Is FLNC p.Pro22Ser (c.64C>T) pathogenic?

FLNC p.Pro22Ser (c.64C>T) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-22). AlphaMissense: likely pathogenic (0.7022); Ultra-rare (popmax 0.0147%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Pro22Ser (c.64C>T)?

FLNC p.Pro22Ser (c.64C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Pro22Ser (c.64C>T) in the general population?

FLNC p.Pro22Ser (c.64C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about FLNC p.Pro22Ser (c.64C>T)?

AlphaMissense predicts likely pathogenic (score 0.7022) — an in-silico prediction, not a clinical call.

FLNC p.Pro22Ser

c.64C>T · rs368812043 · VCV659374

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.7022 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7022	likely pathogenic
REVEL	0.317	indeterminate
SaProt	LLR -4.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.13	unconstrained · MANE · 69 bp · p 0.46 · regional, not allelic
Overall
CADD	25.8	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 0.0147% African / African-American · 11/74,942 alleles

Filtering AF 0.00815% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00633%

Overall 0.000744% 12/1,612,808 alleles · ultra-rare exomes 5/1,460,558 · genomes 7/152,250 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,813
Admixed American	0.00167%	60,008

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.Pro22Ser
Coding: c.64C>T
MANE Select: NM_001458
dbSNP: rs368812043
Type: single nucleotide variant
Location: chr7:128830701 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 22: the 'actin-binding' region; the 'disordered' 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

Also linked: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

Similar variants

FLNC p.Pro22Arg Uncertain significance ★ same residue
FLNC p.Pro22Leu Uncertain significance ★ ⚠ same residue
FLNC p.Pro22= 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

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-pro22ser (accessed [today's date]).

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