Is FLNC p.Ser8Pro (c.22T>C) pathogenic?

FLNC p.Ser8Pro (c.22T>C) is classified Benign/Likely benign in FLNC (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.0841); Rare (popmax 0.152%, eas); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ser8Pro (c.22T>C)?

FLNC p.Ser8Pro (c.22T>C) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Ser8Pro (c.22T>C) in the general population?

FLNC p.Ser8Pro (c.22T>C) is rare (popmax 0.152%, eas) (gnomAD).

What do computational predictors say about FLNC p.Ser8Pro (c.22T>C)?

AlphaMissense predicts likely benign (score 0.0841) — an in-silico prediction, not a clinical call.

FLNC p.Ser8Pro

Q: How is FLNC-related handgrip and calf weakness-distal myopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.22T>C · rs544875797 · VCV774783

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.0841 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.152%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.0841	likely benign
REVEL	0.135	moderately benign-leaning
SaProt	LLR -6.37	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.48	phastCons 0.038
Regional constraint	o/e 1.13	unconstrained · MANE · 69 bp · p 0.46 · regional, not allelic
Overall
CADD	15.96	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 0.152% East Asian · 68/44,826 alleles

Filtering AF 0.123% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.112%

Overall 0.00769% 124/1,612,220 alleles · rare exomes 114/1,460,024 · genomes 10/152,196 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.152%	659
Remaining individualsnot grpmax-eligible	0.032%	3,120
African / African-American	0.004%	25,004
European (non-Finnish)	0.0028%	35,752

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.Ser8Pro
Coding: c.22T>C
MANE Select: NM_001458
dbSNP: rs544875797
Type: single nucleotide variant
Location: chr7:128830659 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 8: the 'actin-binding' region; the 'disordered' region

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

Disease context

distal myopathy with posterior leg and anterior hand involvement — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 5 hypertrophic cardiomyopathy 26

For FLNC-related handgrip and calf weakness-distal myopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult

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-ser8pro (accessed [today's date]).

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