Is FLNC p.Arg334Ser (c.1000C>A) pathogenic?

FLNC p.Arg334Ser (c.1000C>A) is classified Likely benign in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-24). AlphaMissense: likely pathogenic (0.6127); Ultra-rare (popmax 0.0133%, amr); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Arg334Ser (c.1000C>A)?

FLNC p.Arg334Ser (c.1000C>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.Arg334Ser (c.1000C>A) in the general population?

FLNC p.Arg334Ser (c.1000C>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about FLNC p.Arg334Ser (c.1000C>A)?

AlphaMissense predicts likely pathogenic (score 0.6127) — an in-silico prediction, not a clinical call.

FLNC p.Arg334Ser

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.1000C>A · rs372497581 · VCV1412916

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6127 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.6127	likely pathogenic
REVEL	0.249	benign-leaning
SaProt	LLR -5.65	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.22	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	22.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0133% Admixed American · 8/60,000 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000496% 8/1,613,870 alleles · ultra-rare exomes 6/1,461,766 · genomes 2/152,104 · joint denominator

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.Arg334Ser
Coding: c.1000C>A
MANE Select: NM_001458
dbSNP: rs372497581
Type: single nucleotide variant
Location: chr7:128838017 (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.Arg334His Uncertain significance ★★ same residue
FLNC p.Arg334Cys Conflicting classifications of pathogenicity ★ 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-arg334ser (accessed [today's date]).

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