Is FLNC p.Arg490His (c.1469G>A) pathogenic?

FLNC p.Arg490His (c.1469G>A) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.694); Very rare (popmax 0.00333%, amr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Arg490His (c.1469G>A)?

FLNC p.Arg490His (c.1469G>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Arg490His (c.1469G>A) in the general population?

FLNC p.Arg490His (c.1469G>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about FLNC p.Arg490His (c.1469G>A)?

AlphaMissense predicts likely pathogenic (score 0.694) — an in-silico prediction, not a clinical call.

FLNC p.Arg490His

c.1469G>A · rs1046320257 · VCV577227

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.694 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.694	likely pathogenic
REVEL	0.752	pathogenic-leaning
SaProt	LLR -6.26	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
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	29.2	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 0.00333% Admixed American · 2/60,018 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000743% 12/1,614,030 alleles · very rare exomes 10/1,461,770 · genomes 2/152,260 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed Americangrpmax	0.00333%	30,009
East Asian	0.00223%	44,902
African / African-American	0.00133%	74,942
European (non-Finnish)	0.000424%	236,011

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.Arg490His
Coding: c.1469G>A
MANE Select: NM_001458
dbSNP: rs1046320257
Type: single nucleotide variant
Location: chr7:128840080 (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.Arg490Cys Uncertain significance ★★ ⚠ same residue
FLNC p.Arg490Leu Uncertain significance ★★ ⚠ same residue
FLNC p.Arg490= 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-arg490his (accessed [today's date]).

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