Is FLNC p.Phe2649Ser (c.7946T>C) pathogenic?

FLNC p.Phe2649Ser (c.7946T>C) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-05). AlphaMissense: likely benign (0.2208); Very rare (popmax 0.00202%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Phe2649Ser (c.7946T>C)?

FLNC p.Phe2649Ser (c.7946T>C) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Phe2649Ser (c.7946T>C) in the general population?

FLNC p.Phe2649Ser (c.7946T>C) is very rare (popmax 0.00202%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Phe2649Ser (c.7946T>C)?

AlphaMissense predicts likely benign (score 0.2208) — an in-silico prediction, not a clinical call.

FLNC p.Phe2649Ser

c.7946T>C · rs755387909 · VCV949895

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2208 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00202%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2208	likely benign
REVEL	0.763	pathogenic-leaning
SaProt	—	not scored · why
⇒ REVEL calls this damaging; AlphaMissense does not; 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 3.4	phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 1,769 bp · p 1.7e-16 · regional, not allelic
Overall
CADD	25.9	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 0.00202% European (non-Finnish) · 23/1,137,340 alleles

Filtering AF 0.00135% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00113%

Overall 0.00147% 23/1,566,274 alleles · very rare exomes 22/1,414,234 · genomes 1/152,040 · 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.Phe2649Ser
Coding: c.7946T>C
MANE Select: NM_001458
dbSNP: rs755387909
Type: single nucleotide variant
Location: chr7:128858173 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2649: the 'interaction with inppl1' region; the 'self-association site, tail' 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

Also linked: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

Similar variants

FLNC p.Phe2649= Benign/Likely benign ★★ same residue
FLNC c.1047+1G>T Likely pathogenic ★★ same condition
FLNC c.1048-1G>A Likely pathogenic ★★ same condition
FLNC c.1210+1G>A Likely pathogenic ★★ same condition
FLNC c.1549+2T>G Likely pathogenic ★★ same condition
FLNC c.2007+1G>A Likely pathogenic ★★ same condition
FLNC c.2550+1G>C Likely pathogenic ★★ same condition
FLNC c.2550+2T>C 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-phe2649ser (accessed [today's date]).

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