Is FLNC p.Pro2565Ser (c.7693C>T) pathogenic?

FLNC p.Pro2565Ser (c.7693C>T) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-03). AlphaMissense: likely pathogenic (0.9665); Absent from gnomAD v4.1; Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Pro2565Ser (c.7693C>T)?

FLNC p.Pro2565Ser (c.7693C>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.Pro2565Ser (c.7693C>T) in the general population?

FLNC p.Pro2565Ser (c.7693C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FLNC p.Pro2565Ser (c.7693C>T)?

AlphaMissense predicts likely pathogenic (score 0.9665) — an in-silico prediction, not a clinical call.

FLNC p.Pro2565Ser

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.7693C>T · rs1554401906 · VCV539337

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9665 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 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	0.9665	likely pathogenic
REVEL	0.915	moderately pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 7.6	phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 1,769 bp · p 1.7e-16 · regional, not allelic
Overall
CADD	27.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FLNC
Protein: p.Pro2565Ser
Coding: c.7693C>T
MANE Select: NM_001458
dbSNP: rs1554401906
Type: single nucleotide variant
Location: chr7:128857249 (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-pro2565ser (accessed [today's date]).

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