Is FLNC p.Val2724Phe (c.8170G>T) pathogenic?

FLNC p.Val2724Phe (c.8170G>T) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-27). AlphaMissense: likely pathogenic (0.8583); Very rare (popmax 0.00134%, afr); Associated with distal myopathy with posterior leg and anterior hand involvement.

What condition is associated with FLNC p.Val2724Phe (c.8170G>T)?

FLNC p.Val2724Phe (c.8170G>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.Val2724Phe (c.8170G>T) in the general population?

FLNC p.Val2724Phe (c.8170G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about FLNC p.Val2724Phe (c.8170G>T)?

AlphaMissense predicts likely pathogenic (score 0.8583) — an in-silico prediction, not a clinical call.

FLNC p.Val2724Phe

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.8170G>T · rs1220183666 · VCV1400221

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

2/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

distal myopathy with posterior leg and anterior hand involvement

Computational evidence

Protein change
AlphaMissense	0.8583	likely pathogenic
REVEL	0.738	pathogenic-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this damaging; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	phastCons 1
Regional constraint	o/e 0.56	unconstrained · MANE · 1,769 bp · p 1.7e-16 · regional, not allelic
Overall
CADD	25.0	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

Grpmax group 0.00134% African / African-American · 1/74,704 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000372% 6/1,612,960 alleles · very rare exomes 4/1,461,068 · genomes 2/151,892 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,704
European (non-Finnish)	0.000424%	235,956

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.Val2724Phe
Coding: c.8170G>T
MANE Select: NM_001458
dbSNP: rs1220183666
Type: single nucleotide variant
Location: chr7:128858515 (GRCh38)
Gene constraint: LOEUF 0.424 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2724: a β-strand; the 'interaction with inppl1' region; the 'self-association site, tail' region; a UniProt-annotated variant site (in mfm5; likely pathogenic; the mutant is unable to dimerize)

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.Val2724Ala 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-val2724phe (accessed [today's date]).

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