Is FLNC p.Arg421Trp (c.1261C>T) pathogenic?

FLNC p.Arg421Trp (c.1261C>T) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.1566); Very rare (popmax 0.00924%, nfe); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Arg421Trp (c.1261C>T)?

FLNC p.Arg421Trp (c.1261C>T) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Arg421Trp (c.1261C>T) in the general population?

FLNC p.Arg421Trp (c.1261C>T) is very rare (popmax 0.00924%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Arg421Trp (c.1261C>T)?

AlphaMissense predicts likely benign (score 0.1566) — an in-silico prediction, not a clinical call.

FLNC p.Arg421Trp

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.1261C>T · rs759075520 · VCV471966

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1566 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00924%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.1566	likely benign
REVEL	0.424	indeterminate
SaProt	LLR -11.90	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	phastCons 0.97
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.0	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 0.00924% European (non-Finnish) · 109/1,179,998 alleles

Filtering AF 0.00782% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00727%

Overall 0.00744% 120/1,612,848 alleles · very rare exomes 115/1,460,746 · genomes 5/152,102 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0112%	8,925
European (non-Finnish)grpmax	0.00924%	10,826
African / African-American	0.00401%	24,965
South Asian	0.0011%	91,086

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg421Trp
Coding: c.1261C>T
MANE Select: NM_001458
dbSNP: rs759075520
Type: single nucleotide variant
Location: chr7:128838653 (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.Arg421Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNC p.Arg421fs 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-arg421trp (accessed [today's date]).

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