Is FLNC p.Val2017Met (c.6049G>A) pathogenic?

FLNC p.Val2017Met (c.6049G>A) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-14). AlphaMissense: likely pathogenic (0.922); Very rare (popmax 0.00212%, nfe); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Val2017Met (c.6049G>A)?

FLNC p.Val2017Met (c.6049G>A) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Val2017Met (c.6049G>A) in the general population?

FLNC p.Val2017Met (c.6049G>A) is very rare (popmax 0.00212%, nfe) (gnomAD).

How is Muscle filaminopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNC p.Val2017Met (c.6049G>A)?

AlphaMissense predicts likely pathogenic (score 0.922) — an in-silico prediction, not a clinical call.

FLNC p.Val2017Met

c.6049G>A · rs1019545678 · VCV951964

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.922 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00212%, nfe)

Conditions

myofibrillar myopathy 5

Computational evidence

Protein change
AlphaMissense	0.922	likely pathogenic
REVEL	0.488	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	27.7	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 0.00212% European (non-Finnish) · 25/1,180,040 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,702 alleles · very rare exomes 25/1,461,498 · genomes 1/152,204 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00212%	47,202
South Asian	0.0011%	91,088

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.Val2017Met
Coding: c.6049G>A
MANE Select: NM_001458
dbSNP: rs1019545678
Type: single nucleotide variant
Location: chr7:128852872 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2017: the 'required for interaction with pgm5' region

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

Disease context

myofibrillar myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Muscle filaminopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FLNC p.Val2017Leu 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-val2017met (accessed [today's date]).

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