Is FLNC p.Asp646del (c.1935_1937del) pathogenic?

FLNC p.Asp646del (c.19351937del) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-06-29). Ultra-rare (popmax 0.0116%, nfe); Associated with distal myopathy with posterior leg and anterior hand involvement.

How common is FLNC p.Asp646del (c.1935_1937del) in the general population?

FLNC p.Asp646del (c.1935_1937del) is ultra-rare (popmax 0.0116%, nfe) (gnomAD).

FLNC p.Asp646del

Q: What condition is associated with FLNC p.Asp646del (c.1935_1937del)?

FLNC p.Asp646del (c.1935_1937del) 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.1935_1937del · rs765300084 · VCV471992

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, nfe)

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 · substitutions only
Constraint at this position
Conservation	phyloP -3.3
Overall
CADD	19.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0116% European (non-Finnish) · 137/1,180,002 alleles

Filtering AF 0.01% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00939%

Overall 0.0088% 142/1,613,928 alleles · ultra-rare exomes 129/1,461,824 · genomes 13/152,104 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0116%	8,613
Remaining individualsnot grpmax-eligible	0.0048%	20,829
African / African-American	0.00267%	37,438

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.Asp646del
Coding: c.1935_1937del
MANE Select: NM_001458
dbSNP: rs765300084
Type: Deletion
Location: chr7:128841289 (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.Asp646His Uncertain significance ★★ ⚠ same residue
FLNC p.Asp646Asn Conflicting classifications of pathogenicity ★ same residue
FLNC p.Asp646Glu Conflicting classifications of pathogenicity ★ same residue
FLNC c.2390-10_2406del Pathogenic ★★ same condition
FLNC c.2929+2_2929+7del Likely pathogenic ★★ same condition
FLNC p.Ala1902fs Pathogenic ★★ same condition
FLNC p.Ala260fs Pathogenic ★★ same condition
FLNC p.Ala656fs 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-asp646del (accessed [today's date]).

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