Is FLNC p.Arg2206= (c.6616C>A) pathogenic?

FLNC p.Arg2206= (c.6616C>A) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-03-08). Very rare (popmax 0.00892%, eas); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Arg2206= (c.6616C>A)?

FLNC p.Arg2206= (c.6616C>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Arg2206= (c.6616C>A) in the general population?

FLNC p.Arg2206= (c.6616C>A) is very rare (popmax 0.00892%, eas) (gnomAD).

FLNC p.Arg2206=

c.6616C>A · rs867032077 · VCV1754491

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00892%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.62	donor gain · deltas
Pangolin	Δ0.45	gain · loss 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 2.7	phastCons 1
Overall
CADD	20.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00892% East Asian · 4/44,846 alleles

Filtering AF 0.00298% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0018%

Overall 0.00031% 5/1,612,140 alleles · very rare exomes 5/1,459,792 · genomes 0/152,348 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00892%	11,212
European (non-Finnish)	8.48e-05%	1,179,632

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.Arg2206=
Coding: c.6616C>A
MANE Select: NM_001458
dbSNP: rs867032077
Type: single nucleotide variant
Location: chr7:128854105 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2206: the 'required for interaction with pgm5' region; the 'intradomain insert; mediate targeting to z lines' 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.Arg2206Trp Uncertain significance ★★ 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-arg2206 (accessed [today's date]).

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