Is FLNC p.Phe500Ser (c.1499T>C) pathogenic?

FLNC p.Phe500Ser (c.1499T>C) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-03). AlphaMissense: ambiguous (0.3521); Very rare (popmax 8.47e-05%, nfe); Associated with hypertrophic cardiomyopathy 26.

What condition is associated with FLNC p.Phe500Ser (c.1499T>C)?

FLNC p.Phe500Ser (c.1499T>C) is associated with hypertrophic cardiomyopathy 26, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Phe500Ser (c.1499T>C) in the general population?

FLNC p.Phe500Ser (c.1499T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Phe500Ser (c.1499T>C)?

AlphaMissense predicts ambiguous (score 0.3521) — an in-silico prediction, not a clinical call.

FLNC p.Phe500Ser

c.1499T>C · rs2128934879 · VCV1503888

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.3521 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
AlphaMissense	0.3521	ambiguous
REVEL	0.288	benign-leaning
SaProt	LLR -6.81	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.93 · evaluated, not missing
Constraint at this position
Conservation	phyloP 4.2	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.2	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 8.47e-05% European (non-Finnish) · 1/1,180,018 alleles

Overall 6.2e-05% 1/1,614,110 alleles · very rare exomes 1/1,461,788 · genomes 0/152,322 · joint denominator

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.Phe500Ser
Coding: c.1499T>C
MANE Select: NM_001458
dbSNP: rs2128934879
Type: single nucleotide variant
Location: chr7:128840110 (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

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 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-phe500ser (accessed [today's date]).

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