Is FLNC p.Val563Ile (c.1687G>A) pathogenic?

FLNC p.Val563Ile (c.1687G>A) is classified Uncertain significance in FLNC (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-21). AlphaMissense: likely benign (0.1412); Very rare (popmax 0.00134%, afr).

How common is FLNC p.Val563Ile (c.1687G>A) in the general population?

FLNC p.Val563Ile (c.1687G>A) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about FLNC p.Val563Ile (c.1687G>A)?

AlphaMissense predicts likely benign (score 0.1412) — an in-silico prediction, not a clinical call.

FLNC p.Val563Ile

c.1687G>A · VCV4897814

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1412 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1412	likely benign
REVEL	0.634	indeterminate
SaProt	LLR -7.52	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 11 kb · p 8.4e-13 · regional, not allelic
Overall
CADD	25.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00134% African / African-American · 1/74,824 alleles

Overall 0.000124% 2/1,613,680 alleles · very rare exomes 1/1,461,778 · genomes 1/151,902 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,824
European (non-Finnish)	8.48e-05%	1,179,916

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.Val563Ile
Coding: c.1687G>A
MANE Select: NM_001458
Type: single nucleotide variant
Location: chr7:128840844 (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

Similar variants

FLNC p.Val563Ala Uncertain significance ★★ ⚠ same residue
FLNC c.1047+1G>T Likely pathogenic ★★ same type
FLNC c.1048-1G>A Likely pathogenic ★★ same type
FLNC c.1210+1G>A Likely pathogenic ★★ same type
FLNC c.1549+2T>G Likely pathogenic ★★ same type
FLNC c.2007+1G>A Likely pathogenic ★★ same type
FLNC c.2550+1G>C Likely pathogenic ★★ same type
FLNC c.2550+2T>C Pathogenic/Likely pathogenic ★★ same type

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-val563ile (accessed [today's date]).

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