Is FLNC p.Ala266Asp (c.797C>A) pathogenic?

FLNC p.Ala266Asp (c.797C>A) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-21). AlphaMissense: likely pathogenic (0.9694); No allele count reported in gnomAD v4.1 (AN 1,614,210); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ala266Asp (c.797C>A)?

FLNC p.Ala266Asp (c.797C>A) is associated with distal myopathy with posterior leg and anterior hand involvement, myofibrillar myopathy 5, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Ala266Asp (c.797C>A) in the general population?

FLNC p.Ala266Asp (c.797C>A) is no allele count reported in gnomAD v4.1 (AN 1,614,210) (gnomAD).

What do computational predictors say about FLNC p.Ala266Asp (c.797C>A)?

AlphaMissense predicts likely pathogenic (score 0.9694) — an in-silico prediction, not a clinical call.

FLNC p.Ala266Asp

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.797C>A · VCV4258281

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9694 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,614,210)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.9694	likely pathogenic
REVEL	0.805	moderately pathogenic-leaning
SaProt	LLR -9.99	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.5	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

No allele count reported in gnomAD v4.1 (AN 1,614,210). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: FLNC
Protein: p.Ala266Asp
Coding: c.797C>A
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128837495 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)

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 p.Ala266Thr Uncertain significance ★★ same residue
FLNC p.Ala266Val Uncertain significance ★ same residue
FLNC p.Ala266= 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-ala266asp (accessed [today's date]).

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