Is FLNC p.Arg381fs (c.1141_1142insACGC) pathogenic?

FLNC p.Arg381fs (c.11411142insACGC) is classified Pathogenic in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-08). Associated with distal myopathy with posterior leg and anterior hand involvement.

FLNC p.Arg381fs

Q: What condition is associated with FLNC p.Arg381fs (c.1141_1142insACGC)?

FLNC p.Arg381fs (c.1141_1142insACGC) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

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.1141_1142insACGC · VCV3759997

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 48
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.21	phastCons 0.97

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Variant & gene context

Gene: FLNC
Protein: p.Arg381fs
Coding: c.1141_1142insACGC
MANE Select: NM_001458
Type: Insertion
Location: chr7:128838359 (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

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.Arg381Cys Conflicting classifications of pathogenicity ★ same residue
FLNC p.Arg381Gly Uncertain significance ★ same residue
FLNC p.Arg381His Conflicting classifications of pathogenicity ★ same residue
FLNC p.Val1643fs Pathogenic/Likely pathogenic ★★ same condition
FLNC c.1549+3_1549+4insT Uncertain significance ★★ same condition
FLNC p.Gln2499fs Pathogenic ★ same condition
FLNC p.Glu2334fs Pathogenic ★ same condition
FLNC p.Glu919fs 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-arg381fs (accessed [today's date]).

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