Is FLNC p.Pro214Ser (c.640C>T) pathogenic?

FLNC p.Pro214Ser (c.640C>T) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-28). AlphaMissense: likely pathogenic (0.8226); Very rare (popmax 8.5e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Pro214Ser (c.640C>T)?

FLNC p.Pro214Ser (c.640C>T) is associated with Cardiovascular phenotype (ClinVar).

How common is FLNC p.Pro214Ser (c.640C>T) in the general population?

FLNC p.Pro214Ser (c.640C>T) is very rare (popmax 8.5e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Pro214Ser (c.640C>T)?

AlphaMissense predicts likely pathogenic (score 0.8226) — an in-silico prediction, not a clinical call.

FLNC p.Pro214Ser

c.640C>T · VCV3515931

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.5e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.8226	likely pathogenic
REVEL	0.663	pathogenic-leaning
SaProt	LLR -5.16	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.50	unconstrained · MANE · 6,570 bp · p 3e-14 · regional, not allelic
Overall
CADD	24.8	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 8.5e-05% European (non-Finnish) · 1/1,175,952 alleles

Overall 6.23e-05% 1/1,603,892 alleles · very rare exomes 1/1,451,572 · genomes 0/152,320 · 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.Pro214Ser
Coding: c.640C>T
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128837198 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 214: the calponin-homology (ch) 2 domain; the 'actin-binding' region

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

Similar variants

FLNC p.Pro214= Likely benign ★★ same residue
FLNC c.1210+1G>A Likely pathogenic ★★ same condition
FLNC c.2550+2T>C Pathogenic/Likely pathogenic ★★ same condition
FLNC c.2930-1G>A Pathogenic/Likely pathogenic ★★ same condition
FLNC c.5199+1G>T Pathogenic/Likely pathogenic ★★ same condition
FLNC c.5398+1G>C Likely pathogenic ★★ same condition
FLNC p.Arg1313Ter Pathogenic/Likely pathogenic ★★ same condition
FLNC p.Arg1341Ter 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-pro214ser (accessed [today's date]).

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