Is FLNC p.Val586Ala (c.1757T>C) pathogenic?

FLNC p.Val586Ala (c.1757T>C) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-06-01). AlphaMissense: ambiguous (0.3452); Ultra-rare (popmax 0.074%, afr); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Val586Ala (c.1757T>C)?

FLNC p.Val586Ala (c.1757T>C) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Val586Ala (c.1757T>C) in the general population?

FLNC p.Val586Ala (c.1757T>C) is ultra-rare (popmax 0.074%, afr) (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.Val586Ala (c.1757T>C)?

AlphaMissense predicts ambiguous (score 0.3452) — an in-silico prediction, not a clinical call.

FLNC p.Val586Ala

c.1757T>C · rs374132023 · VCV471987

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.3452 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.074%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

myofibrillar myopathy 5

Computational evidence

Protein change
AlphaMissense	0.3452	ambiguous
REVEL	0.836	moderately pathogenic-leaning
SaProt	LLR -8.04	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.4	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 0.074% African / African-American · 55/74,320 alleles

Filtering AF 0.0583% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0527%

Overall 0.00397% 64/1,610,582 alleles · ultra-rare exomes 31/1,459,618 · genomes 33/150,964 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.074%	1,351
Remaining individualsnot grpmax-eligible	0.00963%	10,385
Admixed American	0.00335%	29,812
South Asian	0.0011%	90,814

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.Val586Ala
Coding: c.1757T>C
MANE Select: NM_001458
dbSNP: rs374132023
Type: single nucleotide variant
Location: chr7:128840914 (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.Val586= Likely benign ★★ same residue
FLNC p.Val586Leu 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
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-val586ala (accessed [today's date]).

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