Is FLNC p.Pro1739= (c.5217G>A) pathogenic?

FLNC p.Pro1739= (c.5217G>A) is classified Likely benign in FLNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.0477%, eas); Associated with hypertrophic cardiomyopathy 26.

What condition is associated with FLNC p.Pro1739= (c.5217G>A)?

FLNC p.Pro1739= (c.5217G>A) is associated with hypertrophic cardiomyopathy 26, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Pro1739= (c.5217G>A) in the general population?

FLNC p.Pro1739= (c.5217G>A) is ultra-rare (popmax 0.0477%, eas) (gnomAD).

FLNC p.Pro1739=

c.5217G>A · rs769643482 · VCV1013564

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0477%, eas)

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.24 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.42	phastCons 0.99
Overall
CADD	4.392	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0477% East Asian · 21/44,018 alleles

Filtering AF 0.0319% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0269%

Overall 0.00246% 39/1,585,716 alleles · ultra-rare exomes 34/1,433,430 · genomes 5/152,286 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0477%	2,096
African / African-American	0.00401%	24,909
Admixed American	0.00349%	28,690
Remaining individualsnot grpmax-eligible	0.00162%	61,768
South Asian	0.00114%	87,792
European (non-Finnish)	0.000939%	106,490

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.Pro1739=
Coding: c.5217G>A
MANE Select: NM_001458
dbSNP: rs769643482
Type: single nucleotide variant
Location: chr7:128849993 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1739: the 'hinge 1' 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.Pro1739Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
FLNC p.Pro1739Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro1739 (accessed [today's date]).

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