Is FLNC p.Arg1995Cys (c.5983C>T) pathogenic?

FLNC p.Arg1995Cys (c.5983C>T) is classified Likely benign in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-30). AlphaMissense: ambiguous (0.5251); Very rare (popmax 0.00133%, afr); Associated with hypertrophic cardiomyopathy 26.

What condition is associated with FLNC p.Arg1995Cys (c.5983C>T)?

FLNC p.Arg1995Cys (c.5983C>T) is associated with hypertrophic cardiomyopathy 26, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Arg1995Cys (c.5983C>T) in the general population?

FLNC p.Arg1995Cys (c.5983C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about FLNC p.Arg1995Cys (c.5983C>T)?

AlphaMissense predicts ambiguous (score 0.5251) — an in-silico prediction, not a clinical call.

FLNC p.Arg1995Cys

c.5983C>T · rs1303027892 · VCV1417727

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5251 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
AlphaMissense	0.5251	ambiguous
REVEL	0.356	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	29.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,050 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,613,114 alleles · very rare exomes 3/1,460,792 · genomes 0/152,322 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,050
European (non-Finnish)	0.00017%	589,856

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.Arg1995Cys
Coding: c.5983C>T
MANE Select: NM_001458
dbSNP: rs1303027892
Type: single nucleotide variant
Location: chr7:128852731 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1995: the 'required for interaction with pgm5' region

Full FLNC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hypertrophic cardiomyopathy 26 — 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

Similar variants

FLNC p.Arg1995= 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
FLNC c.2550+1G>C Likely pathogenic ★★ same condition
FLNC c.2550+2T>C 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-arg1995cys (accessed [today's date]).

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