Is FLNC p.Ser2020Cys (c.6058A>T) pathogenic?

FLNC p.Ser2020Cys (c.6058A>T) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-28). AlphaMissense: likely benign (0.141); Very rare (popmax 0.00223%, eas); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ser2020Cys (c.6058A>T)?

FLNC p.Ser2020Cys (c.6058A>T) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Ser2020Cys (c.6058A>T) in the general population?

FLNC p.Ser2020Cys (c.6058A>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FLNC p.Ser2020Cys (c.6058A>T)?

AlphaMissense predicts likely benign (score 0.141) — an in-silico prediction, not a clinical call.

FLNC p.Ser2020Cys

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.6058A>T · rs537114122 · VCV539374

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.141 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

distal myopathy with posterior leg and anterior hand involvement

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
AlphaMissense	0.141	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 8.1	phastCons 1
Regional constraint	o/e 0.66	unconstrained · MANE · 5,636 bp · p 8.4e-23 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,884 alleles

Overall 0.000186% 3/1,613,690 alleles · very rare exomes 2/1,461,472 · genomes 1/152,218 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,250
East Asiangrpmax	0.00223%	44,884

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ser2020Cys
Coding: c.6058A>T
MANE Select: NM_001458
dbSNP: rs537114122
Type: single nucleotide variant
Location: chr7:128852881 (GRCh38)

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

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-ser2020cys (accessed [today's date]).

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