Is FLNC p.Ile549Val (c.1645A>G) pathogenic?

FLNC p.Ile549Val (c.1645A>G) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-21). AlphaMissense: likely benign (0.0813); Ultra-rare (popmax 0.0121%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Ile549Val (c.1645A>G)?

FLNC p.Ile549Val (c.1645A>G) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Ile549Val (c.1645A>G) in the general population?

FLNC p.Ile549Val (c.1645A>G) is ultra-rare (popmax 0.0121%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Ile549Val (c.1645A>G)?

AlphaMissense predicts likely benign (score 0.0813) — an in-silico prediction, not a clinical call.

FLNC p.Ile549Val

c.1645A>G · rs547997371 · VCV423964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0813 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0813	likely benign
REVEL	0.237	benign-leaning
SaProt	LLR -5.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.3	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	21.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0121% European (non-Finnish) · 143/1,180,048 alleles

Filtering AF 0.0105% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00981%

Overall 0.00929% 150/1,614,088 alleles · ultra-rare exomes 138/1,461,874 · genomes 12/152,214 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0121%	8,252
African / African-American	0.00534%	18,733
Remaining individualsnot grpmax-eligible	0.0048%	20,829

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.Ile549Val
Coding: c.1645A>G
MANE Select: NM_001458
dbSNP: rs547997371
Type: single nucleotide variant
Location: chr7:128840643 (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: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

Similar variants

FLNC p.Ile549Thr 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-ile549val (accessed [today's date]).

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