Is FLNC p.Ala236Val (c.707C>T) pathogenic?

FLNC p.Ala236Val (c.707C>T) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-28). AlphaMissense: ambiguous (0.5396); Very rare (popmax 0.00619%, nfe); Associated with myofibrillar myopathy 5.

What condition is associated with FLNC p.Ala236Val (c.707C>T)?

FLNC p.Ala236Val (c.707C>T) is associated with myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement, hypertrophic cardiomyopathy 26 (ClinVar).

How common is FLNC p.Ala236Val (c.707C>T) in the general population?

FLNC p.Ala236Val (c.707C>T) is very rare (popmax 0.00619%, nfe) (gnomAD).

How is Muscle filaminopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FLNC p.Ala236Val (c.707C>T)?

AlphaMissense predicts ambiguous (score 0.5396) — an in-silico prediction, not a clinical call.

FLNC p.Ala236Val

c.707C>T · rs771789906 · VCV965096

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5396 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00619%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

myofibrillar myopathy 5

Computational evidence

Protein change
AlphaMissense	0.5396	ambiguous
REVEL	0.724	pathogenic-leaning
SaProt	LLR -8.47	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
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 0.50	unconstrained · MANE · 6,570 bp · p 3e-14 · regional, not allelic
Overall
CADD	24.4	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 0.00619% European (non-Finnish) · 73/1,180,014 alleles

Filtering AF 0.00503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00462%

Overall 0.00458% 74/1,613,966 alleles · very rare exomes 73/1,461,814 · genomes 1/152,152 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00619%	16,165
African / African-American	0.00134%	74,890

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.Ala236Val
Coding: c.707C>T
MANE Select: NM_001458
dbSNP: rs771789906
Type: single nucleotide variant
Location: chr7:128837405 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 236: the calponin-homology (ch) 2 domain; the 'actin-binding' region

Full FLNC gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

myofibrillar myopathy 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: distal myopathy with posterior leg and anterior hand involvement hypertrophic cardiomyopathy 26

For Muscle filaminopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
FLNC c.2930-1G>A 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-ala236val (accessed [today's date]).

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