Is FLNC p.Arg478His (c.1433G>A) pathogenic?

FLNC p.Arg478His (c.1433G>A) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-11-03). AlphaMissense: likely benign (0.2783); Ultra-rare (popmax 0.0164%, mid); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Arg478His (c.1433G>A)?

FLNC p.Arg478His (c.1433G>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.Arg478His (c.1433G>A) in the general population?

FLNC p.Arg478His (c.1433G>A) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about FLNC p.Arg478His (c.1433G>A)?

AlphaMissense predicts likely benign (score 0.2783) — an in-silico prediction, not a clinical call.

FLNC p.Arg478His

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.1433G>A · rs749593461 · VCV582784

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2783 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.2783	likely benign
REVEL	0.752	pathogenic-leaning
SaProt	LLR -9.60	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	27.7	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.0013% 21/1,613,768 alleles · ultra-rare exomes 20/1,461,528 · genomes 1/152,240 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	30,007
Finnishnot grpmax-eligible	0.00157%	63,692
European (non-Finnish)	0.00136%	73,753
South Asian	0.0011%	91,094

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.Arg478His
Coding: c.1433G>A
MANE Select: NM_001458
dbSNP: rs749593461
Type: single nucleotide variant
Location: chr7:128840044 (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.Arg478= Likely benign ★★ same residue
FLNC p.Arg478Pro Uncertain significance ★ ⚠ same residue
FLNC p.Arg478Cys Likely benign ★ 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

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-arg478his (accessed [today's date]).

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