>C Likely pathogenic ★★ same condition
FLNC p.Arg1313Ter Pathogenic/Likely pathogenic ★★ same condition
FLNC p.Arg1341Ter Pathogenic/Likely pathogenic ★★ 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/flnc-p-ala2289ser (accessed [today's date]).

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