Is FLNC p.Arg461His (c.1382G>A) pathogenic?

FLNC p.Arg461His (c.1382G>A) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-29). AlphaMissense: likely benign (0.0962); Very rare (popmax 0.004%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Arg461His (c.1382G>A)?

FLNC p.Arg461His (c.1382G>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Arg461His (c.1382G>A) in the general population?

FLNC p.Arg461His (c.1382G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about FLNC p.Arg461His (c.1382G>A)?

AlphaMissense predicts likely benign (score 0.0962) — an in-silico prediction, not a clinical call.

FLNC p.Arg461His

c.1382G>A · rs377587489 · VCV1007884

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0962 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0962	likely benign
REVEL	0.225	benign-leaning
SaProt	LLR -7.63	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.6	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,910 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00149% 24/1,612,818 alleles · very rare exomes 23/1,460,666 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,970
European (non-Finnish)	0.00169%	58,999
Admixed American	0.00167%	60,008

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.Arg461His
Coding: c.1382G>A
MANE Select: NM_001458
dbSNP: rs377587489
Type: single nucleotide variant
Location: chr7:128838774 (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

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

Similar variants

FLNC p.Arg461= Likely benign ★★ same residue
FLNC p.Arg461Cys Conflicting classifications of pathogenicity ★ same residue
FLNC p.Arg461Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNC p.Arg461fs 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

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-arg461his (accessed [today's date]).

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