Is FLNC p.Arg695Pro (c.2084G>C) pathogenic?

FLNC p.Arg695Pro (c.2084G>C) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-09). AlphaMissense: likely pathogenic (0.7725); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Arg695Pro (c.2084G>C)?

FLNC p.Arg695Pro (c.2084G>C) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Arg695Pro (c.2084G>C) in the general population?

FLNC p.Arg695Pro (c.2084G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FLNC p.Arg695Pro (c.2084G>C)?

AlphaMissense predicts likely pathogenic (score 0.7725) — an in-silico prediction, not a clinical call.

FLNC p.Arg695Pro

c.2084G>C · rs766592492 · VCV861276

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7725 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7725	likely pathogenic
REVEL	0.67	pathogenic-leaning
SaProt	LLR -15.52	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
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	24.7	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 0.00267% African / African-American · 2/74,938 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000496% 8/1,614,020 alleles · very rare exomes 6/1,461,790 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,469
East Asian	0.00223%	44,892
European (non-Finnish)	0.000424%	235,998

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.Arg695Pro
Coding: c.2084G>C
MANE Select: NM_001458
dbSNP: rs766592492
Type: single nucleotide variant
Location: chr7:128841530 (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.Arg695Cys Uncertain significance ★★ same residue
FLNC p.Arg695Leu Uncertain significance ★★ same residue
FLNC p.Arg695His Conflicting classifications of pathogenicity ★ same residue
FLNC p.Arg695fs 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-arg695pro (accessed [today's date]).

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