Is FLNC p.Ala403Val (c.1208C>T) pathogenic?

FLNC p.Ala403Val (c.1208C>T) is classified Uncertain significance in FLNC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-12-29). AlphaMissense: ambiguous (0.4512); Ultra-rare (popmax 0.0174%, mid); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Ala403Val (c.1208C>T)?

FLNC p.Ala403Val (c.1208C>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Ala403Val (c.1208C>T) in the general population?

FLNC p.Ala403Val (c.1208C>T) is ultra-rare (popmax 0.0174%, mid) (gnomAD).

What do computational predictors say about FLNC p.Ala403Val (c.1208C>T)?

AlphaMissense predicts ambiguous (score 0.4512) — an in-silico prediction, not a clinical call.

FLNC p.Ala403Val

c.1208C>T · rs777199447 · VCV1425522

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.4512 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0174%, mid)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.4512	ambiguous
REVEL	0.685	pathogenic-leaning
SaProt	LLR -4.21	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	Δ0.78	donor gain · deltas
Pangolin	Δ0.36	gain · loss 0.13 · agrees with SpliceAI · independent
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	35.0	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 0.0174% Middle Eastern · 1/5,744 alleles

Filtering AF 0.0014% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000687%

Overall 0.000781% 12/1,536,222 alleles · ultra-rare exomes 10/1,391,158 · genomes 2/145,064 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0174%	5,744
Admixed American	0.00526%	19,013
Remaining individualsnot grpmax-eligible	0.00347%	28,836
Finnishnot grpmax-eligible	0.00179%	55,748
African / African-American	0.0014%	71,252
South Asian	0.00111%	89,926
European (non-Finnish)	0.000265%	377,502

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.Ala403Val
Coding: c.1208C>T
MANE Select: NM_001458
dbSNP: rs777199447
Type: single nucleotide variant
Location: chr7:128838427 (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

Cardiovascular phenotype — 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 hypertrophic cardiomyopathy 26

Similar variants

FLNC p.Ala403Glu Uncertain significance ★★ ⚠ same residue
FLNC p.Ala403= Conflicting classifications of pathogenicity ★ same residue
FLNC p.Ala403Pro Uncertain significance ★ ⚠ same residue
FLNC p.Ala403Ser Uncertain significance ★ same residue
FLNC p.Ala403fs Pathogenic ★ 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

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-ala403val (accessed [today's date]).

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