Is FLNC p.Ala709Thr (c.2125G>A) pathogenic?

FLNC p.Ala709Thr (c.2125G>A) is classified Benign/Likely benign in FLNC (ClinVar, Multiple submitters, 12 submitters; last evaluated 2026-01-28). AlphaMissense: likely benign (0.095); Rare (popmax 0.327%, amr); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Ala709Thr (c.2125G>A)?

FLNC p.Ala709Thr (c.2125G>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.Ala709Thr (c.2125G>A) in the general population?

FLNC p.Ala709Thr (c.2125G>A) is rare (popmax 0.327%, amr) (gnomAD).

What do computational predictors say about FLNC p.Ala709Thr (c.2125G>A)?

AlphaMissense predicts likely benign (score 0.095) — an in-silico prediction, not a clinical call.

FLNC p.Ala709Thr

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.2125G>A · rs192725607 · VCV258132

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.095 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.327%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.095	likely benign
REVEL	0.272	benign-leaning
SaProt	LLR -6.30	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 7.7	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	24.7	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 0.327% Admixed American · 196/60,016 alleles

Filtering AF 0.289% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.275%

Overall 0.0595% 960/1,613,610 alleles · rare exomes 881/1,461,280 · genomes 79/152,330 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.327%	306
Finnishnot grpmax-eligible	0.132%	756
European (non-Finnish)	0.0545%	1,835
Remaining individualsnot grpmax-eligible	0.0272%	3,676
East Asian	0.0156%	6,411
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,869
South Asian	0.00769%	13,011
African / African-American	0.004%	25,018

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.Ala709Thr
Coding: c.2125G>A
MANE Select: NM_001458
dbSNP: rs192725607
Type: single nucleotide variant
Location: chr7:128842234 (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.Ala709Ser Uncertain significance ★★ ⚠ 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
FLNC c.2550+1G>C Likely pathogenic ★★ same condition
FLNC c.2550+2T>C 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-ala709thr (accessed [today's date]).

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