Is FLNC p.Val491Met (c.1471G>A) pathogenic?

FLNC p.Val491Met (c.1471G>A) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-01). AlphaMissense: likely benign (0.2437); Ultra-rare (popmax 0.0132%, sas); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Val491Met (c.1471G>A)?

FLNC p.Val491Met (c.1471G>A) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Val491Met (c.1471G>A) in the general population?

FLNC p.Val491Met (c.1471G>A) is ultra-rare (popmax 0.0132%, sas) (gnomAD).

How is Muscle filaminopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNC p.Val491Met (c.1471G>A)?

AlphaMissense predicts likely benign (score 0.2437) — an in-silico prediction, not a clinical call.

FLNC p.Val491Met

c.1471G>A · rs770264114 · VCV568601

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.2437 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0132%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

myofibrillar myopathy 5

Computational evidence

Protein change
AlphaMissense	0.2437	likely benign
REVEL	0.586	indeterminate
SaProt	LLR -11.71	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 9.9	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	27.0	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 0.0132% South Asian · 12/91,096 alleles

Filtering AF 0.0075% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00593%

Overall 0.00675% 109/1,614,020 alleles · ultra-rare exomes 106/1,461,762 · genomes 3/152,258 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0132%	7,591
European (non-Finnish)	0.00746%	13,410
Finnishnot grpmax-eligible	0.00626%	15,981
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,604
African / African-American	0.00267%	37,471
Admixed American	0.00167%	60,016
Remaining individualsnot grpmax-eligible	0.0016%	62,486

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.Val491Met
Coding: c.1471G>A
MANE Select: NM_001458
dbSNP: rs770264114
Type: single nucleotide variant
Location: chr7:128840082 (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

myofibrillar myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Muscle filaminopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

FLNC p.Val491Leu Uncertain significance ★★ same residue
FLNC p.Val491= Likely benign ★ same residue
FLNC p.Val491Glu Uncertain significance ★ ⚠ 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-val491met (accessed [today's date]).

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