Is FLNA p.Pro1587Ser (c.4759C>T) pathogenic?

FLNA p.Pro1587Ser (c.4759C>T) is classified Uncertain significance in FLNA (ClinVar, Single submitter, 1 submitter; last evaluated 2017-03-08). AlphaMissense: ambiguous (0.5008); Ultra-rare (popmax 0.0317%, sas); Associated with familial thoracic aortic aneurysm and aortic dissection.

What condition is associated with FLNA p.Pro1587Ser (c.4759C>T)?

FLNA p.Pro1587Ser (c.4759C>T) is associated with familial thoracic aortic aneurysm and aortic dissection (ClinVar).

How common is FLNA p.Pro1587Ser (c.4759C>T) in the general population?

FLNA p.Pro1587Ser (c.4759C>T) is ultra-rare (popmax 0.0317%, sas) (gnomAD).

What do computational predictors say about FLNA p.Pro1587Ser (c.4759C>T)?

AlphaMissense predicts ambiguous (score 0.5008) — an in-silico prediction, not a clinical call.

FLNA p.Pro1587Ser

Q: How is Familial thoracic aortic aneurysm and aortic dissection inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.4759C>T · rs782258746 · VCV590099

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5008 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0317%, sas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

familial thoracic aortic aneurysm and aortic dissection

Computational evidence

Protein change
AlphaMissense	0.5008	ambiguous
REVEL	0.831	moderately pathogenic-leaning
SaProt	LLR -8.95	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 3.1e-20 · regional, not allelic
Overall
CADD	23.3	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 0.0317% South Asian · 18/56,798 alleles

Filtering AF 0.0204% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0169%

Overall 0.00165% 20/1,209,885 alleles · ultra-rare exomes 18/1,096,728 · genomes 2/113,157 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0317%	3,155
Remaining individualsnot grpmax-eligible	0.0042%	23,787

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: FLNA
Protein: p.Pro1587Ser
Coding: c.4759C>T
MANE Select: NM_001110556
dbSNP: rs782258746
Type: single nucleotide variant
Location: chrX:154357620 (GRCh38)
Structure: AlphaFold pLDDT 77.37 · 26 PDB
Residue 1587: the 'interaction with furin' region

Full FLNA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

familial thoracic aortic aneurysm and aortic dissection — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial thoracic aortic aneurysm and aortic dissection (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood

Similar variants

FLNA p.Pro1587= Likely benign ★ same residue
FLNA p.Gln2546Ter Pathogenic ★★ same condition
FLNA p.Gly1554Arg Pathogenic/Likely pathogenic ★★ same condition
FLNA p.Pro207Leu Pathogenic/Likely pathogenic ★★ same condition
FLNA p.Thr1739= Pathogenic ★★ same condition
FLNA c.2826+4G>A Uncertain significance ★★ same condition
FLNA c.3979+4C>T Uncertain significance ★★ same condition
FLNA c.720+4C>T Uncertain significance ★★ 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/flna-p-pro1587ser (accessed [today's date]).

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