Is FLNC p.Ile1387Phe (c.4159A>T) pathogenic?

FLNC p.Ile1387Phe (c.4159A>T) is classified Conflicting classifications of pathogenicity in FLNC (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-08-12). AlphaMissense: likely pathogenic (0.9056); Very rare (popmax 0.00667%, afr); Associated with Cardiovascular phenotype.

What condition is associated with FLNC p.Ile1387Phe (c.4159A>T)?

FLNC p.Ile1387Phe (c.4159A>T) is associated with Cardiovascular phenotype, myofibrillar myopathy 5, distal myopathy with posterior leg and anterior hand involvement (ClinVar).

How common is FLNC p.Ile1387Phe (c.4159A>T) in the general population?

FLNC p.Ile1387Phe (c.4159A>T) is very rare (popmax 0.00667%, afr) (gnomAD).

What do computational predictors say about FLNC p.Ile1387Phe (c.4159A>T)?

AlphaMissense predicts likely pathogenic (score 0.9056) — an in-silico prediction, not a clinical call.

FLNC p.Ile1387Phe

c.4159A>T · rs1032003580 · VCV1015811

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9056 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9056	likely pathogenic
REVEL	0.88	moderately pathogenic-leaning
SaProt	LLR -13.08	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.2	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	24.5	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 0.00667% African / African-American · 5/74,944 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00161%

Overall 0.000372% 6/1,614,036 alleles · very rare exomes 3/1,461,814 · genomes 3/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00667%	14,989
South Asian	0.0011%	91,084

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.Ile1387Phe
Coding: c.4159A>T
MANE Select: NM_001458
dbSNP: rs1032003580
Type: single nucleotide variant
Location: chr7:128846776 (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.Ile1387Val Uncertain significance ★★ same residue
FLNC p.Ile1387= Benign/Likely benign ★★ same residue
FLNC p.Ile1387Leu 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

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-ile1387phe (accessed [today's date]).

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