Is FLNC p.Val326Ala (c.977T>C) pathogenic?

FLNC p.Val326Ala (c.977T>C) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-11-27). AlphaMissense: ambiguous (0.3758); Ultra-rare (popmax 0.0496%, mid); Associated with hypertrophic cardiomyopathy 26.

What condition is associated with FLNC p.Val326Ala (c.977T>C)?

FLNC p.Val326Ala (c.977T>C) is associated with hypertrophic cardiomyopathy 26, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Val326Ala (c.977T>C) in the general population?

FLNC p.Val326Ala (c.977T>C) is ultra-rare (popmax 0.0496%, mid) (gnomAD).

What do computational predictors say about FLNC p.Val326Ala (c.977T>C)?

AlphaMissense predicts ambiguous (score 0.3758) — an in-silico prediction, not a clinical call.

FLNC p.Val326Ala

c.977T>C · rs570010538 · VCV1044831

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3758 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0496%, mid)

Conditions

hypertrophic cardiomyopathy 26

Computational evidence

Protein change
AlphaMissense	0.3758	ambiguous
REVEL	0.629	indeterminate
SaProt	LLR -9.97	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	24.8	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 0.0496% Middle Eastern · 3/6,054 alleles

Filtering AF 0.0313% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0263%

Overall 0.00328% 53/1,613,844 alleles · ultra-rare exomes 45/1,461,682 · genomes 8/152,162 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0496%	2,018
East Asian	0.0468%	2,137
South Asian	0.0209%	4,794
Remaining individualsnot grpmax-eligible	0.0032%	31,247
European (non-Finnish)	0.000678%	147,479

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.Val326Ala
Coding: c.977T>C
MANE Select: NM_001458
dbSNP: rs570010538
Type: single nucleotide variant
Location: chr7:128837994 (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

hypertrophic cardiomyopathy 26 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: myofibrillar myopathy 5 distal myopathy with posterior leg and anterior hand involvement

Similar variants

FLNC p.Val326= 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
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-val326ala (accessed [today's date]).

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