Is FLNC p.Ser2258= (c.6774G>A) pathogenic?

FLNC p.Ser2258= (c.6774G>A) is classified Likely benign in FLNC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-01-14). Very rare (popmax 0.00843%, amr); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ser2258= (c.6774G>A)?

FLNC p.Ser2258= (c.6774G>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.Ser2258= (c.6774G>A) in the general population?

FLNC p.Ser2258= (c.6774G>A) is very rare (popmax 0.00843%, amr) (gnomAD).

FLNC p.Ser2258=

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.6774G>A · rs767691386 · VCV1157454

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00843%, 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	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -11
Overall
CADD	0.352	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00843% Admixed American · 5/59,330 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00209%

Overall 0.00255% 41/1,609,234 alleles · very rare exomes 37/1,456,966 · genomes 4/152,268 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00843%	11,866
Remaining individualsnot grpmax-eligible	0.00321%	31,123
European (non-Finnish)	0.00272%	36,825
African / African-American	0.00267%	37,440

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.Ser2258=
Coding: c.6774G>A
MANE Select: NM_001458
dbSNP: rs767691386
Type: single nucleotide variant
Location: chr7:128854459 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2258: the 'required for interaction with pgm5' region; the 'disordered' 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.Ser2258Pro Uncertain significance ★ same residue
FLNC p.Ser2258fs Pathogenic ★ 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

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-ser2258 (accessed [today's date]).

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