Is FLNC p.Glu2270= (c.6810G>A) pathogenic?

FLNC p.Glu2270= (c.6810G>A) is classified Likely benign in FLNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-19). Ultra-rare (popmax 0.0563%, amr); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Glu2270= (c.6810G>A)?

FLNC p.Glu2270= (c.6810G>A) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Glu2270= (c.6810G>A) in the general population?

FLNC p.Glu2270= (c.6810G>A) is ultra-rare (popmax 0.0563%, amr) (gnomAD).

FLNC p.Glu2270=

Q: How is FLNC-related handgrip and calf weakness-distal myopathy inherited?

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

c.6810G>A · rs745858001 · VCV539516

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0563%, amr)

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.6	phastCons 1
Overall
CADD	4.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0563% Admixed American · 33/58,596 alleles

Filtering AF 0.0412% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0359%

Overall 0.00237% 38/1,606,038 alleles · ultra-rare exomes 35/1,453,632 · genomes 3/152,406 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0563%	1,776
Remaining individualsnot grpmax-eligible	0.00322%	31,099
African / African-American	0.00133%	74,996
South Asian	0.00112%	89,652
European (non-Finnish)	8.5e-05%	1,176,833

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.Glu2270=
Coding: c.6810G>A
MANE Select: NM_001458
dbSNP: rs745858001
Type: single nucleotide variant
Location: chr7:128854495 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2270: the 'required for interaction with pgm5' region

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

Disease context

distal myopathy with posterior leg and anterior hand involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 5 hypertrophic cardiomyopathy 26

For FLNC-related handgrip and calf weakness-distal myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

Similar variants

FLNC p.Glu2270Lys Conflicting classifications of pathogenicity ★ same residue
FLNC p.Glu2270Val Conflicting classifications of pathogenicity ★ same residue
FLNC p.Glu2270Gln Benign ★ 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-glu2270 (accessed [today's date]).

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