Is FLNC p.Ser2655Pro (c.7963T>C) pathogenic?

FLNC p.Ser2655Pro (c.7963T>C) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-24). AlphaMissense: ambiguous (0.5474); Very rare (popmax 9.12e-05%, nfe); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ser2655Pro (c.7963T>C)?

FLNC p.Ser2655Pro (c.7963T>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.Ser2655Pro (c.7963T>C) in the general population?

FLNC p.Ser2655Pro (c.7963T>C) is very rare (popmax 9.12e-05%, nfe) (gnomAD).

What do computational predictors say about FLNC p.Ser2655Pro (c.7963T>C)?

AlphaMissense predicts ambiguous (score 0.5474) — an in-silico prediction, not a clinical call.

FLNC p.Ser2655Pro

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.7963T>C · VCV3758024

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5474 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.12e-05%, nfe)

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	0.5474	ambiguous
REVEL	0.65	pathogenic-leaning
SaProt	—	not scored · why
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 3.4	phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 1,769 bp · p 1.7e-16 · regional, not allelic
Overall
CADD	26.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 9.12e-05% European (non-Finnish) · 1/1,096,066 alleles

Overall 6.58e-05% 1/1,520,814 alleles · very rare exomes 1/1,368,884 · genomes 0/151,930 · 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.Ser2655Pro
Coding: c.7963T>C
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128858190 (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-ser2655pro (accessed [today's date]).

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