Is FLNC p.Pro2298Ser (c.6892C>T) pathogenic?

FLNC p.Pro2298Ser (c.6892C>T) is classified Likely pathogenic in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-23). AlphaMissense: likely pathogenic (0.64); Very rare (popmax 8.49e-05%, nfe); Associated with restrictive cardiomyopathy.

What condition is associated with FLNC p.Pro2298Ser (c.6892C>T)?

FLNC p.Pro2298Ser (c.6892C>T) is associated with restrictive cardiomyopathy (ClinVar).

How common is FLNC p.Pro2298Ser (c.6892C>T) in the general population?

FLNC p.Pro2298Ser (c.6892C>T) is very rare (popmax 8.49e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Pro2298Ser (c.6892C>T)?

AlphaMissense predicts likely pathogenic (score 0.64) — an in-silico prediction, not a clinical call.

FLNC p.Pro2298Ser

c.6892C>T · rs1554401403 · VCV544829

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.64 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.49e-05%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

restrictive cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.64	likely pathogenic ✓ concordant with ClinVar
REVEL	0.806	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	25.0	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 8.49e-05% European (non-Finnish) · 1/1,178,372 alleles

Overall 6.21e-05% 1/1,609,332 alleles · very rare exomes 1/1,456,954 · genomes 0/152,378 · 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.Pro2298Ser
Coding: c.6892C>T
MANE Select: NM_001458
dbSNP: rs1554401403
Type: single nucleotide variant
Location: chr7:128854577 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2298: the 'required for interaction with pgm5' region

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

Disease context

restrictive cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FLNC p.Pro2298Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNC p.Pro2298= Likely benign ★★ same residue
FLNC p.Val2297Met Pathogenic/Likely pathogenic ★★ same condition
FLNC p.Gly1184Val Uncertain significance ★★ ⚠ same condition
FLNC p.Pro2298fs Pathogenic ★ same residue
FLNC p.Tyr2563Cys Pathogenic ★ same condition
FLNC p.Gly2011Arg Conflicting classifications of pathogenicity ★ ⚠ same condition
FLNC p.Ile1621Phe 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-pro2298ser (accessed [today's date]).

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