Is FLNC p.Arg490Cys (c.1468C>T) pathogenic?

FLNC p.Arg490Cys (c.1468C>T) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-02-02). AlphaMissense: likely pathogenic (0.7605); Very rare (popmax 0.00445%, eas); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Arg490Cys (c.1468C>T)?

FLNC p.Arg490Cys (c.1468C>T) is associated with Cardiovascular phenotype, cardiomyopathy, dilated cardiomyopathy (ClinVar).

How common is FLNC p.Arg490Cys (c.1468C>T) in the general population?

FLNC p.Arg490Cys (c.1468C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about FLNC p.Arg490Cys (c.1468C>T)?

AlphaMissense predicts likely pathogenic (score 0.7605) — an in-silico prediction, not a clinical call.

FLNC p.Arg490Cys

c.1468C>T · rs1422233407 · VCV1479172

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely pathogenic

0.7605 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7605	likely pathogenic
REVEL	0.759	pathogenic-leaning
SaProt	LLR -9.55	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	28.6	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,900 alleles

Filtering AF 0.00196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00168%

Overall 0.00217% 35/1,614,008 alleles · very rare exomes 33/1,461,762 · genomes 2/152,246 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,450
European (non-Finnish)	0.00271%	36,876
African / African-American	0.00133%	74,938

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.Arg490Cys
Coding: c.1468C>T
MANE Select: NM_001458
dbSNP: rs1422233407
Type: single nucleotide variant
Location: chr7:128840079 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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

Similar variants

FLNC p.Arg490Leu Uncertain significance ★★ ⚠ same residue
FLNC p.Arg490= Likely benign ★★ same residue
FLNC p.Arg490His Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg490cys (accessed [today's date]).

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