Is FLNC p.Val642Ile (c.1924G>A) pathogenic?

FLNC p.Val642Ile (c.1924G>A) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1759); Ultra-rare (popmax 0.0561%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Val642Ile (c.1924G>A)?

FLNC p.Val642Ile (c.1924G>A) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Val642Ile (c.1924G>A) in the general population?

FLNC p.Val642Ile (c.1924G>A) is ultra-rare (popmax 0.0561%, afr) (gnomAD).

What do computational predictors say about FLNC p.Val642Ile (c.1924G>A)?

AlphaMissense predicts likely benign (score 0.1759) — an in-silico prediction, not a clinical call.

FLNC p.Val642Ile

c.1924G>A · rs369387744 · VCV471991

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1759 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0561%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1759	likely benign
REVEL	0.305	indeterminate
SaProt	LLR -7.70	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; 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	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 0.0561% African / African-American · 42/74,898 alleles

Filtering AF 0.0426% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0379%

Overall 0.00688% 111/1,613,964 alleles · ultra-rare exomes 84/1,461,812 · genomes 27/152,152 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0561%	1,783
South Asian	0.00549%	18,218
European (non-Finnish)	0.00492%	20,345
East Asian	0.00445%	22,448
Admixed American	0.00333%	30,004
Remaining individualsnot grpmax-eligible	0.0032%	31,244

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.Val642Ile
Coding: c.1924G>A
MANE Select: NM_001458
dbSNP: rs369387744
Type: single nucleotide variant
Location: chr7:128841280 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 642: a β-strand

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 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
FLNC c.2550+2T>C Pathogenic/Likely pathogenic ★★ same condition
FLNC c.2930-1G>A Pathogenic/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-val642ile (accessed [today's date]).

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